Extracellular vesicles (EVs) are lipid bilayer-enclosed microparticles that have prominent roles in the intercellular crosstalk. EVs are secreted after fusion of endosomes with the plasma membrane (exosomes) or shed from the plasma membrane (microvesicles). These microparticles modulate bone marrow microenvironment and alter differentiation and expansion of normal hematopoietic cells. EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. In addition, megakaryocytic microparticles stimulate differentiation of hematopoietic stem and progenitor cells into mature megakaryocytes. The ability of EVs in induction of maturation and expansion of certain hematopoietic cells has implications in transfusion medicine and in targeted therapeutic modalities. Important prerequisites for these interventions are identification the specific targets of EVs, transferred biomolecules and molecular mechanisms underlying the fate decision in the target cells. EVs are also involved in the pathogenesis and progression of hematological malignancies including acute leukemia and multiples myeloma. In the current review, we provide a summary of studies which evaluated the significance of EVs in normal hematopoiesis and hematological malignancies. Extracellular vesicle, Hematopoiesis, Hematological malignancy Microvesicles (MV) and exosomes include two important kinds of EVs . While M2Normal hematopoiesis is influenced by biomolecules that exist in EVs. For instance, EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. This speculation is based on an experiment in murine stromal cells where EVs derived from these cells stimulated loss of quiescence in hematopoietic stem and progenitor cells (HSPCs) and enhanced expansion of myeloid progenitors. Such effects were exerted through the MyD88 adapter protein. Notably, inhibition of TLR4 could suppress this process to some extent. Canonical NF-κB pathway and subsequent induction of Hif-1α and CCL2 were also involved in this process . Megakar3EVs also mediate different roles in hematological malignancies.3.1Both primary acute myelocytic leukemia (AML) and AML cell lines have been shown to produce exosomes that are transferred to bystander cells. These EVs contain numerous coding and noncoding RNAs which are involved in the pathobiology of AML. EVs entrance into bone marrow stromal cells results in the modulation of their potential in growth factors production. The signals transmitted by these EVs change the proliferative, angiogenic, and migratory features of cocultured stromal and hematopoietic progenitor cells . EVs als3.2Exosomes originated from patients with chronic myelogenous leukemia (CML) patients are enriched in amphiregulin (AREG), therefor inducing EGFR signaling in stromal cells. Activation of this signaling pathway leads to over-expression of SNAIL, MMP9 and IL-8. Prior exposure of stromal cells with CML cells exosomes has enhanced expression of annexin A2 which increases the adhesion of leukemic cells to the stromal monolayer, facilitating the growth and invasion of leukemic cells . CML-der3.3Microvesicles released from MSCs from patients with myelodysplastic syndrome (MDS) have been shown to alter CD34 + cells characteristics .Multiple myeloma (MM) MSCs have also been shown to produce EVs that are conveyed to MM cells, thus changing tumor growth. Exosomal levels of miRNA such as miR-15a were different between MM and normal MSCs. Besides, EVs originated from MM bone marrow MSCs had greater amounts of oncogenes, cytokines, and adhesion molecules. While these EVs enhanced MM tumor growth, normal bone marrow MSC-derived EVs suppressed the growth of MM cells . MM pati4The presence of EVs in the body fluids including saliva, urine, peripheral blood and other body fluids indicates the potential of these vesicles in diagnostic and prognostic procedures . Notably5EVs have been shown to mediate critical functions during normal hematopoiesis and in the course of initiation and progression of hematological malignancies. The cell-cell communication mediated by EVs has important effects in bone marrow milieu and regulation of innate immune responses . The abiFinally, EVs which are released into bone marrow microenvironment might affect response of malignant cells to therapeutic modalities including tyrosine kinase inhibitors. Therefore, EVs components not only predict patients' outcome and their response to therapy, but also they represent potential manipulable resources for conferring drug resistance. Alteration in exosomal level of certain proteins might also reveal responses to chemotherapy. Moreover, the exosomal content may reflect the existence of residual disease in patients thought to be in complete remission . MalignaTaken together, EVs contain several protein and RNA molecules that could alter lineage differentiation, expansion and function of bone marrow cells in both physiological and pathologic conditions. The ability of these microparticles in specific targeting of the recipient cells potentiates them as vehicles for combating drug resistance in hematological malignancies. Moreover, malignant cells-derived EVs are potential diagnostic and prognostic markers in this kind of malignancy.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper.


A 48-year-old-female presented to the emergency department with dislodgement of her percutaneous endoscopic gastrostomy (PEG) tube, necessitating bedside replacement. Replacement was done without difficulty and gastrografin radiography was obtained to confirm positioning. Radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation.The patient required hospitalization with surgical consultation, initiation of parenteral nutrition, and conservative management of the fistula with surgical replacement of the PEG tube. Although rare, it is paramount for the emergency physician to be aware of this complication when undertaking bedside replacement of PEG tubes. A 48-year-old female with past medical history of failure to thrive requiring percutaneous endoscopic gastrostomy (PEG) tube placement presented to the emergency department (ED) with PEG tube dislodgement. Her PEG tube was initially placed in 2009, with surgical replacements in 2012 and 2018. Examination revealed a soft, nontender, non-distended abdomen with an open gastrostomy tract. ED course included placement of a new gastrostomy tube into the existing tract and confirmatory gastrografin radiography .The confirmatory radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation, without peritoneal extravasation. This required hospitalization with surgical consultation for removal of the misplaced PEG tube, initiation of parenteral nutrition, intravenous antibiotics, and surgical reinsertion of the PEG tube after conservative management of the colocutaneous fistula. Colocutaneous fistulas are a rare complication of PEG tube insertion with incidence rates of 0.5–3%.CPC-EM CapsuleWhat do we already know about this clinical entity?Colocutaneous fistulas are a rare complication of percutaneous endoscopic gastrostomy (PEG) tube insertion mediated by PEG tube penetration of interposed colon between the stomach and abdominal wall.What is the major impact of the image(s)?Contrast filling the splenic flexure and proximal descending colon suggests colocutaneous fistula formation, requiring prompt recognition and surgical consultation.How might this improve emergency medicine practice?Emergency physicians change a large number of PEG tubes; therefore, recognition and awareness of this rare complication is important to clinical practice.


Racial and ethnic disparities in age-related cognitive function and dementia risk in the US are well recognized. However, the psychosocial drivers of these disparities and underlying mechanisms are less well studied. This symposium will highlight novel research regarding our current understanding of racial/ethnic differences in brain and cognitive aging and the underlying mechanisms of the disparities. Frist, two papers will describe results regarding racial/ethnic differences in cognitive function and brain aging markers. Few studies have assessed racial/ethnic differences in cognitive function across age groups. Indira Turney will utilize data from a multigenerational study to explore how age impacts racial/ethnic differences in cognitive function. Underlying brain mechanisms of racial/ethnic differences in cognitive outcomes are also not well defined. Sara Godina will present a systematic review of racial/ethnic differences in structural markers of brain aging and neuropathology. Second, three papers will explore how various risk factors may explain the racial/ethnic disparities in cognitive outcomes. Melissa Lamar will demonstrate the differential associations of various blood pressure indicators with cognitive change among black older adults. B. Gwen Windham will present data from two studies that illustrate differential effects of common risk factors by race and region, highlighting inherent difficulties in race-place disparity research. Finally, Laura Zahodne will present results on how psychosocial factors, beyond socioeconomic status, contribute to racial/ethnic disparities in cognitive function. Jen Manly will lead a discussion on the implications of these results for the future of dementia prevention efforts for an increasingly diverse older US population.


Using two studies, we examined the late life prevalence and health consequences of discrete positive emotions posited to motivate rest and recovery  or pursuit of novelty and stimulation (excitement). Study 1 assessed the salience of these discrete emotions in older adults  relative to younger adults  over a one-week period. Multilevel models showed that older (vs. younger) adults reported higher calmness and lower excitement. Study 2 examined the longitudinal health consequences of calmness and excitement in old age , as moderated by perceived control. Multilevel growth models showed that calmness, but not excitement, buffered against 10-year declines in psychological well-being  and physical health  for older adults with low perceived control. Results suggest that positive emotions with disparate motivational functions become more  or less (excitement) salient and have diverging implications for health in old age.


Indices quantifying allostatic load (AL) and biological aging (BA) have received widespread use in epidemiological and health science literature. However, little attention has been paid to the conceptual and quantitative overlap between these indicators. By reviewing literature utilizing measures of AL and BA, we highlight differences with respect to biological markers employed and approach toward scale construction. Further, we outline opportunities where AL indices might be improved by adopting analytical features of BA measures. We demonstrate the utility of this approach using data from The MIDUS National Survey, constructing three indices of allostatic load: one standard approach modeled after Gruenewald et al, 2012, and two alternative formulations informed by BA procedures. The performance of AL indices are juxtaposed against two commonly employed indices of biological aging: Klemera-Doubal Method Biological Age and Homeostatic Dysregulation. All measures were significantly associated with chronological age. Alternative AL formulations were more strongly associated with biological aging measures than with the standard approach. MIDUS participants with increased allostatic load and older biological ages performed worse on tests of physical, cognitive, perceptual, and subjective functioning. Further, MIDUS participants with history of childhood-trauma and mental-health problems were measured as having increased AL and BA. Alternative AL formulations tended to have effect-sizes equivalent to or larger than those observed for BA measures. In conclusion, indices of allostatic load and biological age approximate similar processes when constructed with comparable biomarkers and rigor, in line with their conceptual overlap as proxies of cumulative wear and tear.


Background: Hypoglossal nerve stimulators (HNS) are an increasingly popular form of upper airway stimulation for obstructive sleep apnea (OSA) in adults who are unable to tolerate positive pressure treatment. However, HNS use is currently limited in the pediatric population. Case presentation: We present a case series detailing the anesthetic management of three pediatric trisomy 21 patients receiving HNS for refractory obstructive sleep apnea. The patients tolerated the procedure well and experienced no complications. The average obstructive apnea–hypopnea index (AHI) change was 87.4% with the HNS. Conclusions: Proper anxiolysis, safe and controlled induction, multimodal analgesia, and minimization of post-operative respiratory compromise are all necessary to ensure anesthetic and surgical success. After a tailored anesthetic regimen, proper device placement and close follow-up, our patients had a marked improvement in obstructive symptoms. Patients with trisomy 21 are predisposed to an increased risk of obstructive sleep apnea (OSA) at baseline with as many as 70% meeting criteria ,4. PersiThe HNS  is one of several implantable devices that aims to improve upper airway obstruction . The proA previous case series of twenty pediatric trisomy 21 syndrome patients receiving HNS has been published examining post-operative efficacy and safety . HoweverWe present the anesthetic management of the first three patients receiving an HNS at our institution. This manuscript adheres to the applicable EQUATOR guideline. Three patients, two female and one male, underwent hypoglossal nerve stimulator placement from 2017–2019 at Egleston Children’s Hospital of Children’s Healthcare of Atlanta as part of trial NCT02344108, “A Pilot Study to Evaluate the HNS in Adolescents with Down Syndrome and OSA.” Currently, HNS use in pediatric populations is still investigational under the Federal Drug Administration. All legal guardians for the subjects gave their informed consent for inclusion prior to participation in this case series.Baseline demographic characteristics are presented in All patients were diagnosed with severe refractory OSA despite previous surgery and non-invasive positive pressure ventilation (NIPPV). The previous surgeries included tonsillectomy and adenoidectomy (two patients) as well as lingual tonsillectomy with turbinate reduction and adenoidectomy (one patient). Despite surgical intervention, all patients then required NIPPV therapies including continuous positive airway pressure (CPAP) in two patients and bi-level positive airway pressure (BiPAP) in one patient. All patients failed NIPPV due to poor compliance, primarily caused by inability to tolerate the CPAP or BiPAP device. Each patient underwent a drug induced sleep endoscopy prior to HNS to characterize their residual OSA. Two patients received premedication with oral midazolam for pre-operative anxiety See . One patThe average case length was 244 min (range 227–260 min). Intra-operative courses were overall uneventful. Glycopyrrolate was used for secretions in two patients. One patient received bolus doses of 0.32 mcg/kg epinephrine and 0.08 mg/kg ephedrine for transient bradycardia. Multimodal analgesia was used in all patients  and all All patients were extubated “deep” during stage 3 of anesthesia, transferred to the post-anesthesia care unit (PACU), and placed on blow-by oxygen supplementation. One patient required post-operative oral airway placement, and one patient was placed on his home NIPPV. One patient required post-operative fentanyl and dexmedetomidine for residual pain in PACU. There was no reported post-operative nausea or vomiting. All patients were transferred to the floor for post-operative observation. No anesthetic complications were noted on follow-up. There were no reported complications to the Federal Drug Administration as no serious adverse events occurred at our institution. On follow-up PSG, all patients had notable improvement see . The aveThis case series specifically addresses the anesthetic management of HNS implants in pediatric trisomy 21 patients with refractory OSA. The patients tolerated the procedure well despite their pre-existing conditions, refractory OSA, and relatively prolonged case time. The unique nature of anesthetic management for HNS placement is in the balance between addressing the high-risk patient and operative factors with minimizing respiratory depression and adequately controlling pain. While the majority of our recommendations follow known anesthesia tenants for the care of trisomy 21 patients with OSA, we feel like our recommendations vary in three major ways: the use of premedication, inhalational induction, and deep extubation.Providing appropriate anxiolysis for parental separation in this patient population is essential. To balance preexisting OSA with the need for preoperative anxiolysis, we found judicious midazolam premedication beneficial in certain patients. Parental presence inductions or other sedative premedications are reasonable alternatives. However, caution should be exercised when administering any sedative medication to this patient population due to theoretical concern of airway obstruction. When sedative premedication is used, either continuous pulse oximetry or direct observation by the anesthesia team is recommended. Inhalational inductions are common in pediatric anesthesia in the United States and are to be used with caution in patients with a high risk of airway obstruction. Airway obstruction during stage 2 of an inhalational induction can limit oxygenation and ventilation, especially in a patient with known OSA. However, patients with trisomy 21 may benefit from an inhalational induction as it avoids awake intravenous line placement, anxiety, and fear of medical procedures. Our patient population had minimal obstruction with inhalational induction despite their refractory OSA. We believe that a smooth and controlled inhalational induction is a safe alternative in these patients. Certain equipment should be immediately available including nasopharyngeal and oropharyngeal devices, CPAP capabilities, intubating materials, and intramuscular doses of emergency medications including paralytic.The intra-operative components attempt to mitigate patient and surgical factors to optimize postoperative patient comfort and safety. We found that the use of primarily short-acting opioids such as fentanyl, multimodal pain control with dexmedetomidine and ketorolac, as well as local anesthetic injected by the surgeon at an insertion site provide satisfactory pain control while avoiding respiratory depression. Other key factors we have recognized include utilizing short-acting inhaled anesthetics such as sevoflurane to ensure timely emergence after deep extubation. We believe that low-dose dexamethasone can decrease the risk of postoperative tongue edema while also synergistically working with ondansetron to prevent post-operative nausea and vomiting, which has the potential to result in subsequent lead dislodgement . Other specific anesthetic considerations include placement of monitors and lines opposite of the operative side to avoid complications with use and secure endotracheal tube taping as the bed is turned 180 degrees. Neuromuscular blocking agents are avoided and bite block placed due to intra-operative nerve monitoring. Eye lubrication and careful pressure point padding is required given the case length. Given that sensing lead placement may be complicated by violation of the pleural space, nitrous oxide should be avoided once induction is complete.Despite the risk of postoperative airway obstruction, operative factors make extubation under a deep plane of anesthesia preferable. The coughing and bucking associated with awake extubation has the potential to cause significant impairment such as a post-operative airway hematoma or HNS lead dislodgement. While no surgical complications occurred in our group, a previous case series on HNS cite a surgical complication risk up to 10% [None of the patients experienced anesthetic complications despite their refractory OSA. There were no airway difficulties or significant post-operative respiratory depression that was not able to be managed with supplementary oxygen or home NIPPV. One patient experienced transient bradycardia without hypotension that was not associated with inhalational induction. While bradycardia is common in trisomy 21 patients during inhalational induction, this bradycardia was not thought to be related due its timing in the maintenance phase of anesthesia . The occPatient selection is an important consideration for success of this procedure. Appropriate patients should have high functional capacity with responsible and involved caretakers. As the device requires on/off capabilities, patients should be monitored during use of the device. Close follow-up immediately after implantation can identify early problems and maximize successful use. Our patients had excellent response to the HNS placement with an improvement in the obstructive AHI, meeting or exceeding previously reported percentages ,13.Pediatric trisomy 21 patients with refractory sleep apnea who present for HNS are a growing population ,13. Prop


Probabilistic Programming offers a concise way to represent stochastic models and perform automated statistical inference. However, many real-world models have discrete or hybrid discrete-continuous distributions, for which existing tools may suffer non-trivial limitations. Inference and parameter estimation can be exceedingly slow for these models because many inference algorithms compute results faster (or exclusively) when the distributions being inferred are continuous. To address this discrepancy, this paper presents Leios. Leios is the first approach for systematically approximating arbitrary probabilistic programs that have discrete, or hybrid discrete-continuous random variables. The approximate programs have all their variables fully continualized. We show that once we have the fully continuous approximate program, we can perform inference and parameter estimation faster by exploiting the existing support that many languages offer for continuous distributions. Furthermore, we show that the estimates obtained when performing inference and parameter estimation on the continuous approximation are still comparably close to both the true parameter values and the estimates obtained when performing inference on the original model.


Orofacial pain comprises multiple pain conditions that affect oral, head, face, and neck area. Such pain can be divided into different types based on its origin, including neuropathic, musculoskeletal, neurovascular, psychogenic, and idiopathic pain. Patients with orofacial pain often show sex differences with high prevalence in women. However, mechanisms underlying orofacial pain conditions and their sexual dimorphism remain elusive. With obvious differences in anatomical structures, gonadal hormones, and immune responses between males and females, it is proposed that these factors contribute to sexual dimorphism in orofacial pain. In the Special Research Topic entitled “Mechanisms of Orofacial Pain and Sex Differences,” we collected six relevant articles. These studies provide new insights into understanding orofacial pain and may aid target identification for future development of sex-specific therapies for orofacial pain.Bereiter et al.)  investigated the effects of ovarian hormones progesterone and allopregnanolone on estrogen-exacerbated nociception in TMJ inflammation model. Using a complete Freund's adjuvant-induced TMJ inflammation model, they observed that ovariectomized female rats show reduced nociceptive behavior in the TMJ inflammation model and daily administration with estradiol benzoate causes recurrence of the nociception in the TMJ, which is rapidly attenuated by the treatment with progesterone or allopregnanolone. This study suggests that supplying progesterone or its metabolite allopregnanolone when gonadal hormone levels get lower may be an effective approach to treating estrogen-evoked inflammatory TMJ pain. It has been demonstrated that estrogen plays a critical role in the pathogenesis of TMD pain. Besides ovarian sources, estrogen can also be synthesized in brain neurons. Interestingly, acute stimulation of nociceptors in the TMJ enhances estradiol secretion in the trigeminal subnucleus caudalis in a sex-dependent manner . In a varicella zoster virus infection-induced postherpetic trigeminal neuropathic pain model, aromatase-derived estradiol attenuates such orofacial nociception by interacting with estrogen receptors to increase γ-aminobutyric acid-mediated neuronal inhibition in the thalamus . In addition, pituitary hormones can regulate nociceptive transmission in different orofacial pain conditions and may contribute to sex-dependent mechanisms of orofacial pain by intermodulation with gonadal hormones .Temporomandibular disorders (TMDs) are associated with chronic orofacial pain, which includes myofascial and/or Temporomandibular Joint (TMJ) pain. Women report TMD pain around three times more than men. Previous studies have demonstrated sex differences and sex hormonal effects in peripheral and central mechanisms of orofacial pain .In a masseter muscle tendon ligation-induced myogenic orofacial pain model, it has been reported . In an immune-competent oral cancer mouse model, neutrophil-mediated endogenous analgesia occurs only in male mice , suggesting that this immune cell-mediated endogenous analgesia for treating oral cancer pain is sex-specific.Additionally, in an oral cancer patient cohort, sex differences in prevalence and severity of oral cancer pain have been identified (In conclusion, giving that there are sex differences in the underlying mechanisms of orofacial pain, we need to consider outcome measurements for each sex in future animal studies and clinical investigations of such pain conditions. Further understanding of sexual dimorphism in orofacial pain will help us develop sex-selective pain therapies and improve pain management for patients with chronic orofacial pain.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Previous research has shown that despite experiencing more negative life events, older adults maintain relatively high levels of well-being compared to their younger counterparts. This effect appears to be at least partially mediated by trait mindfulness in older adults . The current study expanded into an investigation as to how trait mindfulness might intervene on the relationship between age and other well-being indicators: anxiety and depressive symptomology. Participants included 30 older adults (aged 60-83) and 41 young adults (aged 18-35). Trait mindfulness was examined using the Mindful Attention Awareness Scale (MAAS), while depressive symptoms and trait anxiety were measured using the Center for Epidemiological Studies Depression Scale (CES-D) and the State-Trait Anxiety Inventory (STAI), respectively. Two separate mediated multiple regression models were conducted using Hayes’ PROCESS Macro in SPSS. Trait mindfulness exhibited a significant indirect effect on the relationship between age and depressive symptoms , which was also seen for the relationship between age and trait anxiety . Older age predicted higher trait mindfulness, which in turn predicted diminished self-reported anxiety and depressive symptomology. Controlling for mindfulness in these models reduced the direct effect of age on depression and anxiety to non-significance. These findings imply that the relationship between age and trait mindfulness can be extended to alternative markers of well-being.


Social ecological models of health identify intrapersonal, interpersonal, institutional, community, and policy-level contexts as social factors influencing individual and population health outcomes. However how institutions such as Area Agencies on Aging (AAA) shape rural older adults’ social networks and influence health is little explored. This research examines institutional influences of social networks for rural older adults, particularly the social connections resulting from their AAA services and programs. AAAs are local social service organizations that coordinate home- and community-based supports. Our 2020 case study of a rural AAA in upstate New York involved in-depth semi-structured interviews with AAA staff, volunteers and participants included key themes related to older adults’ social networks, social wellbeing, and physical and mental health. Our findings have both theoretical implications for rural community social structure as experienced by older adults, and practical implications to build AAA’s capacity to address social isolation for rural older adults. Part of a symposium sponsored by the Rural Aging Interest Group.


Because prescribing practices in long-term care settings may reflect regional influences, we examined how potentially inappropriate antipsychotic and antianxiety medication prescribing in assisted living (AL) compared to prescribing in nursing homes (NHs) based on their proximity, using generalized linear models adjusting for facility characteristics and state fixed effects. Data were derived from a seven state sample of AL communities and data for the same seven states drawn from publicly available data reported on the Nursing Home Compare website. In adjusted analyses, AL rates of antipsychotic use were not associated with the rates in the nearest or farthest NHs. However, AL communities that were affiliated with a NH had lower rates of potentially inappropriate antipsychotic use . In a separate model, antianxiety medication prescribing rates in AL were significantly associated with neighboring NHs’ rates of prescribing . Findings suggest efforts to change prescribing in NHs may influence prescribing in AL.


The COVID-19 pandemic and the subsequent lockdown brought about an exogenous and unparalleled stock market crash. The crisis thus provides a unique opportunity to test theories of environmental and social (ES) policies. This paper shows that stocks with higher ES ratings have significantly higher returns, lower return volatility, and higher operating profit margins during the first quarter of 2020. ES firms with higher advertising expenditures experience higher stock returns, and stocks held by more ES-oriented investors experience less return volatility during the crash. This paper highlights the importance of customer and investor loyalty to the resiliency of ES stocks.


Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of trauma by measuring TL in both CSA-exposed and non-exposed mothers and their children. TL was measured in a subset of participants and their children from a prospective-longitudinal cohort study of sexually abused females and a demographically matched comparison group. Linear regression models were used to test for associations between CSA-exposure and age-adjusted TL in females . Multilevel linear models were used to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children (N=124 children mean age 10.5 years across 61 mothers). CSA-exposure was not associated with TL in females. Replicating previous work in this area, maternal TL and sex were significant predictors of child TL in all models tested. Longer maternal TL predicted longer TL in children, and female children had longer TL than male children. Maternal-CSA exposure did not predict TL in children. This finding is in line with some previous results on CSA and TL measured in adulthood. Previous significant results associating child maltreatment with shorter TL in adulthood may be capturing a population of individuals exposed to either multiple types of maltreatment or maltreatment in childhood with concurrent TL measurements.


Measles is a highly contagious respiratory disease; both locally acquired and travel-associated cases continue to occur across the United States  after the exposure (The patient recovered and was discharged home from the hospital on April 27. None of his contacts developed measles, and no additional cases were identified through heightened surveillance, which included monitoring ED syndromic surveillance data in ESSENCE-FLThe Advisory Committee on Immunization Practices recommends that adults without documentation of measles immunity who are traveling internationally receive 2 documented doses of measles, mumps, and rubella virus vaccine (


Protamine sulfate is a common reversal agent of systemic heparinization used during procedures. While the exact epidemiology of adverse events is unknown, prior allergic response to protamine-containing compounds or concomitant use of neutral protamine Hagedorn (NPH) insulin is associated with an increased risk of tachyarrhythmias and bradyarrhythmias. We present a case of a 68-year-old woman with no prior history of protamine sulfate intolerance that suffered bradycardic arrest following protamine infusion.Healthcare providers should recognize the potential for life-threatening tachyarrhythmias and bradyarrhythmias following protamine reversal, especially in diabetic patients at risk for autonomic dysfunction; medication and allergy review are encouraged prior to heparin reversal, especially in diabetic patients. Protamine sulfate is a cationic polypeptide that binds to negatively charged unfractionated heparin and can be used to decrease the risk of bleeding during procedures in patients with systemic heparinization . Though A 68-year-old female with a past medical history of hypertension, peripheral artery disease, and type 2 diabetes complicated by peripheral neuropathy underwent a peripheral angiographic intervention on an occluded left femoral arterial stent, after which she received 20 mg of protamine. During the postoperative period, she experienced bradycardia and hypotension progressing to cardiac arrest. Cardiac monitoring at the time indicated no ventricular arrhythmias. Advanced cardiac life support (ACLS) was initiated and the patient received three rounds of epinephrine prior to transport to the emergency department (ED).In the ED, initial evaluation demonstrated agonal cardiac activity on cardiac ultrasound. The patient received three more rounds of epinephrine, two amps of bicarbonate, and one gram of calcium chloride. The initial cardiac monitoring demonstrated pulseless electrical activity, which progressed to ventricular fibrillation. Defibrillation was performed, resulting in the return of spontaneous circulation (ROSC).The patient was admitted to the medical intensive care unit. She was determined to be neurologically intact and targeted temperature management was not initiated. Medical history was notable for insulin NPH use. She had no prior allergic reaction to NPH, exposure to protamine sulfate, or history of food allergies.Labs showed a rise and fall in troponin I with a peak value of 6.21 mcg/L (reference range ≤0.030 mcg/L). Initial electrocardiogram (ECG) after ROSC showed diffuse ST depression suggestive of subendocardial ischemia  and potential medication reactions. Healthcare providers should recognize the potential for bradyarrhythmias and tachyarrhythmias before protamine administration, particularly in diabetic patients.


Coronary involvement is rare but can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons.A 71-year-old woman was referred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery occlusion. Contrast-enhanced computed tomography revealed severe left coronary main trunk stenosis, right coronary artery occlusion, and porcelain aorta. Ultrasonic echocardiogram showed severe aortic regurgitation. We performed emergent coronary artery bypass grafting, aortic valve replacement and ascending aorta replacement under hypothermic circulatory arrest.The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis. Unilateral cerebral perfusion from the right subclavian artery enabled good visualization and sufficient time to perform distal anastomosis. Coronary involvement is rarebit can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons. We present a 71-year-old woman with left main coronary trunk stenosis, occluded right coronary artery, left subclavian artery occlusion, severe aortic valve regurgitation and porcelain aorta with aortitis.A 71-year-old woman was transferred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery (LSCA) occlusion. Her past medical history included hypertension and dyslipidemia. Twelve-lead electrocardiogram showed marked ST-segment depression in the precordial and inferior leads. Contrast-enhanced cardiac computed tomography (CT) revealed severe left coronary main trunk (LMT) stenosis, which had not been detected 9 months previously, right coronary artery (RCA) occlusion which had occurred previously Fig. . These fAdditional file 1.Takayasu’s arteritis (TA) is a chronic, granulomatous vasculitis that causes stenosis, occlusion and ectasia of the aorta and its branches. Although coronary involvement is rare, it can be critical. Coronary ostial stenosis (COS) with normal distal part of the artery is a specific feature of TA.In our case, the patient had not been in the active phase of TA for years. LMT stenosis progressively worsened over 9 months. It is not clear whether LMT stenosis in our patient was associated with TA, because stenosis occurred in the distal part of LMT, and not at the coronary ostium. In view of her diagnosis of dyslipidemia, this might have caused LMT stenosis over a short time period.We had to perform emergent CABG because jeopardized left main coronary artery supplying the chronically occluded RCA caused global ischemia of the entire heart. Although percutaneous coronary intervention (PCI) for LMT stenosis can relieve ischemia quickly, it can be more dangerous compared with CABG because the RCA is already occluded and receives blood supply from the left coronary artery. Furthermore, PCI is not able to solve AR. Although the internal thoracic artery (ITA) is commonly used for CABG, it might not be adequate in patients with Takayasu’s arteritis because stenosis often occurs in the subclavian artery. However, the ITAs have been used in young patients in whom the subclavian arteries did not have stenosis , 2. AlthAnother issue is calcified aorta, which is always a concern when surgeons try to clamp it. Transcatheter aortic valve insertion (TAVI) + off-pump CABG is the procedure of choice for patients with aortic valve stenosis, porcelain aorta and coronary ostial stenosis . HoweverAnother issue is how to acquire good visualization of the proximal arch during hypothermic circulatory arrest. The proximal aortic arch was severely calcified, and its diameter was normal. Usual elasticity of the aorta was lost. It seemed difficult to obtain good visualization and enough time to apply the abovementioned technique using usual antegrade selective cerebral perfusion (ASCP) in which three perfusion cannulas are inserted into the innominate artery, left common carotid artery and LSCA, respectively. We considered that three cannulas in the calcified proximal aortic arch with normal size would prevent us from performing any maneuvers. Although controversy exists whether UCP can provide sufficient blood supply to both the left and right hemispheres compared to usual ASCP, we believe it is acceptable in emergent surgery . In factAlthough the patient did not have active phase TA, LMT stenosis progressively worsened over a short period. The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis and avoiding bleeding from the suture holes in the porcelain aorta. UCP from the RAXA provided good visualization and sufficient time to perform distal anastomosis.


Nearly 48 million individuals worldwide have a neurocognitive disorder with projections estimating that as many as 75 million may be afflicted by 2050.Although approximations vary, a substantial portion of those affected live in the community alone, accounting for up to one-third of cases. The true proportion of persons with neurocognitive disorders living alone in the community may be underestimated as dementias are often underdiagnosed and underreported. As the baby boom generation ages and trends towards nuclear families, geographic dispersion of families, and fewer children continue, the number of live-alone persons with neurocognitive impairment is anticipated to rise; creating increased potential for difficult, ambiguous circumstances involving the rights and needs of this population. Despite these trends, available information about this population remains limited. This symposium represents papers from social gerontology, bioethics, and policy; offering unique, but complimentary perspectives on live-alone persons with neurocognitive impairment. The four papers explore 1) how non-traditional & absent support networks impact one’s ability to live alone with dementia [NIA funded], 2) social isolation and vulnerabilities of living alone with dementia [NIA-funded], 3) how bioethics can inform gerontological dementia research [NIA bioethics supplement], and 4) exploration of how law enforcement and adult protective services policies influence the precarity of living alone with dementia. Together, these papers illuminate the importance of actively including live-alone persons with dementia into research and assessing this overlooked vulnerable population from multiple research perspectives .


A substantial number of studies have documented paradoxical findings when examining race differences in later life psychological well-being. Despite experiencing significant structural disadvantages, Black older adults have been found to report significantly higher overall life satisfaction and lower depressive symptoms than White adults. This study relies on double consciousness framework which allows us to understand why satisfaction with material conditions  among Black older adults could differ from their evaluation of overall well-being . Based on a survey of successful aging (n=409 aged 60 years or older) conducted by the Elderly Care Research Center (ECRC) in Cleveland, Ohio, we examined race differences in coping resources, and their role in shaping overall life satisfaction, domain-specific life satisfaction, and depressive symptoms. Findings show that Blacks on average have a higher likelihood of experiencing recent negative life events than their White counterparts. Despite adverse life circumstances, Blacks older adults expressed significantly higher overall life satisfaction than Whites. They, however, reported significantly lower domain-specific life satisfaction than their White counterparts. The differences in depressive symptoms between Black and White older adults was not statistically significant. The race differences in overall life satisfaction was explained by religiosity, religious coping, and social support. Education, income, and adverse life events were found to contribute to such differences in domain-specific life satisfaction. Our findings underscore the need to consider the unique role of racialized life course circumstances and coping resources in shaping disparities in later life psychological well-being.


Older adults make up the majority of the U.S. patient population and age differences in information avoidance have potential implications for their ability to participate in informed medical decision making. Meta-analytic evidence suggests that older adults seek less information before making a decision than younger adults do . However, age differences in explicit information avoidance have yet to be quantified. We hypothesized that older adults would avoid decision-relevant information more strongly than younger adults do. We also examined the self-reported reasons for information avoidance and hypothesized that older adults would express more concern about unwanted information influencing their affect  and decision preferences , both of which are known predictors of information avoidance . To test these assumptions, we conducted a pre-registered online study involving three different health-related decision scenarios. For each scenario, an adult lifespan sample  chose to either receive or avoid information. Responses were highly correlated across scenarios and results were pooled into a single avoidance measure. Analyses indicated that concerns about consequences for decision preferences positively predicted decision avoidance (p<.001), whereas concerns about consequences for affect did not (p=.079). Contrary to predictions, older age was not significantly associated with information avoidance (p=.827). Further, self-reported concerns about the influence of unwanted information on affect and decision preferences were negatively associated with age (ps<.001). This suggests that interventions to foster pre-decisional information seeking should be tailored to the target age group.


The recent opioid crisis is one of the rising challenges in the history of modern health care. New and effective treatment modalities with less adverse effects to alleviate and manage this modern epidemic are critically needed. The FDA has recently approved two non-invasive electrical nerve stimulators for the adjunct treatment of symptoms of acute opioid withdrawal. These devices, placed behind the ear, stimulate certain cranial nerves with auricular projections. This neural stimulation reportedly generates a prompt effect in terms of alleviation of withdrawal symptoms resulting from acute discontinuation of opioid use. Current experimental evidence indicates that this type of non-invasive neural stimulation has excellent potential to supplement medication assisted treatment in opioid detoxification with lower side effects and increased adherence to treatment. Here, we review current findings supporting the use of non-invasive neural stimulation in detoxification from opioid use. We briefly outline the neurophysiology underlying this approach of auricular electrical neural stimulation and its role in enhancing medication assisted treatment in treating symptoms of opioid withdrawal. Considering the growing deleterious impact of addictive disorders on our society, further studies on this emerging treatment modality are warranted. Approximately 36 million people are affected with opioid use disorder globally , the distress in the first few days after abrupt discontinuation can be rather severe. Without adequate treatment, many patients are unable to complete opioid discontinuation  . This stimulation provides relief from symptoms associated with opioid withdrawal, including cravings, anxiety, agitation and depression. The device can be worn up to 5 days at a time, and company officials report that symptoms have eased within an hour of wearing the device.Relatively recently, in June 2018, an additional auricular stimulation device, the “Drug Relief” aural neurostimulator mobile health device, developed by DyAnsys, also received FDA 510(k) premarket approval for patients dealing with opioid addictions (Fig. Pain and emotional disturbances are common symptoms during opioid withdrawal. Of note, auricular neural stimulation had been used for chronic pain management with success in various health settings (e.g., reviewed in (Chen et al. Experimental evidence indicates that non-invasive device-generated auricular neural stimulation of certain cranial nerves, primarily vagus nerve, provides an innovative approach to alleviate opioid withdrawal symptoms. This approach may specifically help expedite the recovery phase during acute detoxification from opioids. This can ultimately reduce the need of supportive medications and can facilitate smooth transition from detoxification to commencing medication-assisted treatment in opioid dependent patients. This treatment modality has so far been associated with only minor local side effects at the device placement site. While this non-invasive modality appears to be an exciting new opportunity in alleviating the current opioid epidemic, more studies are clearly needed to further validate the potential of this intervention and support its use with the hope of helping our patients and their families.


Portal vein thrombosis (PVT) poses a unique challenge in liver transplant. The management of PVT differs according to the extent of thrombosis. Anastomosis of a donor portal vein to a varix is a viable option when an adequate size varix is identified on preoperative imaging or intraoperatively. Here, we describe our experience in two liver transplant cases with cavernous transformation of the portal vein where the donor portal vein was anastomosed to a varix using a donor iliac vein interposition graft. In 1985, Shaw and colleagues described successful liver transplantation in seven patients with severely reduced or absent portal flow, and since that time, portal vein thrombosis (PVT) has no longer been considered an absolute contraindication to liver transplantation . As fibrOur first patient was a 58-year-old male with primary biliary cirrhosis and nonalcoholic steatohepatitis. Portal flow was not visualized on preoperative Doppler ultrasound. Contrast enhanced CT demonstrated complete PVT with cavernous transformation  and clotOur second case was a 61-year-old male with cryptogenic cirrhosis and hepatocellular carcinoma. Preoperative imaging revealed cavernous transformation with numerous portal venous collaterals most prominent in the paraesophageal  and periIntraoperative portal vein thrombovenectomySMV jump graftingEstablishing renal-portal inflow from left renal vein and donor ileac vein conduitVarix-to-portal anastomoses with or without conduitPortacaval transpositionPortal vein thrombosis can range from mild partial nonocclusive thrombus to complete occlusion with cavernous transformation, and varied surgical techniques are required to handle each scenario . QualityIn all cases, we consider left renal vein ligation or ligation of other collateral vessels to enhance portal inflow. Preoperative IR-guided portal vein recanalization has been described , as has Physiologic portal inflow is associated with better 1-, 5-, and 10-year outcomes than any alternative described , and theIn summary, successful surgical management of PVT requires preoperative imaging, thoughtful planning, surgical creativity, and adherence to a practice-based algorithm for establishing portal inflow.


Providing interprofessional geriatric care via telehealth is a unique clinical skillset that differs from providing face-to-face care. The lack of clear guidance on telehealth best practices for providing care to older adults and their care partners has created a systems-based practice educational gap. For several years, GRECC Connect has provided interprofessional telehealth visits to older adults, frequently training interprofessional learners in the process. Using our interprofessional telehealth expertise, the GRECC Connect Education Workgroup created telehealth competencies for the delivery of care to older adults and care partners for interprofessional learners. Competencies incorporate key telehealth, interprofessional and geriatric domains, and were informed by diverse stakeholders within the Veterans Health Administration. During this symposium, comments will be solicited from attendees. Once finalized, these competencies will drive the development of robust curricula and evaluation measures aimed at training the next generation of interprofessional providers to expertly care for older adults via telehealth.


Changing age demographics are reshaping societies and challenging institutions of higher education to consider how they can respond to aging populations through new approaches to teaching, research, and community engagement. As well, institutions are facing a range of challenges as they look to respond to the contemporary needs of traditional-aged students. The pioneering Age-Friendly University (AFU) initiative, endorsed by GSA’s Academy for Gerontology in Higher Education (AGHE), offers a framework within which institutions can begin to address these issues through more age-friendly programs, practices, and partnerships. This symposium will feature AFU advocates discussing innovate ways in which older adults can serve as teaching allies and support the educational mission of higher education. Farah (Lasell University) will discuss how older adults can engage in diverse teaching and learning activities with examples as crime scenario developers in a forensics class, conversation partners in an international oral communication class, and professional interviewers in an internship skills class. Kaye (University of Maine) will discuss how older adults can serve as citizen scientists performing critical functions in participatory research and in community-based test-beds and co-design laboratories. Ermer (Montclair State University) will discuss how older adults can engage students in discourse as guest speakers and panel participants in classes across the curriculum. Manoogian (Western Oregon University) will describe the innovative ways that older adult students (for credit or audit) mentor and engage younger student peers in course activities as well as increase their own understanding of the aging process.


Liquid biopsy has emerged in the last ten years as an appealing noninvasive strategy to support early cancer diagnosis and follow-up interventions. However, conventional liquid biopsy strategies involving specified biomarkers have encountered unexpected inconsistencies stemming from the use of different analytical methodologies. Recent reports have repeatedly demonstrated that integrated detection of multiple liquid biopsy biomarkers can significantly improve diagnostic performance by eliminating the influence of intratumoral heterogeneity. Herein, we review the progress in the field of liquid biopsy and propose a novel integrated liquid biopsy framework consisting of three categories: elementary, intermediate, and advanced integration. We also summarize the merits of the integration strategy and propose a roadmap toward refining cancer diagnosis, metastasis surveillance, and prognostication. Bodily fluids, such as blood, urine, cerebrospinal fluid, and saliva, contain numerous biomarkers corresponding to patient-specific pathological information. From the perspective of biodetection, any biomarkers that are highly associated with tumor growth and metastasis, including circulating proteins (CPs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated blood platelets (TEPs), can be indicators of carcinomas. Liquid biopsy has been recognized as one of the most promising strategies for conquering cancers owing to its unparalleled advantages over classical solid biopsy in improving patient compliance, partially due to its noninvasive sample collection and reduced potential for surgical complications  e.g., protein-protein, RNA-RNA or DNA-DNA combinations e.g., protein-DNA combinations This review will intensively discuss the hurdles facing liquid biopsy prior to its clinical application and propose potential solutions. Here, we propose a novel analytical framework, termed “integrated liquid biopsy”, that could be a useful toolkit bridging conventional liquid biopsy and clinical requirements. “Integrated liquid biopsy” is defined as integrating multiple liquid biopsy biomarkers or detection methods for improved analytical sensitivity and specificity to refine cancer management. Since a single biomarker is inefficient in accurately identifying most cancers, integrated liquid biopsy using multiple markers might be a promising method to facilitate early detection and treatment of cancer. According to the complexity of the combined data types, we categorize integrated liquid biopsy into the following three groups: 1) Elementary integration refers to the combination of biomarkers or methods of the same type,e.g., CA19-9, CEA, AFP, and prostate-specific antigen (PSA)) achieved prevalence due to its convenience and low cost + exosomes containing diverse RNA and proteins may distinguish healthy subjects from patients with pancreatic cancer Liquid biopsies have been regarded as robust tools for routinely screening and identifying tumors before symptoms appear. Historically, the detection of a single CP  mutations and CA19-9 provided an improved sensitivity of 64%, compared to 30% for KRAS alone Regarding intermediate integration, CP-ctDNA integration is particularly attractive because ctDNA indicates specific genetic alterations and because the relatively high concentrations of CPs compensate for the drawback of low ctDNA abundance. Joshua et al. reported that the conjunction of Despite the popularity of liquid biopsy in a clinical setting, the conventional detection of a single biomarker has encountered numerous obstacles in assessing samples with tissue or organ heterogeneity. These reported discrepancies among different detection approaches primarily originate from the small amounts and easy degradability of these biomarkers, features that severely compromise their value in indicating abnormal clonal cell proliferation. The latest studies have revealed that a CP-ctDNA integration strategy significantly improves the sensitivity of earlier cancer detection without substantially decreasing specificity. Additionally, integrated assays of CPs and genetic alterations further localize the original organs of these cancers, which could greatly benefit further therapy. Meanwhile, the CP-ctDNA integration concept could be expanded to other liquid biomarkers, such as metabolites, mRNA transcripts, miRNAs, methylated DNA sequences, or markers in EVs to increase the efficiency of early cancer detection.N-ras and phosphatidylinositol 3-kinase mutations in ctDNA can predict drug resistance against monoclonal antibodies targeting EGFR, potential negative errors have been observed due to biological heterogeneity Surviving cancer cells tend to develop drug resistance due to mutation and evolutionary selection when different therapeutic means are employed on heterogenic tissues Figure  33. TherEGFR mutation detection in plasma, and significant improvement was observed in NSCLC patients without distant metastasis EGFR T790M detection, overcoming the limitation of low T790M abundance in the blood (58% sensitivity and 80% specificity using an FDA-approved cobas® test) Integrated liquid biopsy might be an effective means of eliminating such discrepancies and probing unknown mutations. RNA-seq is a typical form of detection included in elementary integration, and a recent ctDNA profiling method known as cancer personal profiling by deep sequencing (CAPP-seq) found a high frequency of inter- and intrapatient heterogeneity in resistance mechanisms after initial EGFR tyrosine kinase inhibitor therapy Dozens of studies employing integrated liquid biopsy have demonstrated its effectiveness in improving the sensitivity of cancer diagnosis, suggesting that this strategy is ideal for cancer management. Therefore, it is highly desirable to elucidate the biological origins and mutual interactions of different biomarkers in anticipation of clinical applications.CPs are secreted from diverse human cells, including immune cells and tumor-associated cells, and were the first such biomarkers to be exploited and commercialized. The demonstrated high specificity of CPs in reflecting tumor-associated characteristics makes them attractive for cancer surveillance. In contrast to CPs, ctDNA fragments are principally released from apoptotic or necrotic cells. Given the short circulating time of ctDNA (ranging from 16 min to 2.5 h), the dynamic and continuous monitoring of ctDNA fragments plays a paramount role in cancer prediction in vitro, it is necessary to use an indirect strategy involving an enrichment step prior to detection e EVs, comprising exosomes, microvesicles, and apoptotic bodies, are free-floating bodies enwrapped by lipid rafts and contain tumor-specific signatures of nucleic acids and proteins. Briefly, exosomes emerge by budding in multivesicular bodies and are released into the plasma by fusion of multivesicular bodies with the cell membrane, whereas microvesicles and apoptotic bodies are leaked from dying cells due to external stimulation. Notably, selective accumulation of certain functional mRNA, microRNA, and protein species in microvesicles can occur. In contrast to normal cell sprouting, CTCs are spontaneously released from primary tumors to the peripheral blood circulation, constituting seeds for subsequent metastases in distant organs epithelial cell adhesion molecule (EpCAM), human EGFR2, PSA and oncolytic viruses In vivo CTC enrichment using either an inserted metal wire or magnetic separation in vitro integration of biomimicry and nanotechnology have remarkably improved capture efficiency Integrating methods with distinctive principles to strengthen integrated liquid biopsy is likely the most reliable strategy for ideal cancer management. The quantification and characterization of CTCs/EVs represent major technological challenges in liquid biopsy due to the extremely low concentrations of these targets. All the methods developed to quantify CTCs and EVs in the peripheral blood could be categorized as biological or physical. Biological methods are typically based on antigen-antibody or ligand binding; these methods are involved in typical tests for + CTCs, which reduces cell adhesion and promotes polarization and metastasis. Meanwhile, platelets immediately adhere and mechanically protect CTCs from anoikis or destruction by forming a cell fibrin-platelet aggregate surrounding CTCs Tumorigenesis, metastasis and tumor evolution are the typical forms of cancer development, and the above-noted biomarkers can reflect the accumulation of either genetic mutations or epigenetic modifications Figure . During in vitroin silico target prediction.In summary, any detection approach based on a single biomarker reflects limited information that may result in misleading predictions regarding tumor progression. Thus, integrating multiple biomarker approaches provides comprehensive information that may compensate for the drawbacks of single biomarkers in facilitating early cancer detection and intervention Table . MeanwhiKRAS mutant cells effectively drive cancer progression after the suppression of the MEK1 mutant population by panitumumab and trametinib Early and accurate cancer diagnosis is the key to reducing the economic burden of cancer. Classical tissue biopsy has arguably presented a heavy burden according to US Medicare analysis: as of 2017, the average cost of a solid biopsy for lung cancer is $8,869, and the total cost per patient will reach $37,745 for the 20% of needle biopsies that lead to follow-up complications. Compared with single liquid biopsy alone, integrated liquid biopsy provides improved cost-effectiveness in the following ways. First, integrated liquid biopsy is less expensive per marker than its counterpart. For instance, the current cost for single ctDNA mutant detection with digital PCR is approximately $300, while the cost for elementarily integrated detection of all ctDNA mutants with DNA sequencing is < $1,000 with Illumina Several fundamental questions need to be answered prior to effective integration under physiological and pathophysiological conditions: What is the relationship between the degree of ctDNA variations and the RNA/protein abundance of hundreds of functionally coherent gene sets? What are the differences between primary circulating biomarkers such as ctRNA or CP and secondary biomarkers such as RNA/protein analysis from EVs or CTCs? Will different cancer stages  and mesenchymal-to-epithelial transition (MET)) or tumor cell status (primary or circulating) significantly affect the spatial and temporal distributions of ctDNA or exoRNA? Understanding the gene regulatory networks of biomarker integration will lead to significant insights and has tremendous implications for cancer intervention and management. Therefore, for integration detection, the core purpose is to reflect the real developmental stage and increase therapy efficiency for cancer.How can users predict and confront the inconsistent results stemming from different biomarkers or detection methods in integrated detection? Considering the complexity of tumorigenesis, any single-marker-based diagnosis will have a risk of error, integrated detection may naturally increase the possibility of exposing these errors by presenting contradictory results, by which the error can be significantly reduced in further diagnosis.What types of integration could be optimal? Both elementary integration and intermediate integration can provide characteristic molecular profiles of cancers in the spatial scale. Advanced integration might provide integrated information in a higher dimension by combining these comprehensive evidences, including medical imaging, tissue diagnosis, and molecular profiling, to map the characteristics of a cancer in detail based on the complementarity of these results.How can we establish a risk prediction model using the acquired integrated data from a time series? Integration in the temporal domain will help us characterize the law of cancer progress or metastases. Therefore, combining the dynamic changes in various biomarkers with previous medical records would facilitate the prognosis analysis of cancers. It is highly plausible that this type of dynamic method focusing on the whole process, including patient diagnosis and treatment, will become the mainstream of prognostic analysis in the near future.KRAS mutation rate reached 94% in a pancreatic intraepithelial neoplasm population The feasibility of integrated liquid biopsy is largely guaranteed by the quality control and standardization of each detection method. In particular, the standardization of annotations resulting from liquid biopsy is challenging due to varied cohort compositions  and diverse environmental factors  when analyzing the same biomarker. For instance, noticeable discordance exists among different populations: the Integrated liquid biopsy produces data that are substantially more complicated than data from any single biomarker, requiring a canonical big data processing methodology. Deep learning has recently been introduced to assist with diagnostic and therapeutic decision making by reading patients' medical images Liquid biopsy has demonstrated unparalleled advantages over conventional tissue biopsy and medical images in terms of earlier cancer detection and better surveillance of cancer metastasis and prognosis. Different from conventional imaging approaches, which mainly reveal changes in tumor size, profiling the dynamic distribution of various tumor-associated molecular biomarkers may provide continuous genetic mutation information, which will reflect different cancer stages and provide improved guidance for clinical therapy. Furthermore, the rational integration of liquid biopsy, solid biopsy, and medical imaging would prevent discordance or disagreements caused by tumor heterogeneity or individualized analytical methodologies. This advantage would facilitate cancer prevention and early intervention.Integrated liquid biopsy covers both the integration of different detection methods and the combination of multiple biomarkers, including proteomics, genomic sequencing, and DNA methylation profiling, that could reveal mechanistic differences in the development of different cancers. During carcinogenesis, integrated biomarkers could provide an earlier diagnosis than any single biomarker alone. Furthermore, ctDNA could identify the position of the tumor by detecting DNA methylation in an accurate and noninvasive manner Socioeconomic factors should also be considered in the clinical implementation of the integrated liquid biopsy strategy. In the early stage, additional blood tests for enriching the database will carry relatively high costs. However, with the gradual growth of the database, we will benefit from the mathematical model as it provides increasingly accurate and specific guidance on cancer management.


Globally, conservation efforts have moved millions of people out of protected areas since the 1970s, yet quantitative studies on post-resettlement well-being remain a challenge due to poor documentation. Since 2008, the Indian forest department records demographic and financial details at the household level under standardized guidelines for resettlement. Here, we examine the food security of approximately 600 households’ post-resettlement from Kanha National Park (KNP) in central India between 2009 and 2014. We compare food security of resettled households with host community households with a total of 3519 household surveys, conducted over three seasons within one year. We measure food security using food consumption scores (FCSs), coping strategies index (CSI) and household hunger scale (HHS). Food insecurity is widespread in the landscape, with over 80% of households reporting poor or borderline FCSs year-round. Additionally, we recorded food insecurity increases in monsoon for all households regardless of resettlement status. Results indicate that resettled households are comparable to their host community neighbors in FCS and all households use mild coping strategies to combat food insecurity. While widespread, food insecurity in the KNP landscape is not acute with very few (<10) reports of severe hunger (as measured by the HHS). Almost all foods are market bought (>90%) and sometimes supplemented by gathering locally prevalent greens or from kitchen gardens (forest dependency for food was negligible). Accruing assets and diversifying incomes from non-labor avenues would alleviate food insecurity for all households. The patterns of market dependence and food security associated with diversified stable incomes around protected areas is in contrast with many studies but is likely to occur in similar human-dominated landscapes. Conservation-related resettlements trace back to the establishment of Yellowstone National Park in 1872 and spread rapidly with fortress management policies to conserve endangered species habitats. Globally recognized areas of high biodiversity are inhabited by more than a billion people and populations in these regions continue to grow at a rapid pace –5. In InUnderstanding the impacts of conservation-related resettlement on people requires meaningful measures of human well-being. Income based metrics of well-being are unidimensional and do not reflect livelihoods reliant on goods with little economic value (for example–wild foods or self-provisioning via non-economic landscape resources) , 25. MorIn India, the current resettlement policy is explicit in its goal to resettle people to expand and maintain critical tiger habitats within 50 protected areas (Tiger Reserves) with detailed resettlement records and standardized compensations . ResettlWe explore food security at resettled households compared to their neighbors at their new settlement locations across the Kanha National Park landscape to answer the following questions:Are resettled households moving into remote areas compared to all existing villages in the study site, specifically with respect to–road access, food markets and forest availability?Do resettled households have comparable Food Consumption Scores (FCSs) and Coping Strategy Index (CSI) measurements to their host community neighbors? , leopard (Panthera pardus), wild dog , sambar (Cervus unicolor), chital (Cervus axis), barasingha (Cervus duvaucelii) and gaur (Bos gaurus) . We. We51]. The FCS and CSI are weighted scores based on the food groups consumed and coping behaviors exhibited in the last seven days in the surveyed household respectively , 57. We We used propensity scoring and visual inspection (of the overlap between resettled households and host community households) for all measured variables to test balance in our study sample, especially to ensure that our sampled host community households provided a comparable baseline for surveyed resettled households . AdditioIn the KNP landscape, households buy foods from weekly markets and therefore restock each week for fresh vegetables, meats and staples. For availability of market items and their prices, we visually compared market checklists as most markets in the landscape have the same produce with similar prices . We alsoWe used Euclidean nearest neighbor distances to find distances between household locations and nearest road, border of protected area (KNP core), market and built up area. We used existing GIS layers of roads, protected area borders, built up area and our GPS locations of markets , 59. We tehsil—for all households) and origin village (only when modelling food access in resettled households) (http://www.r-project.org) and QGIS 2.10.0- Pisa . Data is available at (https://bit.ly/2GvxGid).To understand patterns and associations in our household level data we used cluster analyses (ClustVis PCA–see ), randomseholds) . We stanResettled households have predominantly moved into existing villages in similar proportions to host community human densities across the KNP landscape . HoweverHouseholds in the KNP landscape typically access the bulk of their foods (>90%) from weekly markets at their village or a neighboring village See . Thus, rtehsil during summer, resettled households  had higher mean FCSs compared to host community households  . However, across all surveyed households with acceptable FCSs, vegetables were not consumed every day and meats very occasionally.Resettled households reported similar Food Consumption Scores when compared to their host community neighbors across all three survey seasons . The yeaResettled households had higher CSIs in monsoon across two administrative units (Baihar and Panderia) and higher CSIs than host community households in winter in Baihar and in summer in Panderia . MoreoveWhile resettled households consume food groups in similar frequencies to host community households, we find that approximately 80% of all households have inadequate levels of food consumption (borderline or poor) . ResettlAll households predominantly access food through market purchases (>90%) supplemented by self-provisioning  year round . Only a Our results of modelling livelihood characteristics associated with resettled and host community households highlight that increasing asset index values were positively associated with FCSs year-round . PredomiApart from the above livelihood associations with FCSs, resettled households supplement market bought foods  with self-provisioned foods  while host community households engage in winter cropping to attain similar FCSs . Owning Our study contributes to the growing quantitative assessment of resettlement on human well-being measurements, tying together conservation and social goals , 65, 66.Our study finds widespread food insecurity for all households. However, the current state of food insecurity around KNP is not acute with very few reports of hunger and coping strategies associated with higher food access. Food insecurity is largely due to the economic inability to access high nutrient food groups (tehsil (administrative block) there were seasonally changing differences in resettled and host community household FCSs and CSIs but these require further study to understand the underlying mechanisms  while host community households predominantly rely on winter cropping to end up with similar FCSs . Our resThese differences aside, both resettled and host community households with increasing assets and diversified incomes showed positive associations with FCSs. Households with incomes from poultry and agriculture had comparable positive associations with FCSs as salaried jobs. We suggest that gains from poultry farming might be an avenue for on-the-ground interventions that aid alleviation of poverty as well as food insecurity , 73. We The key objective of our study was to assess post-resettlement food security of resettled compared to their host community households at the new settlement location in the KNP landscape. Our findings suggest that the current resettlement does not constrain resettled households and that they are comparable to host community households in terms of livelihood opportunities, physical food availability and food access. Approximately 20% of our surveyed households are within the KNP buffer. Households within the administrative buffer of KNP are more similar to households outside the KNP than those previously living within the KNP core in terms of economic activities, access to the road network in the KNP landscape and commercial livelihoods . The multiuse buffer around KNP is predominantly agricultural land with more than 260 existing villages. Resettled households join existing villages outside of KNP and comprise a minor proportion of the total village population .To increase overall wealth, an obvious but difficult application of our results would be to generate more opportunities for salaried jobs and make agricultural practices more profitable. Such an obvious result seems a moot point to discuss but we do so to ensure our results are not seen as a contrast of two separate livelihoods–resettled households with forest livelihoods separated from rural host community households with more wealth driven livelihoods. Our results confirm that the reality is one where rural livelihoods predominantly feature wealth accruement and market bought foods regardless of being resettled and host community households . Our stuOwning more cattle suggests that households have means to increase assets which are in turn associated with higher FCSs. Cattle are culturally important, most often as work animals and easily traded assets in times of distress. Cattle for dairy incomes are rare in the KNP landscape. Incomes from cattle might be occasional  or low (dairy farming practices). Similar findings about the complicated relationship between livelihoods and cattle owning have been found in Ghana . We alsoFood security for resettled households, and their host community neighbors, in the Kanha National Park landscape will be best achieved by integrating the poorer households into the economy with more opportunities, such as steady jobs and poultry farming, for higher incomes and seasonal stability. Managers for resettlement and rural development around KNP, and in other human-dominated conservation landscapes, might consider the importance of training for employment with steady incomes in future interventions. At the national policy level, the NTCA can use the methods from our study to explore links between livelihoods and social goals in resettlement from tiger reserves across India that vary ecologically, geographically and culturally. While this study concluded that steady incomes are highly relevant for food security in the KNP landscape, other landscapes around tiger reserves might indicate the need for access to forests or efforts to improve food availability.Our study focuses on a short time-frame after resettlement to look at immediate impacts on food security as a metric of human well-being. Longer studies or studies after a decade of resettlement might provide further insight into how compensations under the current guidelines allow resettled households to integrate into their new locations. Furthermore, studies that include metrics of well-being that are difficult to quantify are important to understand social impacts on people living around protected areas , 65. StuWe conclude that there is low level of food insecurity in the KNP landscape that is largely driven by low and unstable household incomes. Resettled households are comparable to their host community neighbors in food availability . We also found that resettled households are comparable to their host community neighbors in food security (FCSs and CSIs) and that households with higher food security had more assets as well as more income sources. Resettled households have more seasonal income sources and supplement foods locally (kitchen gardens) while their more established host community neighbors rely on winter cropping incomes to attain similar food security. Our results suggest that increased opportunities for diversifying non-labor incomes could be effective to alleviate food insecurity for both resettled and host community households in the KNP landscape. This result reinforces multiple studies that highlight livelihood diversification as a means for alleviating household food insecurity , 66. OurS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S6 File(PDF)Click here for additional data file.S7 File(PDF)Click here for additional data file.S8 File(PDF)Click here for additional data file.S9 File(PDF)Click here for additional data file.S10 File(PDF)Click here for additional data file.


Older adults with subjective memory complaints (SMCs) are at increased risk for episodic memory decline. Episodic memory decline is an important predictor of objective memory impairment (one of the earliest symptoms of Alzheimer’s disease) and an often-suggested criterion of successful memory aging. Therefore, it is important to explore the determinant factors that influence episodic memory in older adults with SMCs. Roy adaptation model and preliminary evidence suggest that older adults with SMCs undergo a coping and adaptation process, a process influenced by many health-related risks and protective factors. This study aimed to explore the relationship between coping capacity and episodic memory, and the mediating role of healthy lifestyle between coping capacity and episodic memory in a sample of 309 community-dwelling older adults with SMCs. Results from the structural equation modeling showed that coping capacity directly affects episodic memory , and there is a partial mediating effect (60.5%) of healthy lifestyle among this sample of older adults with SMCs. This study demonstrates that coping capacity and adaptation positively correlate with episodic memory in older adults with SMCs, and that these correlations are mediated by healthy lifestyle. The results suggest that older adults with poor coping capacity should be assessed and monitored regularly, and clear lifestyle-related interventions initiated by healthcare providers that promote healthy lifestyles may effectively improve coping capacity and episodic memory in this population group. Note: First author: Feilong Wang, Co-first author: Shijie li, Corresponding author: Yanni Yang


This study investigated the association between childhood socioeconomic status (cSES) risk of cognitive impairment but not dementia (CIND), cognitive impairment (dementia or CIND), and dementia and whether adult personality mediated this association. A sample of 10,289 participants (aged 50 and older) from the Health and Retirement Study (HRS) were followed across 2-year periods between 2006 - 2018. Estimates of mediation effects in Cox Proportional Hazards regressions were conducted using Mplus software to approximate the total effects of cSES on the cognitive outcomes and the natural indirect effects and natural direct effects derived when personality causally mediated this outcome. cSES was associated with increased risk of all three cognitive outcomes. Conscientiousness partially mediated the relationship between cSES and dementia, CIND, and cognitive impairment risk while neuroticism partially mediated dementia and impairment, but not CIND. Personality improved the overall model fit between cSES and both CIND and impairment, and conscientiousness was specifically associated with significantly lowered cognitive impairment risk over time. Conscientiousness and neuroticism substantially mediated the relationship between cSES and risk of impairment in old age. This research adds to lifespan models and suggests that distinct personality traits attenuate early childhood factors that contribute to lifespan development and cognitive aging. Conscientiousness in particular may act as a protective buffer mediating risk factors associated with cognitive impairment in old age.


Cereals and legumes play a major role in the production systems and diets of farmers in the semi-arid eastern region of Kenya. Efficient postharvest management can tremendously contribute to food security in these regions. A study was carried out in three counties in eastern Kenya to assess pre and postharvest management practices among farmers. Data was collected using semi-structured questionnaires designed and administered using Kobo Toolbox via android tablets. Results showed that farmers cultivated three main crops: maize (98%), beans 66%), and pigeon peas (28%). The most saved seed crops were beans (80%) and pigeon peas (50%). Majority of the farmers (80%) experienced pre-drying losses due to insects (48%), rodents (40%) and birds (39%). Farmers stored grain for consumption (80%) and for sale (19%). About 48% of farmers stored the grain for more than 9 months. Challenges during grain storage were insects (57%) and rodents (43%). Primary methods of grain preservation included hermetic methods (61%) followed by insecticides (33%). While progress is being made in addressing storage challenges, there still a need to continue building awareness about improved storage technologies and find solutions for pest infestations in the field and drying after harvest. Cereals and legumes are the most important food staples in Sub-Saharan Africa , beans (Phaseolus vulgaris L.), green grams (Vigna radiata L.), pigeon peas (Cajanus cajan L.), millets (Pennisetum spps), sorghum (Sorghum bicolor L.), cowpea (Vigna uncguiculata L.) and dolichos lablab (Lablab purpureus L.) to ensure self-sufficiency in the face of climate change  in the Eastern region of Kenya . The surWe purposively selected 50 villages in the three counties . The number of villages per country was determined based on cereal and legume production. We targeted to interview 13 farmers randomly selected in each village. We were able to survey a total of 613 farmers . The selected farmers were interviewed using a semi-structured questionnaire with open and close-ended questions. Questions included qualitative and quantitative data focused on the socio-economic characteristics of the respondents; major cereal and legume crops produced, the quantity produced; seed sources and storage, grain drying before and after harvest, storage practices; farmers’ knowledge of the causes of postharvest losses and loss prevention measures. The questionnaire was uploaded to Kobo Toolbox, deployed and administered via handheld devices (android tablets). Five enumerators collected data and received consent from individual farmers before each interview. Data collected were coded and analyzed using the SPSS 24.0 (IBM Corp., About half of the farmers were an aging demographic, above 50 years. Older farmers are usually viewed least productive because most field work require physical effort. In addition, this may be a hindrance to adoption of new technologies which has a negative impact on food security. This is a universal trend caused by youth migration to urban centers among other factors. Policy-makers need to develop programs that incentivize the youth to be involved in agriculture. The average household size was five members which is similar to the Kenyan national average of between 4.9 to 5.7 people Munene, . Bigger The three major crops grown across the three counties were maize, beans and pigeon pea. Most farmers grew at least two major crops including a cereal and a legume. This agrees with the report that farmers in semi-arid areas of eastern Kenya grow two major and one minor grain crops (Wambugu & Muthamia, There was little variation in postharvest practices among the three study sites. Ideally, rainfall in these regions is bimodal with the long rains occurring from March to May and short rains from October to December. However, all these counties have been experiencing an overall decrease in precipitation and increase in temperatures, with negative impact on crop yields (Ojwang’ et al., Farmers had a good understanding of storage and its implications for food security. Studies have shown the importance of storage in enhancing food security in semi-arid areas (Nduku et al., The major challenges during storage were insects and rodents. Farmers reported using new storage technologies and insecticides to deal with these pest challenges. Farmers have relied on pesticides for grain preservation, but they have been shifting towards hermetic storage in recent years. Concerns with pesticides stem from food poisoning due to overuse and misuse of insecticides as well as their ineffectiveness linked to insect resistance (Nicolopoulou-Stamati et al., Overall, farmers have a greater understanding of postharvest practices in the three counties in Eastern Kenya. Maize and common beans are the most important crops grown by farmers in these areas. Postharvest challenges linked to drying and storage such as aflatoxins and insects are serious challenges. Farmers are increasingly accessing new technologies and solutions to deal with these issues. Maize being such a staple crop grown by all farmers, there is a need to improve and promote pre-harvest and postharvest management practices to increase the use of new technologies such as improved seed, dryers, and hermetic storages devices.