Patient portals are popular health care tools. Few portals target caregiving families and few use predictive modeling to assist caregiving families make decisions about elder care options. Our goal is to incorporate the algorithms being developed for predicting tipping points in elder care to assist caregiving families visualize changes in older adults’ activity patterns, understand possible implications for continued in-home safety, and access educational information and consultation. While many patients use portals, use is restricted among persons in racial and ethnic minorities, with lower educational levels and poorer health literacy, and with fewer economic resources. The following strategies help us address these issues. Our portal archives data from affordable, wearable technology. Portal access uses similarly technology. Our educational materials use techniques known to be appealing and effective with older individuals in unique groups, e.g., results displays; fotonovelas. Input from community members/users helps maintain sensitivity to cultural appropriateness and health literacy.


Culture change represents an organizational transformational process to become person-centered, through staff and resident empowerment. Culture change initiatives have been associated with fewer health-related deficiency citations and better psychosocial outcomes. Knowledge management, defined as the process of creating or locating knowledge, and managing the dissemination of knowledge within and between organizations, has been shown to be associated with the adoption of innovations such as culture change initiatives. This study examines the relationship between knowledge management activities of high Medicaid census (70% or higher) nursing homes (NHs) and the adoption of culture change initiatives. This study used facility survey data from approximately 324 nursing home administrators (30% response rate) from 2017- 2018, merged with data from LTCFocus, Area Health Resource File, and Medicare Cost Reports. Binary logistic regression models revealed that the probability of adopting a culture change initiative was 0.12 higher for facilities reporting a one-unit higher level of knowledge management activities. Additional interaction analysis revealed that knowledge management activities were associated with a greater likelihood of adopting a culture change initiative for NHs where the director had been in his/her position fewer years. Similarly, higher levels of overall knowledge management activities were significantly associated with greater adoption of culture change initiatives at intermediate levels of nurse retention. Results suggest that knowledge management activities may help high Medicaid NHs acquire and mobilize informational resources in ways that can support the adoption of patient-centered initiatives. These activities may be particularly effective in nursing homes with leadership and nursing staff instability.


Circulating microRNAs offer attractive potential as epigenetic disease biomarkers by virtue of their biological stability and ready accessibility in liquid biopsies. Numerous clinical cohort studies have revealed unique microRNA profiles in different disease settings, suggesting utility as markers with diagnostic and prognostic applications. Given the complex network of microRNA functions in modulating gene expression and post-transcriptional modifications, the circulating microRNA landscape in disease may reflect pathophysiological status, providing valuable information for delineating distinct subtypes and/or stages of complex diseases. Heart failure (HF) is an increasingly significant global health challenge, imposing major economic liability and health care burden due to high hospitalization, morbidity, and mortality rates. Although HF is defined as a syndrome characterized by symptoms and findings on physical examination, it may be further differentiated based on left ventricular ejection fraction (LVEF) and categorized as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The presenting clinical syndromes in HFpEF and HFrEF are similar but mortality differs, being somewhat lower in HFpEF than in HFrEF. However, while HFrEF is responsive to an array of therapies, none has been shown to improve survival in HFpEF. Herein, we review recent HF cohort studies focusing on the distinct microRNA profiles associated with HF subtypes to reveal new insights to underlying mechanisms and explore the possibility of exploiting these differences for diagnostic/prognostic applications.  Heart failure (HF) is a complex clinical syndrome arising from deficient cardiac output that is unable to meet the metabolic needs of the organs and tissues in the body. HF evolves from systolic and/or diastolic contractile dysfunction caused by progressive structural and functional alterations of the heart . MultiplThe overall prevalence of HF is about 1–2% worldwide with an estimated 37.7 million people affected globally ,8. In thSymptoms of HF include breathlessness, cough, interrupted sleep, exercise intolerance, edema, and fatigue. However, the nonspecificity of these symptoms can confound the diagnosis of HF as they also occur in noncardiac conditions including renal impairment and chronic obstructive pulmonary disease. More specific signs of HF include elevated jugular venous pressure and the displacement of the apical cardiac impulse. However, these signs may be hard to detect and difficult to interpret in patients with comorbidities such as obesity or airway diseases . Thus, tLeft ventricular ejection fraction (LVEF) is a widely adopted phenotypic parameter to define HF. HF with reduced ejection fraction  and HF with preserved ejection fraction  are two major HF subtypes that differ in terms of pathophysiology and etiology, as well as treatment responses . The twoThe poor prognosis in HF, despite advances in treatment, mandates efforts to enhance management and improve patient outcomes. HF is underpinned by multiple risk factors, comorbidities, and pre-existing conditions which have an adverse impact on cardiac structure and function. The first line of HF drugs were directed towards improving quality of life by attenuating symptoms and slowing down disease progression, as well as reducing morbidity and mortality in HFrEF. However, to date, no HF therapeutics have consistently and permanently halted progression of structural and functional cardiac deterioration. Drugs targeting the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), β-adrenergic receptor blockers, and mineralocorticoid receptor antagonists (MRAs) have been shown to ameliorate the symptoms of HF and improve outcomes including HF re-admissions and mortality ,35. ReceTo facilitate the development of next generation HF therapeutics, key knowledge gaps in the underlying mechanisms and pathophysiology of HF must be addressed. The current lack of circulating biomarkers that could provide definitive diagnosis, prognosis, risk stratification, and subtype categorization of HF remains an ongoing challenge. The detailed molecular mechanisms underlying HF pathogenesis and how pathological pathways differ between subtypes and their translation to phenotype-specific therapeutic strategies remain elusive. Unravelling the relationship between biomarkers and HF pathogenesis may shed the light for developing precision medicine for HF in the near future. MicroRNAs comprise a cluster of noncoding RNA species that are known to play important roles in modulating the expression of most protein coding genes at the post-transcriptional level . MicroRNWith increasing understanding of the characteristic differences between HFrEF and HFpEF, there has been active interest in finding signature microRNA profiles to facilitate HF subtype categorization. Ellis et al. pioneered early work on HFrEF and HFpEF microRNA profiling and reported a set of differentially expressed microRNAs in a dyspnea cohort comprising 16 HFrEF and 16 HFpEF with high NT-proBNP plasma concentrations . HoweverIt is noteworthy that each study reported a unique set of differentially dysregulated microRNAs and no overlap of microRNAs was observed across all four cohort studies. This discrepancy is not totally unexpected and may be attributed to the heterogenous comorbidities of HF and sample size of cohorts, as well as the different criteria used for patient enrollment. Profiling reported in the five studies highlighted in http://www.microrna.gr/miRPathv3), an online pathway analysis software [In addition to potential diagnostic applications, the discovery of microRNA clusters that are differentially expressed in HFrEF and HFpEF patients provides an approach to delineate the different pathobiological pathways underlying HFrEF and HFrEF. software . Based osoftware . The sigChanges in plasma concentrations of free fatty acids across three different HF subtypes have been reported previously . ResultsInterestingly, predicted targets analysis (microT-CDs) revealed that transforming growth factor beta (TGF-β) signaling and Forkhead box O (FoxO) transcription factors signaling are among the top pathways predicted to be affected by the eight HF signature microRNAs. TGF-β signaling is known to play pivotal roles in the pathogenesis of cardiac remodeling and fibrosis. The putative roles of microRNAs in TGF-β signaling have been reported and tested in various diseased models. For instances, miR-101a was shown to target the TGF-β1 receptor, subsequently attenuating fibrogenesis and improving cardiac function in a rodent transverse aortic constriction (TAC) model . FoxOs aThe discovery of microRNAs and their roles in post-transcriptional modification have led to further advances in understanding the complexity of gene regulation. However, translating findings of distinct circulating microRNA compositions and their pathophysiological implications in different disease states to decipher underlying mechanisms with a view towards therapeutic exploitation remains challenging. MicroRNA-3’UTR interactions do not require perfect Watson–Crick pairing and this significantly increases the functional flexibility of microRNA. It is now known that one microRNA can have multiple 3’UTR targets, and one 3’UTR can be recognized by more than one microRNA so that biological homeostasis could be tightly controlled in the normal state while dynamic biochemical responses could also be triggered upon stimulation. Although it has been established that microRNAs play important roles in post-transcriptional modification, scientists have yet to fully understand the operating rhythm of microRNAs. The traditional approach of deciphering the regulatory effect of one microRNA on one gene is manifestly inadequate in bringing together the influence of the microRNA landscape on gene expression regulatory networks. Dysregulated microRNAs can be viewed as functional clusters that variously contribute to HF pathogenesis. This concept was supported by our previous study where data from microRNA/3’UTR binding and gain-of-function assays demonstrated putative regulatory effects of HF-related microRNAs upon key molecules involved in neurohormonal signaling . Given the potential application of signature microRNAs in HF diagnosis, further independent verification of our findings by other reputable investigators is needed. Furthermore, the diagnostic performance of microRNAs may require further refinement according to comorbidities and clinical background. Further studies to clarify the association between HF-related microRNAs and pathogenesis will be essential to translate these epigenetic alterations into therapeutic applications. It is conceivable that linear algorithms will not be adequate to describe the interaction networks between transactivation and post-transcriptional regulation of microRNAs with their target genes. Hence, large scale international multi-disciplinary collaborative research integrating expertise in biomedicine, clinical practice, bioinformatics, artificial intelligence, and machine learning will be pivotal to advancing progress in HF research.


The human hair follicle is a neuroendocrine mini-organ that can be used to study aging processes in vitro. Neurotrophins maintain homeostasis in hair biology via the Trk-family of receptors. TrkA, the high affinity receptor for nerve growth factor (NGF), is expressed in hair follicle melanocytes and keratinocytes, where it regulates proliferation, differentiation and apoptosis and may thereby play a role in hair pigmentation and growth. We investigated TrkA expression during the human hair cycle and the effects of a selective high affinity TrkA agonist, Gambogic Amide, on hair pigmentation and hair growth in human hair follicles in vitro. In human scalp skin, TrkA expression was strongest in proliferating melanocytes re-establishing the pigmentary unit in the hair bulb during the early hair growth phase, anagen. During high anagen and in the de-composing pigmentary-unit of the regression phase, catagen, bulb-melanocytes lost TrkA expression and only undifferentiated outer root sheath melanocytes maintained it. In cultured human anagen hair follicles, Gambogic Amide was able to prevent gradual pigment loss, while it stimulated hair shaft elongation. This was achieved by increased melanocyte activation, migration and dendricity, highlighted by distinct c-KIT-expression in melanocyte sub-populations. Our results suggest that Gambogic Amide can maintain hair follicle pigmentation by acting on undifferentiated melanocytes residing in the outer root sheath and making them migrate to establish the pigmentary-unit. This suggests that the selective TrkA agonist Gambogic Amide acts as an anti-hair greying and hair growth promoting molecule in vitro. In today’s society healthy aging is crucial for well-being. One of the clinically visible signs of aging is greying hair . This isHair follicle pigmentation involves exact temporal and spatial regulation of the cells that produce the pigment, the melanocytes. Melanocyte turnover within the hair follicle, meaning renewal , maturation (differentiation) and removal (senescence and apoptosis) is highly regulated to prevent melanoma development and spontaneously occurring primary hair follicle melanoma is in fact rarely reported . To prevTo identify safe intervention strategies, it is therefore necessary to monitor melanocyte dynamics during hair growth. Hair shaft pigmentation, also called follicular melanogenesis, in both mice and humans is tightly linked to the growth phase (anagen) of the hair cycle –8, whichIdeally, the mechanisms allowing hair pigmentation to be reestablished with each hair cycle are in a state of homeostasis. This homeostasis works optimally for the first 10–15 hair follicle growth cycles (until about 40 years of age). Thereafter, the mechanisms that maintain pigmentation seem to exhaust and the regeneration potential of the pigmentary-unit diminishes, leading to grey or white hair .An agent stimulating hair follicle pigmentation should improve homeostasis but not interfere with it. One of the main routes studied to improve hair pigmentation focusses on melanin synthesis in hair follicle melanocytes and the gradual loss of factors maintaining it, such as alpha-melanocytes stimulating hormone  . In addiSkin has documented neuroendocrine properties , 21, andGarcinia hanburryi tree in South-eastern Asia [The question therefor arises, if expression and manipulation of TrkA plays a role in hair follicle pigmentation homeostasis . Gambogiern Asia , was ideern Asia . In addiern Asia . Based oTissue collection was essentially done as previously described . In brieAnagen VI HF were cultured for seven days in supplemented Williams’ E medium  as published before , 37. On 8-μm-thick longitudinal cryosections through full thickness human scalp skin and cultured HF were processed and analyzed using a digital image analysis system  as previously described . For NKIStatistical analysis was performed as previously described . Means wNative human scalp skin was investigated for TrkA expression of distinct sub-populations of hair follicle melanocytes during the hair cycle and showed a staining of keratinocytes in the outer root sheath throughout. In addition, in early anagen hair follicles round undifferentiated melanocytes in the re-establishing pigmentary-unit strongly expressed TrkA . In highNext the capacity of the TrkA agonist nerve growth factor (NGF) to modulate pigmentation in cultured human hair follicles was tested. 5 ng/ml NGF maintained pigmentation in cultured human anagen hair follicles  over theBased on the findings in Figs To analyze target melanocyte subpopulations of Gambogic Amide we investigated c-KIT-expression of hair follicle melanocytes in response to Gambogic Amide in various compartments of the hair bulb after 7 days of culture . While cFurthermore, we observed a slight increase in melanocyte dendricity in response to Gambogic Amide (50–1000 nM) . No signTo control, if these effects occurred within the anagen phase or were associated with premature catagen development in cultured anagen hair follicles, hair follicles exposed to Gambogic Amide were subjected to hair cycle progression analysis. By histomorphometry, Gambogic Amide at all tested concentrations did not significantly alter hair cycle progression compared to control samples . In factConcerning melanocyte turnover and cellular homeostasis, we found here an increased p16 expression at all tested concentrations with a peak at 500 nM of Gambogic Amide in melanocytes of all follicular compartments . HoweverFinally, growth of hair follicles exposed to Gambogic Amide was analyzed and revealed that in addition to hair pigmentation maintenance, Gambogic Amide was able to increase hair shaft elongation at all concentrations tested . This fuIn this study we investigated the expression of TrkA in human hair follicles and studied the effects of a selective, plant derived TrkA agonist Gambogic Amide on the pigmentation of hair follicles in vitro to investigate its potential as an anti-aging ointment. We found TrkA expression during the human hair cycle in distinct melanocyte subpopulations suggestive of its expression primarily in undifferentiated melanocytes and potentially melanoblasts Figs  and 2. AIn the human scalp skin, we found that TrkA was strongly expressed in hair follicle melanocytes in the outer root sheath and in the developing pigmentary-unit at the beginning of anagen as well as in the outer root sheath of fully developed anagen hair follicles. This is in line with previous findings showing that TrkA is mainly expressed in melanocytes and keratinocytes in anagen hair follicles . HoweverIn addition, TrkA-positive melanocytes were round-shaped and expressed the melanocyte migration marker c-KIT. In mice, c-KIT was previously shown to be predominantly expressed in migrating melanoblasts in the developing hair follicle  and it iIn line with c-KIT being also a melanocyte differentiation marker, the melanocytes in hair follicle treated with Gambogic Amide also displayed slightly enhanced dendricity. Since melanocytes are derived from the neural crest it resembled the capability of Gambogic Amide to induce neurite outgrowth in various neuronal cell lines , 34. In Looking at hair follicle pigmentation we found that Gambogic Amide showed a similar activity as nerve growth factor NGF, which is the natural high affinity agonist of TrkA. In contrast to NGF however, we found that Gambogic Amide showed pro-pigmenting activity dose-dependently at higher concentrations, whereas NGF showed a maximum at 5 ng/ml. High concentrations of NGF like 50 ng/ml decreased hair follicle pigmentation in vitro . NotablyWe used here the Philpott model of hair follicles which are truncated below the bulge region. This means Gambogic Amide acted on undifferentiated melanoblasts released from the bulge already, and as such was able to sustain pigmentation in vitro more efficiently  without In summary, we provide evidence that it is possible to halt the hair aging process represented by hair greying in vitro with Gambogic amide. An important mechanism how Gambogic Amide stimulates pigmentation in hair follicle melanocytes is via induction of c-KIT expression . GambogiThe potential of Gambogic Amide or other molecules activating TrkA signaling in human hair follicle as a remedy to reverse signs of aging hair like greying is further corroborated by the finding that Gambogic Amide is able to induce hair follicle growth in vitro . In addiThe notion that Gambogic Amide recruits melanocytes of the outer root sheath while the hair continues or even improves its growth activity is evidenced by the maintenance of anagen morphology and increased hair shaft elongation. This is intriguing, as it was shown previously that without treatment, in vitro pigmentation correlated negatively with hair shaft elongation in cultured human anagen hair follicles and vice-versa and that this links with up-regulated gene-expression of keratins involved in active hair growth , 51. OurIn conclusion, we provide evidence that the TrkA agonist Gambogic Amide is a promising molecule able to protect hair follicle pigmentation in vitro by mobilizing TrkA and c-KIT-positive hair follicle melanocytes. Furthermore, Gambogic Amide has a growth promoting activity on hair follicles in vitro, further highlighting its potential as a hair health or hair anti-aging active.


Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies and hemothorax as a presenting feature of PAVM is a very rare occurrence.A 45-year old woman presented with chest pain and breathlessness. A chest x-ray showed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation was shown. Diagnostic thoracocentesis revealed hemorrhagic exudate with negative cytology and microbiology findings. Thoracic drainage was performed resulting with complete regression of hemothorax. Three months later, patient was treated with transcatheter embolization of PAVM with good clinical outcome.We have shown that management of PAVM related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM could lead to a successful outcome. Pulmonary arteriovenous malformations (PAVMs) are abnormal direct communications between pulmonary arteries and veins . They arA non-smoker 45-year old woman presented with left-sided chest pain and breathlessness over 7-day duration, with no history of chest trauma. She had no signs of hemodynamic instability and did not appear to be in significant respiratory distress with only mild partial respiratory insufficiency.Laboratory findings were within normal limits apart from mild normocytic anemia (Hgb 106 g/L) and elevated D dimers (2.06 mg/L). Accordant to clinical examination of the chest, chest x-ray confirmed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation 17 mm in diameter was shown in anterior segment of left upper lobe . DiagnosMSCT scan with contrast performed three months later then confirmed a simple PAVM in the peripheral lingular area supplied from superior left pulmonary artery, and with a drainage vein entering the pulmonary veins and left atrium . The fee During further treatment, the patient participated in pulmonary rehabilitation program because of persistent dyspnea on exertion and since then has been attending regular follow-ups with normal radiological and pulmonary function test findings without recurrence of pleural effusion .Pulmonary arteriovenous malformations (PAVMs) are rare abnormal communications between the branches of pulmonary arteries and veins , 3. TheyThe clinical manifestations and complications of idiopathic PAVMs are also similar to those associated with HHT . More thPotentially life-threatening complications that occur in less than 10-20 percent of patients with PAVMs are hemothorax and hemoptysis . HemothoWhile hemoptysis is likely due to rupture of either parenchymal PAVM or an endobronchial teleangiectasia, hemothorax results from rupture of a subpleural PAVM. As seen in our patient, probable rupture of PAVM in peripheral area led to this rare complication. Massive hemoptysis and massive hemothorax from rupture of PAVM into the pleural space have been reported, with fatal outcomes , but hem Contrast-enhanced pulmonary angiography remains the gold standard for defining the anatomy of PAVMs that are considered potentially suitable for embolotherapy, which has largely replaced surgical intervention. PAVMs were historically treated with surgical resection. As endovascular techniques developed, embolization became the mainstay of treatment. Initial management with therapeutic embolization may well be appropriate in most patients who present with symptomatic PAVM. In patients who are hemodynamically unstable or in whom embolization has failed, open surgical resection of the PAVM has been successful . Treatme Transcatheter embolotherapy has proven to be a safe and effective treatment for sporadic PAVMs providing excellent functional and radiological improvement , 4, as sIn reviewed cases, which included mostly acute onset of PAVM associated with hemothorax, primary treatment was surgical or urgent embolization interventions, or combination of both , 12, 13.In conclusion PAVMs are relatively rare disorders with very common presentations and they are an important part of the differential diagnosis of pulmonary problems like hemoptysis, pulmonary nodule and hypoxemia. Although rarely seen, a PAVM as underlying cause of a spontaneous hemothorax should also be considered.  Contrast-enhanced computed tomography is a valuable and widely available diagnostic tool for patients with abnormal chest radiography suspicious of PAVM. There is little data on idiopathic PAVMs in the literature, especially presenting with hemothorax, and hopefully this case could benefit treatment of some of PAVM patients, which is why we consider our case worthy of reporting.We have shown that management of PAVM-related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM in a low risk patient could lead to a successful outcome.


Cancer cells accelerate glycolysis to maintain ATP and other metabolites which are necessary to maintain their survival and chemoresistance. Glutathione (GSH) is the major antioxidant in living organisms and has multiple functions including maintenance of intracellular redox homeostasis. Cancer cells produce reactive oxygen species (ROS) that results from mitochondrial dysfunction, aberrant metabolism, and frequent genetic mutations. Such circumstances cause accumulation of large amounts of oxidized molecules including proteins, DNA and lipids. Therefore, cancer cells require active synthesis and recycling of GSH under regulating the balance of glucose utilization between glycolysis and pentose phosphate pathway which is necessary to synthesize NADPH and nucleic acid precursors . Excess Ferroptosis has recently been identified as a novel type of regulated cell death caused by severe oxidative stress and subsequent lipid peroxidation against which GSH-dependent antioxidant system protects. Inhibition of xCT cystine transporter or the GSH-dependent enzyme glutathione peroxidase 4 has been shown to induce ferroptosis in cancer cells . Since mOncotarget, Okazaki et al. performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine and identified the oral anesthetic dyclonine. Dyclonine possesses a unique structure responsible for covalent inhibition of aldehyde dehydrogenase enzymes (ALDHs) [In this issue of  (ALDHs) . Treatme (ALDHs) . They al (ALDHs) . Further (ALDHs) .In this context, of importance is that an engineered human enzyme cyst(e)inase which can degrade cystine/cysteine systemically has been developed . The cli


Due to an editorial error, the Data Availability Statement containing the raw sequences was erroneously omitted from the article. The publisher apologizes for the mistake.MG242652-MG243345.Raw sequences have been deposited in Sequence Read Archive  SRR6187016 and BioProject PRJNA414535; the 694 OTUs (representative sequences) under GenBank accession #


Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered. Because of the narrow time window and complex pathophysiology, CCI is challenging to immediately diagnose and treat.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia. Twelve-lead electrocardiography showed tachycardic atrial fibrillation without any significant ST-T change. Magnetic resonance imaging revealed a proximal middle cerebral artery occlusion. She was immediately treated with alteplase at the dosage approved for ischemic stroke followed by mechanical thrombectomy as bridging therapy, and complete recanalization was achieved. Aphasia improved and she began to complain of chest pain, and reported that she had experienced chest discomfort just prior to right limb weakness. Coronary angiography showed a partial filling defect in the right coronary artery with rapid and adequate distal flow, for which percutaneous coronary intervention was not required. Alteplase was suggested to have effectively resolved the coronary emboli. The occlusions of the cerebral and coronary arteries were assumed to have occurred nearly simultaneously and cardiogenic embolism due to atrial fibrillation was considered as the most likely etiology.As seen in the present case, CCI may benefit from immediate treatment with intravenous tissue plasminogen activator (IV-tPA). Although which of percutaneous coronary intervention or cerebral thrombectomy should be performed first remains unclear, we must decide whether to rescue the brain or heart first in each patient within a limited window of time. This dilemma has recently become evident in this era with mechanical thrombectomy strongly established as an effective intervention for acute ischemic stroke. Close cooperation between stroke physicians and cardiologists is becoming more important. Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered . Because4/μL. No abnormalities were evident on chest roentgenogram.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia and was transported to our emergency service 47 min after onset. Her medical history included hypertension and paroxysmal atrial fibrillation. Anticoagulants have been discontinued because of a few episodes of falls although she had previously received oral anticoagulation. Blood pressure was 105/75 mmHg without any significant difference between right and left limbs. No cardiac murmurs were audible. Twelve-lead electrocardiography (ECG) showed tachycardic atrial fibrillation with a heart rate of 150 beats/min but no significant ST-T changes, although the baseline was undulating due to patient movement  and mechanical thrombectomy, followed by coronary angiography, which did not suggest any requirement for PCI. Coronary angiography suggested that alteplase at the dosage approved for ischemic stroke had resolved the coronary emboli. Because IV-tPA is effective for both cerebral and myocardial infarction, CCI is likely to benefit from immediate treatment with IV-tPA prior to endovascular therapy. Although the recommended dosages of IV-tPA differ between cerebral and myocardial ischemia, in 6 previously reported cases of CCI treated with IV-tPA therapy, the dosage of IV-tPA applied was that used for acute ischemic stroke , 10, 11 A dilemma exists regarding endovascular therapy: although the occluded cerebral and coronary arteries have to be recanalized as soon as possible in the case of CCI, prioritizing one therapy leads to delays in the other. In previous studies, four patients were treated with both PCI and cerebral thrombectomy , 14, witIn conclusion, simultaneous cerebral and coronary embolism is rare and its prompt and appropriate management is difficult. Coexistence of coronary embolization should be considered when planning the treatment strategy for acute cerebral embolism. Further cases need to be studied to resolve the dilemma inherent in the recanalization strategy for CCI.


Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals.Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans .Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction.Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring.Low birthweight due to intrauterine growth restriction (IUGR) encumbers United States and global livestock production by increasing neonatal mortality, reducing growth efficiency, and diminishing carcass yield and quality. Low birthweight food animals that survive typically exhibit impaired muscle growth and metabolic dysfunction that leads to poor feed conversion, lighter carcasses, and reduced carcass merit  . The endThe above models create placental stunting indirectly by imposing maternal conditions that disrupt uteroplacental blood flow during placental development. However, techniques described in this section impair placental function by directly diminishing structural components of the placenta. In one model, 150-μm microspheres are embedded into placental capillaries by infusing them into the surgically catheterized descending aorta of the fetus . This teFetal growth restriction can be achieved through restriction of maternal nutrients, although it is unclear whether it is mediated by placental insufficiency . The resAG- , and y+   . A collerginine)  as the frginine) .fetal adrenal gland  and primary skeletal muscle (ex vivo) was substantially reduced in MI-IUGR fetal sheep  myoblasts and a ~10% reduction in late differentiating (desmin+) myoblasts after 72 hr in differentiation media . The fact that both proliferation and differentiation capacities were reduced in PI-IUGR fetal myoblasts (The β2 adrenergic receptor is the predominant isoform in skeletal muscle, although β1 and β3 receptors are also present. However, we found that skeletal muscle and myoblasts from PI-IUGR fetal sheep as well as skeletal muscle from PI-IUGR neonatal lambs express less mRNA for the β2 adrenergic receptor than controls . Conversyoblasts  shows thyoblasts .enhanced by muscle adaptations in MI-IUGR fetal sheep (Like the β2 adrenergic signaling pathway, inflammatory cytokine pathways appear to be altered in muscle and myoblasts of PI-IUGR and MI-IUGR fetal sheep . Unlike al sheep . In addial sheep . Sustainal sheep . Moreoveal sheep . We specIntrauterine growth restriction is a leading cause of perinatal mortality worldwide and leaves individuals at 18-fold greater risk for metabolic disorders that reduce length and quality of life. Unlike other major maternofetal pathologies, the prevalence of IUGR in the United States has not fallen over the last two decades. The fetal conditions and postnatal outcomes of IUGR are consistent among most mammalian species, which makes observations in animal models translatable to humans. A number of models developed in pregnant sheep have drastically improved our knowledge of IUGR fetal programming, which provides the fundamental basis for improving health outcomes in IUGR-born individuals.


Although bioturbation is commonly recognized in contourites, only a few studies have analyzed the ichnological content of these deposits in detail. These studies have mainly focused on meso-scale bigradational sequence (a coarsening upward followed by a fining-upward sequence resulting from variations in current velocity). Here we present data from gravitational cores collected along the NW Iberian Margin showing systematic variation in ichnological content across proximal to distal depocenters within a large-scale elongated contourite drift. Data demonstrate that tracemakers’ behavior varies depending on the distance relative to the bottom current core. Trace fossils are already known to be a useful tool for studying of contouritic deposits and are even used as criterion for differentiating associated facies , though not without controversy. We propose a mechanism by which the distance to the bottom current core exerts tangible influence on specific macro-benthic tracemaker communities in contourite deposits. This parameter itself reflects other bottom current features, such as hydrodynamic energy, grain size, nutrient transport, etc. Ichnological analysis can thus resolve cryptic features of contourite drift depositional settings. Due to their implications for reconstruction of depositional conditions, contourite deposits have become a critical topic of investigation within the sub-disciplines of paleoceanography, slope-stability, and petroleum exploration. Due to their relative inaccessibility, however, contourites remain somewhat enigmatic. Only few studies have managed to investigate bioturbation and ichnofabrics in contour current settings6. Despite ongoing controversies8, trace fossil content is considered both a criterion for characterizing contouritic deposits and also a proxy for paleoenvironmental conditions7. These records are typically overprinted by bottom current activity9. In recent years, detailed ichnological studies conducted on contourite deposits in outcrops and core material have provided new insights into depositional processes, environmental conditions and the influence of bottom currents on tracemakers11. Due to lack of detailed records, the ichnological paradigm for contourites remains somewhat tentative. Here we describe unequivocal trace fossils in contouritic deposits from deep-sea gravity cores. Comparison of features reveals distinctive lateral variation with relative to bottom current cores.The role of bottom currents in shaping deep-sea deposits  is currently a matter of debate in the scientific community12 during the ForSaGal 09 research cruise around the Galicia Interior Basin  exhibit a clear pattern with contouritic intervals dominated by Thalassinoides and Planolites   experienced relatively low sedimentation rate and low organic matter flux. Organic matter at the sediment surface may be rapidly oxidized, preventing the development of shallow/middle tier structures. Under these conditions, only deep tier structures are produced, by organisms able to store organic matter deeper in the sediment as in the case of the Zoophycos tracemaker. Sediments from site FSG09-07  indicate higher sedimentation rate and organic matter flux. Under these conditions, organic matter burial prevents oxidation and allows the development of shallow/middle tier dwelling structures, e.g. Palaeophycus . In distal settings, sedimentation rate and organic matter availability is lower. Organic matter is rapidly oxidized at the surface, favoring development of middle and deep tier tracemakers, which transport organic matter to deeper layers of the sediment . Systematic lateral variation in ichnological content of contourite drifts demonstrates an impactful role for ichnological analysis in contourite research. Trace fossils not only could differentiate contourites from turbidites and associated deposits, they also record proximal to distal deposition within a contourite drift relative to core bottom current features.Sedimentation rate, oxygen conditions, and organic matter availability influence the macrobenthic tracemaker communities and resulting trace fossil assemblage in actively forming contourite drifts. This report provides novel evidence of systematic proximal, to core bottom current, versus distal variation in ichnological features from muddy contourites. Varying depositional conditions are interpreted to reflect distance from the bottom current core. Sedimentation rate and organic matter availability are higher in proximal areas where organic matter is rapidly buried. This prevents oxidation and makes organic matter available for shallow tier tracemakers  were previously characterized based on grain size, composition, sedimentary features and Computed Tomography (CT) scanning17. Contourite deposits, concretely muddy contourites, were identified in three cores. Only cores FSG09-07  and FSG09-17   along the NW Iberian margin36, then calculated according to the Bioturbation Index scale38. These values reflect the spatial extent of discrete trace fossils identified over a common mottled background.Ichnological analysis identified ichnotaxa based on ichnotaxabases , tiering , crosscutting relations, and degree of bioturbation. The degree of bioturbation was determined by calculating the percentage of bioturbated surface using a quantification method based on high resolution digital images14C ages for the cores material analyzed12.Age was calculated using the age model based on XRF data and AMS-


Therefore, this microbial ecosystem is intertwined with host physiology at multiple levels. While it is evident that microbes that reach the blood stream can trigger thrombus formation, it remains poorly explored if the wealth of microbes that colonize the body surfaces of the mammalian host can be regarded as a modifier of cardiovascular disease (CVD) development. To experimentally address the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis, we generated a germ-free (GF) low-density lipoprotein receptor-deficient ( From a perspective of cultural evolution, during the past decades Western societies have faced an enormous shift from traditional fibre-rich nutrition to the consumption of industrial foods that severely affects the diversity and function of the gut microbiota. To a large extent, the mutualistic nature of this microbial ecosystem with its host relies on intact barriers that are typically are formed by the mucus layer, the integrity of epithelial cell layers and by a tightly regulated and multifaceted immune vigilance but is also determined by nutritional factors shaping the diversity of the commensal microbiota. These efficient barriers are disrupted by infectious pathogens and in case of injury. Related to infection, the concept of immunothrombosis views blood clotting as an intravascular effector pathway of innate immunity, constituting a physiologic response that prevents the invasion and dissemination of microbes but becoming detrimental to the host if exceeding, e.g. in sepsis. These microorganisms produce foreign products that, dependent on dietary habits, constitute a continuous stimulus of low-grade inflammation and at the same time possess an enormous metabolic capacity interfering with host metabolism. This is particularly relevant, as, in addition to the nutrition-dependent formation of microbiota-derived metabolites that can cross the intestinal barrier (e.g. the choline metabolite trimethylamine), cholesterol metabolism, a major pathway that drives atherogenesis, is strongly influenced by the gut microbiota. In recent years, numerous studies have identified the gut microbiota as a relevant source of microbial-associated molecular patterns in plasma. These microbial signatures retain their biologic activity and promote chronic low-grade inflammation, influencing for instance steady-state myelopoiesis and turn-over of myeloid cells but also acting on host metabolic pathways that influence atherogenesis.−/−Ldlr) atherosclerosis mouse model, we tested the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis. Given the complexity of the gut microbial ecosystem, it is evident that such gnotobiotic approaches are invaluable to causally pinpoint the influence of the gut microbiota on plasma cholesterol levels and the size and cellular composition of atherosclerotic lesions at defined diets and standardized feeding regimes. Hence, we fed GF −/−Ldlr mice with Western diet and compared them to conventionally raised (CONV-R) −/−Ldlr control mice, which were colonized by a microbiota from birth. Furthermore, these gnotobiotic mouse models are especially interesting to experimentally address whether the absence of microbiota impacts on arterial thrombus growth, the lethal complication arising from the rupture of atherosclerotic lesions.Using a germ-free (GF) low-density lipoprotein receptor-deficient , could in principle result in an extended phenotype of the gut microbial ecosystem that enhances cardiovascular risk.. Due to the non-absorbable properties of coprostanol in the small intestine, an inverse relationship exists between serum cholesterol levels and the coprostanol/cholesterol ratio in feces. It is known for many years that the conversion of cholesterol to coprostanol via biohydrogenation is mediated by cholesterol-reducing enzymatic activities of Eubacterium, Bifidobacterium, Lactobacillus and Peptostreptococcus strains, promoting cholesterol excretion. Furthermore, in the small intestine, the bile salt hydrolases from different gut bacterial genera deconjugate bile salts and reduce their solubility and reabsorption . By studying GF −/−Ldlr mice relative to their CONV-R −/−Ldlr counterparts, our study confirmed increased plasma cholesterol levels and elevated very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels in this GF −/−Ldlr hyperlipidemia model when mice were kept on chow diet. However, this difference was abolished when the −/−Ldlr mice were fed a 0.2% cholesterol-rich diet for 16 weeks. This result was in line with earlier studies on GF apolipoprotein E-deficient (−/−Apoe) mice that also showed increased plasma cholesterol levels at chow diet conditions, but not at Western diet feeding, when compared to CONV-R controls, demonstrating unequivocally the cholesterol lowering impact of the gut microbiota. Hence, the targeted modulation of gut microbial communities towards communities with enhanced cholesterol biohydrogenation capacity and bile salt hydrolase activity could in the future hold promise for new cholesterol-lowering therapies.Atherogenesis is primarily driven by elevated plasma cholesterol levels and an altered lipoprotein profile. Cholesterol absorption takes place in the upper small intestine. Various experimental and analytical approaches have comprehensively shown that the conversion of cholesterol to the more hydrophilic coprostanol essentially depends on established gut microbial communities −/−Ldlr mouse model addressed whether the presence of gut microbiota affects the development of carotid artery lesions. Although we found myeloid blood cell counts significantly reduced in hyperlipidemic GF −/−Ldlr mice and lower counts of adherent leukocytes to the vessel wall of carotid artery plaques, relative carotid artery plaque areas did not differ between late atherosclerotic GF −/−Ldlr mice and their CONV-R −/−Ldlr counterparts. This could be explained by the relatively late time point of our atherothrombosis study (16 weeks of Western diet). Alternatively, the unchanged plasma cholesterol levels and lipoprotein profile of late atherosclerotic GF and CONV-R −/−Ldlr mice might be due to the relatively high cholesterol content (0.2%) of the Western diet. Future studies should therefore test standardized diets with lower cholesterol content and analyze whether the absence of the gut microbiota affects the time course of atherogenesis in the −/−Ldlr mouse model. Based on our results, further in-depth analyses of gnotobiotic mouse models on atherosclerotic lesion size and plaque composition are required to pinpoint whether the cholesterol-lowering impact of the gut microbiota or the pro-inflammatory roles of gut-resident commensals can influence the onset and time course of atherogenesis.As elevated plasma cholesterol levels are a critical determinant for the progression of atherosclerotic lesions, our study on the GF −/−Ldlr mice relative to CONV-R −/−Ldlr mice in standardized flow chamber experiments with anticoagulated whole blood . Interestingly, we observed a diminished exposure of the platelet activation marker phosphatidylserine on the outer leaflet of the platelet membrane of GF −/−Ldlr mice in this standardized flow chamber model. Thus, our data indicate that at Western diet feeding conditions, the presence of gut microbiota promotes adhesion-dependent platelet activation. This observation is largely coherent with recent studies from other laboratories that have linked the gut microbiota with diet-dependent platelet hyperreactivity and demonstrated that fecal microbiota transplantation potentially can influence procoagulant function.As atherosclerotic lesions in the carotid arteries are a frequent cause of stroke, our study put focus on atherothrombosis, the lethal complication of atherosclerosis. In our previous work, we have shown that the gut microbiota promotes carotid artery thrombosis even at chow diet conditions. In addition to the carotid artery ligation model that has revealed reduced platelet deposition to exposed subendothelial matrix in GF relative to CONV-R C57BL/6J mice at chow diet conditions, our recent study demonstrated that GF C57BL/6J mice kept on chow diet also show significantly reduced occlusion times in the ferric chloride injury model of carotid artery thrombosis. At chow diet conditions, pattern recognition of microbiota-derived ligands by hepatic endothelial cells influenced arterial thrombus growth through modulation of hepatic endothelial von Willebrand factor (VWF) synthesis and VWF plasma levels. In contrast, at Western diet conditions, the adhesion-dependent platelet deposition to type III collagen, a major constituent of atherosclerotic lesions, was significantly reduced in GF −/−Ldlr mice and results in a platelet phenotype of increased phosphatidylserine exposure . A number of recent studies have linked the microbiota with metabolic functions that promote platelet reactivity and arterial thrombosis, e.g. by the microbiota's positive impact on the host serotonin biosynthesis pathway or the conversion of choline to trimethylamine. Our study provides an alternative role of the gut microbiota in the modulation of platelet function, as we could show in a standardized flow chamber model that the extent of phosphatidylserine exposure in the platelets of hyperlipidemic −/−Ldlr mice was dependent on the presence of the commensal microbiota. Since at low cholesterol nutrition the gut microbiota protects the host from high blood cholesterol levels, mechanistic insights on how the metabolic capacity of specific community members affects arterial thrombosis might in the future turn out instrumental to develop new therapeutic interventions based on nutrition, prebiotics or the selective inhibition of metabolic functions of gut microbes to prevent cardiovascular risk.Collectively, our study argues for a prothrombotic role of the microbiota under hyperlipidemic Western diet conditions that is due to enhanced adhesion-dependent platelet activation on type III collagen in colonized


Home-delivered meals (HDMs) provided through the Older Americans Act (OAA) are intended to reduce hunger, promote socialization, and maximize wellness. However, HDM recipients are at increased likelihood of being hospitalized due to their complex health needs and risk for social isolation and depression. Drawing data from the OAA-HDM National Survey, we evaluated the predictors of hospitalization among HDM recipients in 2017. From our sample (n = 578), we conducted random forest classification analyses to identify the most important risk factors related to HDM recipient hospitalization. Our random forest model yielded an accuracy rate of 66.3% with risk factors most indicative of hospitalization being attributed to number of co-morbidities, depressive symptoms, and feelings of social isolation. These findings indicate that although HDMs may help alleviate hunger among older adults, innovate strategies are warranted to address the unmet mental health needs of HDM recipients.


Senescent cells drive aging. Preclinical studies suggest that targeted elimination of senescent cells offers a unique therapeutic approach to counter numerous chronic diseases and geriatric syndromes. To foster the translation of basic science discoveries to clinical application, we have sought to identify circulating biomarkers that reflect systemic senescent cell burden. We first analyzed the secretome of multiple senescent human cell-types and developed a candidate panel of proteins that could be reliably measured in human blood. Multiple proteins demonstrated significant associations with chronological age in a community-based cohort of adults aged 20-to-90 years. Impressively, in two distinct surgical cohorts (severe aortic stenosis and ovarian cancer), candidate protein concentrations were associated with biological age indices, including frailty and adverse outcomes. Our data suggest senescence biomarkers may have utility for clinical practice as indicators of risk, and for clinical research as surrogate endpoints in trials of interventions targeting senescent cells.


Throughout a marriage, couples will share countless ordinary moments together, such as laughing together or engaging in leisure activities. Although these moments may seem trivial in isolation, research suggests that accumulating small positive moments together helps couples build emotional capital, which serves as an essential resource for protecting marriages from the harmful consequences of relationship challenges. This study explored whether emotional capital may buffer couples not only from the negative effects of relational stressors, but also from the negative effects of life stressors encountered outside the relationship in a sample of younger (age 30-45) and older (age 60+) married couples. Drawing from theories of socioemotional expertise, we also examined whether the buffering effects of emotional capital may be stronger for older adults. One hundred forty-five couples completed a 21-day daily diary task assessing shared positive experiences with the partner, negative partner behaviors, marital satisfaction, life stress, and mood. Spouses who generally accrued more shared positive moments with their partner across the diary days maintained greater marital satisfaction on days of greater partner negativity compared to spouses who accrued fewer positive moments. Moreover, spouses who generally accrued more shared positive moments with their partner across the diary days also reported lower levels of negative mood on days in which they experienced more life stress compared to spouses who accrued fewer shared positive moments; in both cases, the buffering role of emotional capital was significantly stronger for older adults. All results held when adjusting for relationship length and general marital happiness.


Prediction of transcription factor (TF) binding from epigenetics data and integrative analysis thereof are challenging. Here, we present TEPIC 2 a framework allowing for fast, accurate and versatile prediction, and analysis of TF binding from epigenetics data: it supports 30 species with binding motifs, computes TF gene and scores up to two orders of magnitude faster than before due to improved implementation, and offers easy-to-use machine learning pipelines for integrated analysis of TF binding predictions with gene expression data allowing the identification of important TFs.https://github.com/SchulzLab/TEPIC and can be used on Linux based systems.TEPIC is implemented in C++, R, and Python. It is freely available at Bioinformatics online. TEPIC 2 builds upon and extends the functionality of existing TFBS prediction tools. Among other features, TEPIC 2 allows the direct aggregation of TFBS predictions on the gene level and uses these scores to gain novel insights on cell type specific functions of TFs via several machine learning analysis. This is a unique feature not supported by competitive TFBS prediction approaches  are key players of transcriptional regulation. Prediction of TF binding is essential to gain a deeper understanding of their function. While experimental identification of TF binding is possible through laborious and expensive ChIP-seq assays, several computational approaches have been proposed to identify TF binding sites (TFBSs) . DYNAMITE has been successfully applied to discover regulators of CD4+ T cell differentiation (EPIC-DREM), which was used to analyze mesenchymal stem-cell differentiation of osteoblasts and adipocytes   . DetailsTEPIC 2 is a fast and easy-to-use tool for TFBS prediction combined with integrative analysis capabilities for gene expression and epigenomic data. TFBS prediction and downstream machine learning pipelines for various analysis settings allow a deep, seamless exploration of epigenomic datasets supporting data driven hypothesis generation about the role of individual TFs in complex regulatory landscapes.Supplementary MaterialClick here for additional data file.


Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer’s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer’s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Our review briefly outlines some of the proposed neurobiological mechanisms of TMS benefits in AD, with particular emphasis on the modulatory effects on excitatory/inhibitory balance. On the basis of converging evidence from multiple fields, we caution that TMS therapeutic protocols established in young adults may have unexpected detrimental effects in older individuals or in the brain compromised by AD pathology. Our review surveys clinical studies of TMS in AD alongside basic research as a guide for moving this important area of work forward toward effective treatment development. There is an urgent need for the development of new, effective strategies in the battle against Alzheimer’s disease (AD). Transcranial magnetic stimulation (TMS) has emerged as a promising possibility, but evidence regarding long-term efficacy and mechanism of action is limited. Among the major unresolved issues, findings linking the effects of TMS on excitatory/inhibitory balance with mechanisms of AD pathogenesis merit careful consideration. Our survey of clinical TMS studies in AD alongside basic research aims to move the area forward toward effective treatment development using noninvasive brain stimulation.Alzheimer’s disease (AD), the most common form of dementia, is characterized by progressive memory impairment and associated decline in multiple cognitive domains, ultimately leaving patients incapacitated. Inexorably eroding the lifetime of memories that defines us, AD robs patients of their unique identity. The neuropathological hallmarks of AD prominently include microscopic foci of degenerating neurites and extracellular amyloid β-protein (Aβ) deposition, together with intracellular aggregates of hyperphosphorylated tau protein that disrupt microtubule organization . The sinCurrently approved pharmacological treatments for AD offer limited symptomatic relief for some patients, and none alter the underlying progression of disease. While the search for new drugs with improved clinical efficacy is ongoing, increasing attention is focused on disease-modifying strategies aimed at bending the trajectory of aging toward healthy neurocognitive outcomes. Ideally, intervention would be initiated in at-risk individuals before the clinical expression of disease, during the decades-long prodromal phase thought to precede AD diagnosis. Noninvasive brain stimulation (NIBS) has generated considerable interest in this context. Prominently including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, this family of related technologies shares a generally well tolerated safety profile in healthy young adults and is currently under investigation for treating a growing list of potential indications .Among the various types of NIBS, TMS has received the greatest attention in clinical research on neuropsychiatric disorders. The mechanistic basis of TMS benefits is poorly understood, but there is general agreement that cortical excitability can be persistently modified by the repetitive delivery of a high-intensity magnetic field, generated by passing electrical current through an inductive coil. Repetitive TMS (rTMS), delivered in daily hour-long sessions over the course of several weeks was approved by the US Food and Drug Administration (FDA) for the treatment of pharmacologically refractory depression in 2008. In general, trials of rTMS treatment versus sham showed significant improvement in depression scores and lower rates of remission with rTMS , benefitDeveloping NIBS as a potential intervention for any clinical indication critically involves the choice of an appropriate stimulation protocol. Generally, rTMS protocols are operationally classified as “low frequency” or “high frequency,” and “conventional” or “patterned.” Low-frequency typically refers to stimulation rates ≤1 Hz, whereas rates ≥3 Hz are considered high frequency . In conventional protocols, single TMS pulses are applied in a regular rhythm; in patterned rTMS, short, high-frequency bursts are interleaved with brief periods of no stimulation. Some examples of patterned rTMS include stimulation mimicking theta activity, wherein short bursts of high-frequency pulses repeated at 5 Hz [theta burst stimulation (TBS)] are delivered as continuous TBS or intermittent TBS (iTBS) pulses. Perhaps most important with respect to the clinical effects of stimulation, low-frequency rTMS protocols are understood to result in cortical suppression and inhibition, whereas high-frequency stimulation increases cortical facilitation and excitability . Beyond Initial studies of rTMS effects in AD focused on high-frequency protocols almost exclusively , 2008. OStudies directly comparing cognitive outcomes following high-frequency versus low-frequency stimulation in patients with AD were first reported in 2012. In one investigation, 20 or 1 Hz rTMS was delivered bilaterally over the dlPFC in participants with mild or severe dementia . High-frEncouraged by this background, together with the much larger literature of experimental studies in normal participants , stimulaComplementing these findings, rTMS-COG in a group of probable AD case patients reportedly produced statistically significant or numerical improvement relative to baseline, as assessed by a variety of standard measures , either immediately or 6 weeks after the intervention protocol . Effectswww.fda.gov, March 21, 2019, Neurological Devices Panel of the Medical Devices Advisory Committee: De Novo DEN160053). The following sections briefly consider some of the experimental design challenges in this area of research, and then turn to evidence concerning the neurobiological mechanisms that might mediate the effects of TMS. A comprehensive mechanistic review is available elsewhere  were not considered. Studies examining rTMS-COG protocols have generally lacked groups receiving either rTMS alone or cognitive assessment without stimulation . However, the available evidence regarding clinical efficacy and mechanism of action is limited. The view developed here is that defining the neurobiological substrates responsible for the effects of TMS and other NIBS modalities will be critical for maximizing their efficacy and safety. We encourage a constructive, dispassionate evaluation of the evidence, aimed at establishing an informed platform for moving TMS and related strategies forward toward clinical application in AD.The possibility that a safe, noninvasive, and relatively low-cost treatment such as TMS might prove effective in the battle against AD has generated understandable excitement (The evidence summarized in this review highlights at least three conceptually distinct targets for TMS intervention in AD. in vivo imaging in patients receiving TMS are also needed. Efficacy in appropriately controlled, well powered trials remains to be confirmed, and longer-term cognitive outcomes established. At what stage in the progression of AD pathology will TMS be most effective? If TMS is used to target excitatory/inhibitory balance, at what frequency and in which brain regions, recognizing that such effects may be brain region specific (The need for effective strategies in the battle against AD grows ever more urgent. The disappointing outcome of recent clinical trials encourages the consideration of fresh perspectives, and in this context, NIBS has emerged as a novel alternative to pharmacological therapeutics and other interventions. The exciting potential of this approach, however, should not overshadow the important questions that remain unanswered. Among them, the safety profile established for other indications merits reconsideration in the context of neurobiological changes associated with AD, including hyperexcitability and epileptic activity, consistent with current safety guidelines . Studiesspecific ? Indeed,specific . The cha


Hypomesus transpacificus) and Chinook Salmon (Oncorhynchus tshawytscha). Since many tidal wetland restoration projects are planned or have recently been constructed in the Delta, understanding the diversity and variability of wetland invertebrates that are fish prey items is of increasing importance. During this study, two different invertebrate sampling techniques were tested (leaf packs and sweep nets) in four habitat types within three different wetland areas to evaluate which sampling technique provided the most reliable metric of invertebrate abundance and community composition. Sweep nets provided a better measure of fish food availability than leaf packs and were better able to differentiate between habitat types. Generalized linear models showed submerged and floating vegetation had higher abundance and taxa richness than channel habitats or emergent vegetation. Permutational multivariate analysis of variance showed significantly different communities of invertebrates in different habitat types and in different wetlands, and point-biserial correlation coefficients found a greater number of mobile taxa associated with sweep nets. There were more taxa associated with vegetated habitats than channel habitats, and one area had more taxa associated with it than the other two areas. These results suggest that restoration sites that contain multiple habitat types may enhance fish invertebrate prey diversity and resilience. However, the effect of habitat diversity must be monitored as restoration sites develop to assess actual benefits to at-risk fish species.Restored tidal wetlands may provide important food web support for at-risk fish species in the Sacramento-San Joaquin Delta (Delta) of California, including Delta Smelt ( Tidal wetlands provide an important source of productivity to many estuaries worldwide, subsidizing the surrounding open-water areas with vascular plant detritus, phytoplankton, zooplankton, and nekton biomass –5. ProduOncorhynchus tshawytscha) and Delta Smelt (Hypomesus transpacificus) . Thi. Thi73].We found significant differences in macroinvertebrate communities that may be traced to habitat heterogeneity. This implies that constructing a diverse range of habitats, including emergent vegetation, floating vegetation, submerged vegetation, and open water, during tidal wetland restoration may increase the variety of invertebrates produced on the site. The difference in invertebrates between habitats is not surprising, as research in this and other systems have found large differences between habitats , 30, 71,A wider range of invertebrate prey may increase resiliency of at-risk fishes and the ecosystem as a whole. There are multiple ways a diverse ecosystem may respond to changes in taxon composition , but theSurprisingly, we found no significant differences in invertebrate catch between the two time periods (March versus May). This suggests that invertebrate abundance may remain somewhat constant throughout the spring, however further sample points are required before any conclusions can be drawn. Due to strong seasonal patterns in invertebrate communities found by other studies , 40, 85,Invertebrate community composition was highly variable within and between Delta wetlands. Sweep nets provided a simple, efficient way to sample the invertebrate community, and demonstrated that different areas and habitat types supported different groups of organisms. Measuring invertebrate abundance across all habitat types within a wetland will allow managers to evaluate the effectiveness of their restoration projects in providing food for at-risk fishes. Wetland restoration can benefit from incorporating multiple habitat types in each project to develop a diverse community of invertebrates. Furthermore, restoration projects in different areas may have different benefits, and a variety of restoration projects may provide greatest resilience for the aquatic food web and the at-risk fishes it supports.S1 Data(CSV)Click here for additional data file.


In the accompanying article, Horiuchi et al. (Biosci. Rep. (2019) 39(4), BSR20190213) evaluate the availability of apolipoprotein B-depleted serum for CEC assays. Using their recently developed immobilized liposome-bound gel beads (ILG) method, Horiuchi et al. demonstrate that apolipoprotein B-depleted serum obtained with poly ethylene glycol precipitation enables CEC assays to be easily and accurately introduced into laboratory medicine.Cholesterol efflux capacity (CEC), an important functional step in reverse cholesterol transport, is the main anti-atherosclerotic function of high-density lipoprotein (HDL). Assays that improve the determination of CEC  Lack of symptoms for the risk prediction is one of the leading causes of death by cardio vascular disease (CVD). Serum HDL cholesterol (HDL-C) levels have long been shown to be a biomarker of CVD risk and is a powerful inverse predictor of CVD. Regular blood work estimating the HDL levels in addition to lipid metabolic profile is a guideline by American Heart Association and the National Cholesterol Education Program before administering drug therapies for coronary heart disease in United States. However, recent studies suggest that despite elevated HDL-C levels being consistent with atheroprotection, the causal relation between HDL levels and cardiovascular disease is not clear . Two cliin vitro measure of an individual’s ability to efflux cholesterol [., macrophages in an ex vivo system that involves apolipoprotein B-depleted serum from the study participants, the assay acts as a good predictor of cardiovascular risk [Cholesterol efflux capacity is an lesterol . When aplar risk . CEC is lar risk ,7. This lar risk . The varviz., macrophages. The ex vivo system in a clinical set-up is not ideal as some clinical laboratories, especially in developing countries might lack cell culture, radioisotope handling or ultracentrifugation equipment and facilities. To address this dependency on infrastructure, authors developed a variation of CEC assay using immobilized liposome-bound gel beads  whole serum/plasma; (ii) Apo B depleted serum (BDS); and (iii) pure HDL. Isolation of serum HDL by ultracentrifugation is the most prevalent method. However, the method demands special equipment and is time consuming. In addition, HDL fraction concentrated by ultracentrifugation may not always reflect the concentration of HDL in the serum . The conTo circumvent the ultracentrifugation step for preparation of apolipoprotein B (ApoB)-100 depleted serum, as the cholesterol acceptor, assay developed by Horiuchi et al., use polyethylene glycol (PEG) precipitation. HDL fraction obtained from PEG method (BDS) is indeed an effective alternative instead of using laborious ultracentrifugation method in a clinical setting. Human plasma lipoproteins are routinely fractionated using PEG-6000 ,13 and wTypically, CEC assay requires cells loaded with excess of radiolabeled cholesterol and a cholesterol acceptor (HDL). Instead of radioisotope labeling the assay developed by Horiuchi et al., employs fluorescently labeled cholesterol using boron-dipyrromethene (BODIPY) dye. Fluorescent intensity is measured by using microplate reader, which is routinely available in a clinical setting, to measure the CEC. Use of fluorescently labeled cholesterol instead of radiolabeled one can be a great choice for working in safe laboratory environment. However, testing the effect of BODIPY-cholesterol concentrations during ILG preparation methodology would be a good option.One of the limitations of the Horiuchi et al.  study isBy changing three steps of CEC assay viz., (i) ILGs for cultured cells; (ii) fluorescently labeled cholesterol; (iii) PEG precipitated HDL, authors demonstrate that it sufficient to estimate CEC with a significant correlation with a conventional assay using foam cells derived from THP-1 macrophages. Here is a holistic approach in which an observation arising from using HDL fraction obtained from the simple PEG method as a cholesterol acceptor in CEC assay. Although there is change in cholesterol safe labeling and the quick method of isolation of HDL fraction, the cultured cells are the only choice for CEC assay until recently. Having artificial cells that is liposome containing fluorescent BODIPY-labeled cholesterol as a substitute for the cultured cells is an effective method in clinical laboratories.


Very few studies have compared oral health status between the US-born and foreign-born immigrant older adults. Using data collected among 430 Chinese older adults age 55+ residing in Hawai’i, we examined the association between immigrant status and oral health related quality of life (OHQoL) and the moderating role of resilience in linking the association. Controlling for some key covariates, our study results show that US-born Chinese immigrant older adults had better OHQoL than their foreign born counterparts. Factors such as higher level of education (graduate degree or higher), better self-reported health status and no significant tooth loss were related to better OHQoL. The association between immigrant status and OHQoL was moderated by resilience. Specially, resilience was positively and significantly associated with OHQoL among U.S.-born older adults but not among the foreign-born ones. Our findings indicate the importance of immigration and resilience in shaping oral health outcomes among older Chinese Americans.


Chronic subdural hematoma (CSDH) is one of the most common neurological diseases, which mainly occurs among elderly people and usually develop after minor head injuries. Over the years, a simple burr hole evacuation of the hematoma has been accepted as the widespread method for most cases of CSDH, but acute parenchymal hemorrhage is a rare and deadly complication after surgery. We report three elderly cases of post-operative parenchymal hemorrhage and analyse the underlying factors and formulate relevant strategies in this article. Three advanced age patients had been admitted to our department with gradually increasing headache and limb activity disorder urgently and underwent an emergency operation of burr hole drainage of CSDH in frontal-temporal region after preoperative evaluations and examinations. Unfortunately, acute post-operative parenchymal hemorrhage occurred in three advanced age patients. Ultimately, the patients achieved satisfying outcome with no significant neurological deficit through conservative treatment. The exact mechanism of such uncommon complications are difficult to explain and remain poorly understood. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation were the main mechanisms which were speculated in our report. Simultaneously, positive measures could be adopt to prevent this rare complication. Chronic subdural haematoma (CSDH) is one of the most common neurosurgical conditions and is especially prevalent among elderly individuals . BehavioCase 1: An 71-year-old male patient had been admitted to our department with two-week history of gradually increasing headache and slight limb activity disorder and a 2-month history of minor head trauma as a result of fall to the ground. Cranial CT revealed bilateral CSDH. There was hypertension and multiple lacunar infarction were the systemic diseases which were under normal control  and asthma. Neurological assessment confirmed mental confusion and gait imbalance without focal deficits. The CT scan revealed a sizeable right chronic subdural hematoma which caused midline left shift  loss, oral anticoagulant, primary disease aggravation. Although CSDH drainage is considered as a minimally invasive surgical approach, neurosurgeons must be aware of this rare and deadly event. Correction of coagulation function, control of blood pressure and treatment of primary diseases are essential in order to prevent such complications before operation. Careful and gentle evacuation of the subdural hematoma without excessive head rotation is suggested to avoid rapid shift of intracranial contents and local hyper transfusion during operation. Continuous electrocardiograph monitoring, repeated evaluation of neurologic conditions, prompt radiological assessment, positive therapy of primary disease, volume of drainage control strictly and the height of drainage tube adjustment are mandatory after operation. Above all, when the uncommon complication occurs, conservative treatment is recommended intensively unless enormous intracranial hematoma make the patients unconsciousness, even brain hernia. Unfortunately, evacuation of hematoma and decompressing craniotomy were only adopted to save lives accompanied by poor prognosis.The authors declare no competing interests.


Following publication of the original article , the autEnzyme adsorption comparison on lignin materials derived from acid and alkali pre-treated corn stover.To further understand the role of lignin materials in enzyme adsorption, we enzymatically hydrolyzed dilute acid pre-treated and dilute alkali pre-treated corn stover excessively to remove all the carbohydrates that are hydrolyzable by the enzyme cocktail applied. The obtained cellulolytic enzyme lignin (CEL) materials were used to investigate their enzyme adsorption kinetics Fig. , and theFurther to this, the authors reported an error in Fig. The corrected Fig.


Gaucher disease is an inherited metabolic disorder resulting in deficiency of lysosomal enzyme β-glucocerebrosidase causing the accumulation of abnormal macrophages (“Gaucher cells”) within multiple organs, most conspicuously affecting the liver, spleen, and bone marrow. As the most common glycolipid metabolism disorder, it is important for radiologists encountering these patients to be familiar with advances in imaging of organ and bone marrow involvement and understand the role of imaging in clinical decision-making. The recent advent of commercially available, reliable, and reproducible quantitative MRI acquisitions to measure fat fractions prompts revisiting the role of quantitative assessment of bone marrow involvement. This manuscript reviews the diverse imaging manifestations of Gaucher disease and discusses more optimal quantitative approaches to ascertain solid organ and bone marrow involvement with an emphasis on future applications of other quantitative methods including elastography. Non-neuronopathic Gaucher disease most conspicuously involves bone marrow, liver, and spleen.Organ volumes are commonly used for disease severity and treatment response.Anatomic imaging is relatively insensitive to marrow infiltration in Gaucher disease.Quantitative marrow fat-fractions indicate musculoskeletal severity and show early treatment response.Elastography may aid in assessing fibrosis in Gaucher disease.GBA) gene identified to-date , 6522, 6Marrow infiltration manifests with low signal on T1-weighted imaging Fig. . Early qNumerous semi-quantitative scoring methods have been developed to report overall extent of bone marrow involvement based on signal intensity alterations on MRI, each with specific objectives and limitations summarized in Table Multiple quantitative factors have been proposed to objectively assess marrow involvement in Gaucher disease and are supported by histopathologic evidence of an inverse relationship between marrow glucocerebroside and triglyceride concentrations . Some ofCurrently, quantitative MRI-based fat fraction measurements have been applied to objectively assess marrow involvement in Gaucher disease. Quantitative chemical-shift imaging (QCSI) using Dixon-based techniques and MRS are both capable of reliably measuring bone marrow fat fraction –90. WorkThe importance of understanding developmental increases in marrow fat over the lifespan beginning first in the peripheral skeleton as well as normal variation in bone marrow fat fractions cannot be understated. Patient age, sex, and body mass index should be considered in the interpretation of these values, ideally in the context of normative data relevant to the measurement method , 96–98. DWI may also hold promise with some evidence of decreased vertebral marrow ADC reflecting increased cellularity corresponding with disease status . Last, iNuclear medicine studies are not routinely used for routine follow-up assessment of Gaucher disease at most institutions, although 99 m-Tc-Sestamibi scintigraphy has been studied as an alternative means of quantifying bone marrow involvement with good agreement with MRI-based semi-quantitative scoring , 102. TrOne of the earliest skeletal manifestations of Gaucher disease type 1 in children is osteopenia . The devProgressive osseous involvement in type 1 Gaucher disease may begin with painful bone crises that may eventually result in osteonecrosis  in about half of patients that may be attributed to packing of the marrow with Gaucher cells leading to thrombosis in situ within the marrow , 110. OsRadiographic detection of early osseous complications such as osteonecrosis and bone infarct may be difficult, often being occult on initial imaging with subsequent development periosteal reaction that may be confused with osteomyelitis (“pseudo-osteomyelitis”) , 67. FocGiven these limitations, assessment of acute osseous complications is best performed with initial radiographs followed by prompt MRI assessment . Bone crBone-related malignancies may be slightly more common in Gaucher disease, perhaps related to osteonecrosis as a predisposing factor. MRI may often be warranted for evaluation of discrete lytic lesions given the incidence of malignant bone lesions such as multiple myeloma, osseous lymphoma, sarcomas, and malignant epithelioid hemangioendothelioma –120. ParAs with the liver, spleen, and bone marrow, Gaucher cells can infiltrate in the lungs, typically depositing within interstitial spaces. Such lung involvement is quite rare, more common in the neuronopathic type, nd not likely to occur as an initial manifestation of this disease . ReticulThere are multiple proposed etiologies for pulmonary hypertension in Gaucher patients. Pulmonary hypertension is attributable to perivascular infiltration of Gaucher cells or secondary to hepatic disease . An earlThe extent of cardiac involvement in Gaucher disease is uncertain with small numbers of mitral valve prolapse and valvular calcifications reported in a few patients with homozygous D409H mutations . Given tThere is a clear need for an objective and reproducible scoring system capable of assessing disease severity to standardize patient monitoring. While clinical scoring methods (PGS3 and GD-DS3) are useful tools for estimating disease severity, these scoring methods do not assess diffuse hepatic disease such as fibrosis, iron accumulation, fat infiltration, and portal hypertension, nor do they assess the full extent of asymptomatic marrow involvement with inclusion of only subjective imaging assessment of marrow involvement.While ultrasound is affordable and may be sufficient for the assessment of organ volumes and liver lesion screening, there is increasing use of MRI in Gaucher disease with most authorities considering MRI the standard of care , 45. As Diagnostic imaging of hepatic and splenic involvement should consist of sequences tailored for volumetric organ measurement and screening for focal lesions. In conjunction with these conventional acquisitions, MR elastography should be considered, when available, to provide non-invasive assessment of liver and splenic stiffness. While the role of elastography in the clinical management of hepatic fibrosis in Gaucher disease is not yet established, acquisition of organ stiffness measurements may afford insights into disease and treatment effects in the future with wider clinical adoption. It is important to note that elastography results should be interpreted in the context of known limitations including inaccuracy of gradient recalled echo(GRE)-based elastography in patients with iron deposition and massive ascites ; as suchNewer proton density fat fraction (PDFF) sequences allow for single breath-hold acquisition of the entire liver to provide triglyceride fat fractions, R2* mapping, and some also provide automated liver volumes  –128. TheSingle-voxel MRS for fat fraction measurement may also be considered as a supplement or alternative if PDFF sequences are not available. DWI is included in our protocol as it may also be provide indirect assessment of organ cellularity with ADC as a possible quantitative marker of disease severity .If suspicious focal lesions are noted on this surveillance evaluation, dedicated lesion work-up with dynamic hepatocyte-specific contrast-enhanced MRI, multiphase contrast-enhanced CT, or contrast-enhanced ultrasound should be recommended, depending on institutional resources , 130.Qualitative imaging of both the axial (lumbar spine) and appendicular skeleton  is important for assessment of global marrow involvement, as these sites may respond differently to treatment . While aDiscrete parameters for the frequency of follow-up of Gaucher disease patients with imaging are informed by consensus recommendations and institution-specific practices , 133. CoAs part of clinical severity scoring and recommended care for patients, bone mineral density measurement is recommended beginning at 6 years of age with follow-up obtained every 1 to 2 years , 18, 31.Regional radiographic assessment of acute bone pain should be the first-line examination to assess for the presence of pathologic fracture . HoweverDecisions regarding routine imaging assessment of cardiac abnormalities with echocardiography and cardiac MRI are beyond the scope of this review with some authors recommending baseline echocardiographic screening in all ages at diagnosis and follow-up evaluation in adults on treatment , 122. ThConventional imaging of non-neuronopathic Gaucher disease underestimates multisystem organ involvement in Gaucher disease, and recent clinical and experimental evidence shows a significant role of multifaceted processes of inflammation, chemotaxis, iron deposition, and fibrosis, even in treated patients. Quantitative bone marrow fat fraction measurements have been touted as a reliable marker of skeletal involvement for treatment response assessment but have been relegated to selected academic medical centers previously. Newer commercially available quantitative MRI methods enable efficient quantification of liver, spleen, and bone marrow fat fraction values and a comprehensive imaging protocol is introduced in this article to take advantage of this opportunity to better characterize this complex disease and guide personalized therapy.