In conclusion, even under deep propofol sedation, apneas and hypopneas can be terminated without cortical arousal. However, extensive suppression of the arousal threshold can lead to critical hypoxemia suggesting careful respiratory monitoring.Recent evidences suggest that non-arousal mechanisms can restore and stabilize breathing in sleeping patients with obstructive sleep apnea. This possibility can be examined under deep sedation which increases the cortical arousal threshold. We examined incidences of cortical arousal at termination of apneas and hypopneas in elderly patients receiving propofol sedation which increases the cortical arousal threshold. Ten elderly patients undergoing advanced endoscopic procedures under propofol-sedation were recruited. Standard polysomnographic measurements were performed to assess nature of breathing, consciousness, and occurrence of arousal at recovery from apneas and hypopneas. A total of 245 periodic apneas and hypopneas were identified during propofol-induced sleep state. Cortical arousal only occurred in 55 apneas and hypopneas (22.5%), and apneas and hypopneas without arousal and desaturation were most commonly observed (65.7%) regardless of the types of disordered breathing. Chi-square test indicated that incidence of no cortical arousal was significantly associated with occurrence of no desaturation. Higher dose of propofol was associated with a higher apnea hypopnea index ( Patency of the pharyngeal airway is state-dependent in patients with obstructive sleep apnea (OSA). Reduction of upper airway (UA) dilating muscle activity during loss of consciousness appears to account for UA obstruction during sleep . Burst o2-mediated genioglossus muscle activity [Younes, however, recently proposed that cortical arousals are coincidental events that occur just prior to arousal-independent airway opening through analysis of the breathing and cortical activity in experimentally-induced apneas or hypopneas ,5,6. In activity  and to dactivity . Furtheractivity .Despite physiological evidence suggesting advantages of arousal threshold reduction, cortical arousal was observed to occur at apnea termination even under light sedation . ConsequWe performed a prospective observational study after obtaining approval from the institutional Ethics Committee  and written informed consent from each subject. Ten adult patients  undergoing ESD surgery for early gastric cancer under propofol sedation participated in the study. Relatively higher incidence of obstructive apneas and hypopneas was found in the elderly patients under propofol sedation as the primary result of the study , this seThe patient lying on the left side received 2 L/min oxygen through a nasal prong. In order to minimize body movements during the endoscopic submucosal dissection (ESD), relatively deep sedation maintaining Ramsey score 5 to 6   was achi2), and snoring over a microphone were recorded and stored in a computer for later analyses. For research purposes, a standard polysomnography was performed . Bilateral central and occipital electroencephalograms (EEG), bilateral electrooculograms (EOG), submental electromyogram (EMG), electrocardiogram, airflow measurement with a nasal pressure prong and an oro-nasal thermistor, thoraco-abdominal wall motions with piezo respiratory effort sensors, oxygen saturation , presence or absence of thoraco-abdominal respiratory movements , and presence or absence of cortical arousal evidenced by the electroencephalograms upon restoration from apneas and hypopneas . Apnea hypopnea index (AHI) was determined as the frequencies of apneas and hypopneas per hour of sleep for each of the category combinations with and without the 3 features of apneas and hypopneas [Polysomnography data were manually reanalyzed for this secondary analysis by a certified sleep technician (RK) and an investigator (SI) using a dedicated computer software . Consciousness states (awake or sleep) were determined for each 30 s polysomnography recordings by using the criteria of Rechtschaffen and Kales , and breypopneas .p < 0.05 was considered statistically significant, and all p-values were two sided. All statistical analyses were performed by using a computer software . Arousal rate defined as the ratio between the incidence of respiratory disturbances with cortical arousal and total incidence of the respiratory disturbances occurring in all participants was calculated for each of the categories. Comparison of the arousal rates with and without desaturation was performed by using Chi-square test. Values were presented as frequencies and proportions for categorical data, and means and standard deviations (SD) for continuous variables. A value of −1. Thirty-eight more apneas and hypopneas were identified in this secondary analysis than in the primary analysis [r = 0.673, p = 0.033, n = 10). AHI without desaturation was significantly greater than AHI with desaturation (p = 0.024).Patients’ characteristics and details of the sedation are presented in analysis . Total AThis is the first study which assessed the occurrence of cortical arousal in response to apneas and hypopneas during propofol-induced sleep in elderly patients undergoing endoscopic surgery. Cortical arousal only occurred in 55 of 245 apneas and hypopneas (22.5%) during propofol-induced sleep. Apneas and hypopneas without arousal and desaturation was most commonly observed (65.7%) regardless of types of disordered breathing. The results strongly suggest that cortical arousal is possibly a coincidental event to the non-arousal recovery from respiratory disturbances and is not always necessary to restore breathing even in the elderly.Propofol is a potent GABA agonist and used as a general anesthetic as well as a sedative depending on the administration dose . It doseAccording to recent accumulated knowledge of arousal and obstructive sleep apnea , interacIn contrast, propofol increases arousal threshold over the UA opening threshold and decreases respiratory drives to the diaphragm and UA muscles B. It is Despite common UA obstruction episodes under propofol sedation, few critical respiratory events occurred in this study, which may reflect few reports of fatal complications under propofol sedation for endoscopic procedures ,20. HoweThere are several limitations in this study. Firstly, the sample size is very small and the patient population is severely limited to non-obese elderly without previous OSA diagnosis. Only few respiratory disturbances occurred during propofol sedation resulting in severe hypoxemia commonly observed in patients with severe OSA. Obviously, our study design does not allow generalization of the findings. However, we believe that incidences and natures of respiratory disturbances and restorative capacity without cortical arousals were objectively assessed by polysomnographies during the sedation. Certainly, four electroencephalograms used in this study were probably not able to cover the whole brain activities and undetected cortical arousal may have occurred during recovery from the respiratory disturbance. However, we consider this possibility unlikely due to the propofol dose used in this study ,21. SecoEffects of various types of hypnotics and sedatives on OSA have been assessed in many previous studies, but the results are diverse; some studies demonstrated an increase of AHI and apnea duration, but clinically meaningful AHI reduction without increase of apnea duration was reported particularly in studies using nonmyorelaxant sedatives such as eszopiclone ,24. JordPharmacological sedation is becoming frequently used in various clinical situations such as invasive endoscopy, minor surgery, radiological examinations for children, and mechanical ventilation in ICU ,25,26,27Obstructive apneas and hypopneas during propofol sedation were spontaneously terminated without cortical arousal while repeated periodically. The appropriative depth of propofol sedation appears to reduce both the UA dilating muscle activity and its oscillation, possibly stabilizing respiration and decreasing frequency of respiratory disturbances. However, extensive suppression of the arousal threshold with higher doses of propofol can lead to prolonged apnea and critical hypoxemia suggesting careful respiratory monitoring with both pulse oximetry and nasal pressure monitor during advanced GI endoscopy under propofol sedation.


This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key annulation step and represents the first successful application of catalytic Wittig reaction in multicomponent cascade reaction.Tri- or tetrasubstituted furans have been prepared from terminal activated olefins and acyl chlorides or anhydrides by a multicomponental convergent synthesis mode. Instead of stoichiometric  A broad scope of substrates, bearing various reducible functional groups including ketone, acyl chloride, olefin, nitro, cyano, and ester, are all well tolerated in the presence of reducing agent silane. This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key step and represents the first successful application of catalytic Wittig reaction in a multicomponent cascade reaction. Future efforts in our laboratory will be directed toward exploring the asymmetric reactions involving catalytic chiral phosphine mediated Wittig reaction, the results of which will be reported in due course.In conclusion, a convergent synthetic method for tri- or tetra-substituted furans has been developed by catalytic phosphine mediated multicomponental cascade reactions. Instead of stoichiometric


Orbital emphysema occurs when air enters the soft tissue surrounding the orbit. Although orbital blowout fractures are often caused by face trauma, nontraumatic orbital fractures can also occur but have been rarely described. Here, a case of orbital and palpebral emphysema caused by forceful nose-blowing is presented. Examination uncovered gross swelling of the right eye and discernable subcutaneous emphysema. The patient had normal eye movement and visual acuity. Orbital computed tomography (CT) revealed orbital emphysema secondary to an orbit floor fracture into the maxillary sinus, resulting from high intranasal pressure upon blowing her nose. The patient received conservative management with antibiotics and was given instructions not to sneeze or blow her nose. She fully recovered and all her symptoms completely resolved. Orbital emphysema is a somewhat rare clinical event. A collection of air within the orbits or eyelids is most commonly associated with fracture and trauma of an orbital bone. Although trauma is the most common etiology of orbital emphysema, nontraumatic spontaneous orbital emphysema due to coughing, sneezing, nose blowing, or any type of straining as a result of iatrogenic otolaryngeal and dental procedures and infectious gas-producing microorganisms have been described –5.We describe a patient with orbital emphysema presenting swelling surrounding the left eye several hours after blowing her nose. Most cases of orbital emphysema resolve spontaneously; however, emergency physicians should be aware that early recognition of orbital emphysema is crucial to prevent possible vision-threatening complications if unrecognized . Since oA 59-year-old healthy Japanese female with chronic rhinitis was taken to our emergency department due to a sudden and painless left periorbital swelling following forceful nose-blowing. Examination revealed a gross swelling of the left eye. There was painless palpable emphysema around her left eye; she had normal eyeball movement and visual activity. By ophthalmic consultation, the intraocular pressure was found to be slightly higher in her left eye (20 mmHg) compared to the right (13 mmHg). Noncontrast CT revealed orbital subcutaneous and subconjunctival emphysema and fracture of the median orbital wall of the left eye. Focal herniation of extraconal fat into the ethmoid air cells was noted . OtherwiThis case highlights spontaneous orbital emphysema caused by forceful nose-blowing, which may pose a diagnostic challenge. In our patient, orbital emphysema developed when the patient blew her nose by air transfer from the paranasal sinuses into the orbit along a pressure gradient, causing a one-way valve forcing air into the orbit. Orbital fat may function like a ball-valve, becoming displaced from the fracture site during insufflation but falling back to seal the opening under the pressure of trapped air.Gwaltney et al. measured intranasal pressure during coughing, sneezing, and nose-blowing using fluid dynamic modeling with sinus CT. They reported a mean maximal intranasal pressure of 66 mm Hg during nose-blowing, 4.6 mmHg during sneezing, and 6.6 mmHg during coughing. Intranasal pressures greater than 190 mmHg have been measured during nose blowing with maximal expiratory efforts, offering evidence that air can be introduced into the orbit under substantial pressure . Old traIn our patient, chronic inflammation in the maxillary sinus associated with chronic rhinitis may have caused weakening of the orbital floor, making it more susceptible to fracture with high pressure with forceful nose-blowing.Most orbital emphysema cases require no treatment. However, with progressive emphysema, urgent decompression of the trapped air and acute orbital compartment syndrome is necessary to avoid irreversible vision loss because of mechanical optic nerve stretching or vascular compromise. Extraocular muscle motility and visual acuity are the two most important ophthalmologic functions that should be evaluated emergently in patients with acute orbital trauma. Assessing these abilities may be challenging at times due to head injury severity, level of periorbital soft tissue edema, lack of complete cooperation in alert patients, and reduced consciousness.Reduced vision after trauma may be caused by intraorbital emphysema, retrobulbar hemorrhage, optic nerve thickening presumably secondary to edema, ruptured globe, detached retina, and optic nerve impingement. These complications are ophthalmic emergencies requiring immediate intervention. Therefore, differentiating benign orbital emphysema from an ophthalmic emergency is critical to avoid adverse sequelae. In nontraumatic cases, the most important differential diagnosis to exclude in acute unilateral eye swelling is orbital cellulitis, which may present with pain on eye movement, visual loss, chemosis, and fever .The diagnosis can be easily made by palpation of the pathognomonic cracking and crepitation on the eyelids. CT plays a crucial role in assessing the intraorbital contents of patients with orbital trauma. Most patients with compromised visual acuity or decreased extraocular muscle motility caused by trauma have abnormalities shown by orbital CT.Most cases of orbital emphysema resolve spontaneously, and no treatment is needed. Experts generally recommend prophylactic oral antibiotics to treat sinus pathogens for patients with orbital fracture into a sinus . A 23-gaIn conclusion, clinicians should investigate all suspected orbital blowout fractures with imaging and full ophthalmological examination regardless of trauma history to avoid possible complications like vision loss because of infection and pressure.


Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive  network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases.OBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants  from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power


Traumatic spinal cord injury (SCI) leads to disruption of sensory, motor and autonomic function, and triggers structural, physiological and biochemical changes that cause reorganization of existing circuits that affect functional recovery. Propriospinal neurons (PN) appear to be very plastic within the inhibitory microenvironment of the injured spinal cord by forming compensatory circuits that aid in relaying information across the lesion site and, thus, are being investigated for their potential to promote locomotor recovery after experimental SCI. Yet the role of PN plasticity in autonomic dysfunction is not well characterized, notably, the disruption of supraspinal modulatory signals to spinal sympathetic neurons after SCI at the sixth thoracic spinal segment or above resulting in autonomic dysreflexia (AD). This condition is characterized by unmodulated sympathetic reflexes triggering sporadic hypertension associated with baroreflex mediated bradycardia in response to noxious yet unperceived stimuli below the injury to reduce blood pressure. AD is frequently triggered by pelvic visceral distension (bowel and bladder), and there are documented structural relationships between injury-induced sprouting of pelvic visceral afferent C-fibers. Their excitation of lumbosacral PN, in turn, sprout and relay noxious visceral sensory stimuli to rostral disinhibited thoracic sympathetic preganglionic neurons (SPN) that manifest hypertension. Herein, we review evidence for maladaptive plasticity of PN in neural circuits mediating heightened sympathetic reflexes after complete high thoracic SCI that manifest cardiovascular dysfunction, as well as contemporary research methodologies being employed to unveil the precise contribution of PN plasticity to the pathophysiology underlying AD development. Propriospinal neurons (PN) have intraspinal origins and project to interneurons in other spinal cord segments as reported in electrophysiological and tract-tracing studies in feline and rodent models  SCI, in which transcutaneous electrical stimulation of lower limb nerves evoke motor responses in distal forearms  in the thoracolumbar intermediolateral cell column (IML), which results in the loss of sympathetic modulation from the caudal and rostral ventrolateral medulla  in the brainstem that then modulates the sympathetic response, accordingly. Supraspinal denervation results in the sudden depletion of descending excitatory signals resulting in a 50–70% loss of innervation to SPN  neutralizing antibody or trkA-IgG fusion protein in T4 spinal transected rats decreases CGRP-fiber density in association with reduced AD symptoms in experimental rats undergoing experimental colorectal distension (CRD; Christensen and Hulsebosch, via interneurons that may be excitatory or inhibitory in nature depending on the type and location of the stimuli (Chau et al., Autonomic PN are pre-sympathetic as they innervate the SPN to control their level of excitation (Gebber and McCall, de novo by visceral stimuli following SCI.BDA anterograde tracer injected into the central gray matter at rat L6-S2 spinal levels shows that ascending PN extend projections up to cervical levels through lamina X, and retrograde labeling using wheat germ agglutinin-horseradish peroxidase show projections to laminae VII and VIII at lumbar and thoracic levels indicating the anatomical locations of ascending PN (Matsushita, Ascending PN plasticity is believed to contribute to the development of AD. These neurons relay visceral sensory information towards the SPN in the thoracic cord (Rabchevsky, via intraspinal projection neurons (Pascual et al., via interneurons. After SCI, the supraspinal control is lost but the SPN are activated by peripheral afferent stimuli whose signal is relayed via ascending PN to trigger a sympathetic response, resulting in hypertension (Accordingly, BDA tracers injected into the lumbosacral cord following T4 transection show more labeling of ascending lumbosacral PN fibers that originate at the DGC and terminate proximal to Fluorogold-labeled thoracic SPN (Hou et al., rtension .Excitatory interneuron connectivity with SPN preferentially increases after T3 spinal transection in mice, and repeated CRD induces an increase in these excitatory interneurons co-labeled with vGlut2 (Ueno et al., Electrophysiology and retrograde tract-tracing are the most common tools used to identify the tracts involved in autonomic function. Although several studies labeling long descending PN and short tract PN exist, it is still highly challenging to specifically target and label ascending propriospinal tracts after injury due to unintended labeling of fibers en passage. Moreover, it is reported that transsynaptic labeling by pseudorabies virus is significantly reduced in the T4 transected spinal cord (Duale et al., In this regard, Kinoshita et al.  reversibPN plasticity after traumatic SCI plays a critical role in improving not only spontaneous motor function but also potentially aggravating autonomic dysfunction. In addition to afferent C-fiber sprouting and loss of supraspinal regulation of the IML, maladaptive plasticity of PN below the level of high thoracic SCI appears essential for manifesting chronic autonomic dysfunction. Thus, while selectively promoting PN sprouting might serve as a promising therapeutic target for specific motor functional recovery, it may also be prevented selectively to combat AD development and/or severity, and the advancement of strategies to reversibly silence these interneurons will help further our understanding on their role in AD.FM wrote the first draft of the manuscript. SP reviewed the manuscript. AR critically evaluated the manuscript and wrote the final revised version. All authors contributing to the manuscript have read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed. Epithelial ovarian cancer (EOC), a histopathologically, morphologically, and molecularly heterogeneous group of neoplasms , is the EOC initiation results from accumulation of genetic mutations and epigenetic changes resulting in malicious transformation of epithelial cells, stem cells, or transient metaplastic regions at the primary site, either ovary or the fallopian tube fimbriae ,16,17,18DNA methylation—addition of methyl groups to DNA CpG sites without altering DNA nucleotide sequence. Methylation occurs by means of enzymes called DNA methyltransferases (DNMTs), which place methyl groups on symmetric cytosine residues in double-stranded CpG sites ,47. HypeHistone modifications—various posttranslational modifications (PTMs) at histone protein N-terminal tails, which impair proper interactions between adjacent nucleosomes to affect the compact packing of the chromatin and impede the binding ability of other factors/enzymes that are involved in gene transcription ,58. The Chromatin remodeling—rearrangement of chromatin organization through complete or partial nucleosome repositioning and altering gene access for transcription. Chromatin remodeling can occur via nucleosome sliding (movement of the core histone octamer nexus across DNA segment with no evident disintegration of the octamer itself), nucleosome ejection (nucleosome segregation from the chromatin chain), or histone eviction  ,66,67. TAltogether, the three epigenetic mechanisms that are described above work closely to mediate DNA (un)coiling around the core histones and ensure dynamic chromatin reassembly between heterochromatin  and euchromatin  states.9 methylation with RNA interference machinery, followed by DNA methylation and gene transcription repression) and heterochromatic silencing . . 155]. DWhile the overwhelming majority of research work is focused on the elucidation of cell signaling pathway implications, the epigenetic interplay between MSCs and EOC remains largely unexplored. While considering the well accepted role of epigenetic aberrations in CSC reprogramming (comprehensively outlined in ), emergiTECs refer to endothelial cells that line the inner walls of newly formed blood vessels in tumors. TECs support blood flow, tumor tissue trophics, and accelerate tumor progression. TECs are genetically non-malignant cells, however, they differ from normal endothelial cells by exhibiting cytogenetic abnormalities , distortTECs exhibit considerable heterogeneity (reviewed in ), and di4 methylation was reported, and re-expression of ICAM-1 in TECs by DNMT and HDAC inhibitors successfully restored leukocyte-TEC adhesion and leukocyte infiltration of vessel walls in vitro and in vivo, respectively . . 247]. IEpigenetic regulation of hematopoietic stem cell lineage commitment and subsequent differentiation of dendritic cell precursors into specific dendritic subtypes (including PDCs) and interferon response in the context of chromatin remodeling, miRNA and lncRNAs interference are well documented ,259,260 MCs are simple squamous epithelial cells that line the intra-abdominal cavity as an upper single layer (mesothelium) of the peritoneum, immediately supported by the basal membrane, underneath which is the collagen-rich extracellular matrix A. MCs fuThe bidirectional interplay between EOC cells and MCs has been recently assessed in a study by Matte et al. , who repThe growing body of information on epigenetic control of ovarian cancer metastatic advancement and acquisition of resistance to standard-of-care chemotherapy make epigenomic alterations attractive prognostic markers and druggable targets to improve therapeutic outcomes in EOC patients especially with platinum-resistant and recurrent disease. Our group and others are actively exploiting DNA hypermethylation, modifications of histone marks, and aberrant expression of non-coding RNAs in malignant EOC cells in an attempt to treat EOC, re-sensitize ovarian tumors to conventional chemotherapy, and prevent/delay disease recurrence A. We andContinuous accumulation of knowledge on epigenomic perturbations in ovarian TME cellular compartments in the context of their communication with EOC cells holds great translational promise. The fact that non-malignant stromal cells lack genetic mutations and acquire potentially reversible tumor-specific molecular traits and cancer-indulgent functions via epigenetic reprogramming by EOC cells suggests the epigenetic tailoring of ovarian TME as a promising strategy in ovarian cancer management. Given the varying stroma representation in ovarian malignancies  and higTreatment of different stromal components with HMAs demonstrated tumor-restrictive potential. In particular, the exposure of adipocytes to guadecitabine attenuated HGSOC cells metastasis-associated behaviors . HMA decAlternatively, similarly to an improved anticancer effect of a DNMT/HDAC inhibitor combination on ovarian tumors  and otheGiven that CAF reprogramming is shown to repress ovarian tumor advancement , preventExploiting host immune system in managing ovarian cancer growth and metastatic spread has emerged as another key research and therapeutic direction ,295,296.To summarize, a deeper understanding of epigenomic involvement in reciprocal EOC tumor-stroma interrelationship is essential and it will help to determine pharmacological routes to alter the TME, which in turn could inhibit EOC metastatic progression and the development of chemoresistance and tumor recurrence. Furthermore, we believe epigenetically-mediated pharmacological engagement of certain TME players, such as immune cells, to boost immune responses towards complete malignant cell elimination has tremendous potential.


Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Bothersome tinnitus in single-sided deafness (SSD) is particularly challenging to treat because the deaf ear can no longer be stimulated by acoustic means. We contrasted an SSD cohort with bothersome tinnitus  against an SSD cohort with no or non-bothersome tinnitus  using resting-state functional magnetic resonance imaging (fMRI). All study participants had normal hearing in one ear and severe or profound hearing loss in the other. We evaluated corticostriatal functional connectivity differences by placing seeds in the caudate nucleus and Heschl’s Gyrus (HG) of both hemispheres. The TIN cohort showed increased functional connectivity between the left caudate and left HG, and left and right HG and the left caudate. Within the TIN cohort, functional connectivity between the right caudate and cuneus was correlated with the Tinnitus Functional Index (TFI) relaxation subscale. And, functional connectivity between the right caudate and superior lateral occipital cortex, and the right caudate and anterior supramarginal gyrus were correlated with the TFI control subscale. These findings support a striatal gating model of tinnitus and suggest tinnitus biomarkers to monitor treatment response and to target specific brain areas for innovative neuromodulation therapies. The search for physiological substrates that account for tinnitus persistence and tinnitus severity has led investigators to evaluate the central nervous system (CNS) using a variety of techniques. Some documented CNS changes are synchronous hyperactivity5, tonotopic map cortical plasticity8, thalamocortical dysrhythmia10, and gamma band oscillations13.Tinnitus is a common auditory phantom perceptual disorder where conventional audiometric hearing loss profiles alone cannot help clinicians to distinguish between patients who merely experience tinnitus from those who are troubled by tinnitus15, case reports17, and an early clinical trial18 focused on the caudate nucleus of the basal ganglia support a striatal gating model15 of tinnitus awareness. This model delineates modulators of tinnitus persistence and tinnitus severity, where corticostriatal connections between the striatum and auditory cortex act to gate auditory phantom representations to reach perceptual awareness and connections between the striatum and limbic structures act to modulate auditory phantom distress.Human physiological studies20 or is driven by abnormal auditory-limbic interactions23. Neuroimaging studies in support of abnormal striatal connectivity as a potential biomarker of chronic tinnitus25 have been reported in cohorts with inhomogeneous hearing loss profiles. Those studies used post-hoc statistical techniques to address the possible confound of hearing loss levels on neural correlates of tinnitus. However, there is not yet a neuroimaging investigation that incorporates a specific hearing loss pattern in a cohort contrast study design that could isolate differential network connectivity findings to chronic tinnitus.A striatal gating model of phantom percept awareness is complementary to other CNS hypotheses, including those that posit tinnitus is primarily an expectation mismatch within the auditory system26, although this is not necessarily the case in congenital SSD27. Tinnitus localized to the deaf ear eliminates the treatment option of masking sound delivery to the defective sensory end organ, as it is unresponsive to acoustic stimulation. Moreover, acoustic therapies  directed to the better hearing ear are of minimal to no benefit30. Behavioral therapies  may be beneficial in modulating tinnitus distress, but without effective sound therapy to the deaf ear, have little to no effect on tinnitus loudness32. Neuromodulation of the auditory periphery by cochlear implantation of the deaf ear, an alternative method of auditory system stimulation, often reduces tinnitus severity similar to acoustic therapies in an ear with hearing loss36. However, this intervention requires surgical implantation of hardware to the skull and complicates future head magnetic resonance imaging (MRI) examinations.Patients with bothersome tinnitus in single-sided deafness (SSD) or unilateral severe to profound hearing loss and normal or nearly normal thresholds in the only hearing ear represent an exceptional opportunity to study tinnitus not confounded by hearing loss variations. Bothersome tinnitus in adult acquired SSD is expected to be localized to the deaf ear37 within the TIN cohort.The goal of this study was to identify candidate biomarkers to monitor tinnitus treatment response and targets for brain-based neuromodulation approaches. We evaluated basal ganglia and cortical connectivity patterns by contrasting an SSD cohort with bothersome tinnitus (TIN) against an SSD cohort no or non-bothersome tinnitus (NO TIN). We used resting-state functional magnetic resonance imaging (fMRI) to define whole-brain connectivity patterns of the caudate nucleus and auditory cortex. We report on connectivity differences between TIN and NO TIN cohorts, and voxelwise connectivity strength correlations with subscale scores of the validated Tinnitus Functional Index (TFI)Data on TFI score, age, sex, deafness duration, diagnosis of vestibular schwannoma, and deaf ear laterality for SSD TIN and SSD NO TIN cohorts are shown in Table Resting-state functional connectivity maps were reconstructed for TIN and NO TIN cohorts for the four seed regions (Heschl’s gyrus (HG), and caudate, bilaterally). Functional connectivity seeded from the left caudate was significant with the right caudate, and with multiple regions of pre-frontal cortex (PFC) in both TIN and NO TIN cohorts Fig. . The TINWithin the TIN cohort, voxelwise correlations with TFI subscales showed increased connectivity between the right caudate and cuneus for the relaxation subscale, where increased connectivity was correlated with higher interference with the ability to relax Fig. . Voxelwi18. The striatum is believed to be normally restrictive, blocking out phantom percepts, but becomes dysfunctionally permissive in chronic tinnitus. Initial evidence in support of this model stems from results of acute direct stimulation of the striatum at the junction of the head and body subdivisions (area LC) during deep brain stimulation (DBS) surgery in movement disorders patients with chronic tinnitus, where auditory phantom loudness can be modulated14. In those without tinnitus, caudate DBS can trigger auditory phantom percepts15 and vascular infarction of the dorsal striatum results in enduring tinnitus loudness reduction16. Furthermore, chronic caudate DBS has been shown to significantly improve TFI in some patients with severe, chronic tinnitus18. Although the exact physiological mechanisms are not clear, alteration of excitation and inhibition balance either within the caudate nucleus or in its connections to auditory cortex may be modulating phantom percept gating permissiveness39. Findings from this study extend generalizability of results from human neurophysiological18 and resting-state fMRI25 studies in binaural patients.The key finding of this study is increased connectivity between the caudate nucleus and auditory cortex in the SSD cohort with chronic, bothersome tinnitus. All patients relied on monaural hearing with normal audiometric thresholds, thereby removing hearing loss variation as a possible confound and isolating abnormal striatal functional connectivity to chronic tinnitus. This independent replication of the critical finding in our prior studies, where tinnitus cohorts had variable hearing loss profiles, further supports a striatal gating model of tinnitus awareness where the limbic system may be driving tinnitus severity40, as measured by the Tinnitus Handicap Inventory41 (THI) score, is positively correlated with pre-treatment activities of the left insula42. Increased functional connectivity between the caudate and the insula observed in this study suggests that the left insula may be an important structure within corticostriatal loops that link the auditory system with language networks and the limbic system44. Tinnitus awareness burden is negatively correlated with delta band activity of rostral and dorsal anterior cingulate cortices. Those areas are considered to be at the core of a descending noise cancellation system whose dysfunction may contribute to the percentage of daytime tinnitus awareness45. Increased striatal functional connectivity between the left caudate and the right supplementary motor area (SMA) observed in this study may possibly include neighboring dorso-rostral anterior cingulate cortices, thereby contributing to overall tinnitus distress.Other tinnitus neuroimaging studies using EEG methodologies have yielded interesting insights that are relevant to our findings. Tinnitus severity response to Tinnitus Retraining Therapy24. Increased connectivity with the superior lateral occipital cortex and anterior supramarginal gyrus is correlated with reduced sense of control over the phantom percept, regions that are part of task-positive visual and dorsal attention networks, suggesting enhanced attentional engagement for control of tinnitus46. Although the right caudate connectivity shows significant correlation with TFI subscale scores, it did not survive across cohort differences in functional connectivity, most likely due to the underlying small sample size. Nevertheless, the highest connectivity of the right caudate is with the left caudate , constant, non-pulsatile tinnitus  to collect both high-resolution structural T1-weighted fast spoiled gradient echo brain volume images  and to collect spontaneous fMRI data using a resting-state echo planar imaging (EPI) sequence . Foam earplugs with a 32 dB noise reduction rating were inserted into both ears during data acquisition.https://www.nitrc.org/projects/artifact_detect/), tissue segmentation, spatial normalization to the Montreal Neurological Institute (MNI) template, and spatial smoothing (using a 8 mm FWHM kernel). Prior to functional connectivity analyses, resting-state data were temporally filtered (0.008Hz-0.09 Hz bandpass) and denoised by applying a regression model using 12 realignment parameters and the global mean signal of the white matter.Resting-state fMRI data were spatially preprocessed using a standardized pipeline implemented in the CONN toolbox. Imaging data preprocessing steps were as follows: functional realignment and unwarping, translation to center, outlier detection using Artifact Detection Tools  as implemented in the CONN toolbox. Correlation coefficients were computed across all voxels of these pre-defined regions of interest (ROIs) with the rest of the brain. Voxelwise regression analyses were performed only within the TIN cohort (n = 15) between functional connectivity and TFI subscale scores. Voxelwise analyses within and between groups (TIN versus NO TIN) were performed using parametric one-tailed t-tests for determining regions with increased and decreased connectivity separately for each of the four seeds. We report on within and across-group whole-brain analyses that survived a threshold of p < 0.05 following a false discovery rate based cluster-mass correction for multiple comparisons59.All functional connectivity and group analyses were performed using the CONN toolbox. For resting-state functional connectivity, four seed regions (right/left Heschl’s gyrus (HG); right/left caudate) were anatomically defined using AAL labelled regions (


As populations age, identifying factors that foster the maintenance of health is crucial for improving the health and well-being of older adults. Yet, most psychological, biomedical, and public health efforts have focused on reducing harmful risk factors. While the risk management approach has contributed greatly to prevention and treatment programs, our aging society continues to grapple with the steadily rising tide of chronic conditions. Expanding the focus to include upstream, health-promoting psychosocial assets may help inform a more comprehensive response effort. Mounting research suggests that different dimensions of psychological well-being are uniquely associated with reduced risk of chronic conditions. However, the mechanisms underlying these associations remain understudied. This symposium presents 4 studies evaluating potential mechanisms. The first talk presents research evaluating how a spouse’s level of optimism may be uniquely associated with an individual’s cognitive health over time . A second talk, draws upon a multi-burst daily diary study and focuses on affective stress response as a potentially modifiable target that could explain the health benefits of optimism. A third talk evaluates how baseline levels purpose in life might be associated with repeated measures of five key health behaviors over time. A fourth talk discusses results from a longitudinal-burst daily diary study determining the reciprocal relationships among optimism, pain interference, and goal-directed activity among older women who experience pain. Overall, these studies add to the growing research on psychological well-being and physical health by providing evidence around potential biobehavioral pathways.


An 8-year-old male patient presented after suffering blunt trauma to the left side of the face during a football game. On initial evaluation, the patient denied malocclusion or chin deviation. Computed tomography (CT) identified a displaced intracapsular left-sided mandibular condylar fracture , and conWhat is the etiology of pediatric mandibular fractures?How are pediatric patients affected by condylar fractures?What are the different methods of treatment of pediatric condylar fractures?What are the benefits of closed reduction with dynamic elastic therapy?Several types of traumatic mandibular injury are seen in the pediatric population. According to one recent study, the most common events leading to mandibular fractures were sports injuries, falls, and road traffic accidents.Several differences exist between pediatric and adult condylar fractures. Pediatric bones are more likely to remodel, which can partially compensate for malunion unlike mandibular fractures in adolescents and adults.,Treatment modalities for pediatric condylar fractures include conservative management with liquid diet, jaw rest, and careful clinical follow-up, closed reduction with maxillomandibular fixation (MMF), or open reduction with internal fixation (ORIF). Most authors advocate for closed management due to the lack of outcomes data on open surgery and due to the risks of damaging growth centers with open treatment. Remodeling and dental evolution can also overcome malocclusion in closed treatment, especially in patients with primary/deciduous dentition, as there will be more dental evolution compared with patients with secondary teeth.6Closed reduction of pediatric condylar fractures with MMF may be accomplished through several methods but can be difficult in pediatric patients when attaching arch bars, brackets, or screws to primary or deciduous dentition. Prior work discusses risks of tooth avulsion and damage to developing dentition.Dynamic elastic therapy is suitable for the management of condylar fractures with any degree of displacement or dislocation in pediatric patients and offers superior or similar results compared with rigid maxillomandibular fixation while minimizing patient discomfort.


The high mortality rate associated with pancreatic cancer necessitates accurate and early detection methods. Computed tomography currently is the primary diagnostic modality used; however, subtle imaging features in concert with novel clinical presentations may obscure the initial diagnosis. Here, we describe a unique initial presentation of pancreatic cancer as a pancreatic leak, with subtle initial CT evidence of malignancy. An 83-year-old female with prior surgical history of open splenectomy and ventral hernia repair presented with two weeks of vague abdominal pain and leukocytosis. Initial CT revealed abdominal peripancreatic fluid collections. Interventional radiology-guided drain placement was performed, which revealed amylase-rich pancreatic fluid within the collections. Repeat CT scan revealed subtle pancreatic duct dilation with slow resolution of the fluid collections. Ultimately, endoscopic ultrasound identified an ill-defined pancreatic mass, revealed to be pancreatic adenocarcinoma. The patient subsequently underwent an open distal pancreatectomy. Diagnosis of pancreatic cancer relies heavily on cross-sectional imaging, with no screening tests currently available. However, subtle radiographic features and unique clinical presentations may delay accurate diagnosis and staging. EUS may be a useful tool for initial evaluation of high-risk individuals. Pancreatic cancer has one of the lowest five-year survival rate of all malignancies 8.5%), accounting for 10.9 out of 100,000 deaths in the US –4. When %, accounHere, we describe an unusual case of pancreatic adenocarcinoma initially presenting as pancreatic duct disruption in a patient with a prior splenectomy. Initial CT did not suggest pancreatic cancer; however, EUS was eventually used to evaluate subtle pancreatic duct dilation and revealed the presence of pancreatic adenocarcinoma. Our experience demonstrates that EUS is an accurate modality for detecting pancreatic cancer with both an initial negative CT and a complex clinical presentation.An 83-year-old female presented to the emergency department with two weeks of vague abdominal pain. Her past medical history was significant for open splenectomy for spontaneous rupture three years prior to presentation and subsequent ventral hernia repair with mesh. She denied history of pancreatitis, diabetes mellitus, nor family history of gastrointestinal disease or malignancy. She was found to have a UTI and leukocytosis of 20,000, with LFTs and lipase within normal limits. Initial CT demonstrated abdominal fluid collections around the stomach and pancreatic tail, extending to segment two of the liver Figures . She wasHere, we describe a diagnosis of pancreatic cancer in an 83-year-old female patient characterized by a unique clinical presentation and equivocal initial radiologic findings. EUS revealed the ill-defined pancreatic mass, and EUS-guided biopsy confirmed pancreatic adenocarcinoma. Given the high morbidity and mortality of this disease, evaluation and improvement of current diagnostic techniques is crucial.Initial clinical symptoms of pancreatic cancer are vague and nonspecific, and patients typically present with abdominal pain and weight loss . PainlesCT, the recommended first line imaging modality for pancreatic cancer evaluation, has high sensitivity for large lesions and is useful in disease staging . Recent As demonstrated in this case of pancreatic cancer presenting initially as peripancreatic fluid collection, an atypical clinical presentation coupled with negative initial imaging studies may obscure the underlying diagnosis of pancreatic cancer. EUS has high diagnostic accuracy and allows for immediate tissue biopsy. Thus, EUS should be rigorously evaluated to determine its potential use in the initial screening of patients with high clinical suspicion for pancreatic cancer.


Research efforts in these areas have already yielded critical insights into pathophysiological mechanisms and will continue to stimulate innovation in this promising area of translational research.Neural circuits are the underlying functional units of the human brain that govern complex behavior and higher-order cognitive processes. Disruptions in neural circuit development have been implicated in the pathogenesis of multiple neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Until recently, major efforts utilizing neurological disease modeling platforms based on human induced pluripotent stem cells (hiPSCs), investigated disease phenotypes primarily at the single cell level. However, recent advances in brain organoid systems, microfluidic devices, and advanced optical and electrical interfaces, now allow more complex hiPSC-based systems to model neuronal connectivity and investigate the specific brain circuitry implicated in neurodevelopmental disorders. Here we review emerging research advances in studying brain circuitry using  Neural circuits can be detected as early as 18–22 weeks gestational age (GA) during human brain development. Transient circuitries in the brain are initially established in the subplate, formed by afferent inputs from multiple brain regions, including the basal forebrain, brainstem, and somatosensory thalamus . Then thin vitro  are emerging to complement these animal models. Since hiPSCs were first generated –21, patiin vitro disease modeling has significantly accelerated following the generation of hiPSCs in 2007. The ability to harness patient-specific somatic cells and reprogram them into pluripotent stem cells indistinguishable from human embryonic stem cells (hESCs) has opened a novel area of research for modeling neurodevelopmental disorders. Development of robust hiPSC reprogramming methodologies has been an area of intense research with more than a dozen methods currently available  the ability to physically segregate cell bodies of different neural subtypes while still allowing axonal growth between compartments (ii) compatibility with high-resolution video microscopy to investigate morphological and functional connectivity (iii) the ability to control axonal growth and monitor stages from early synaptic formation through late synaptic maturation. Thus, microfluidic chip platforms provide compelling systems to investigate neural circuit dysfunction in neurodevelopmental disorders.The development of compartmentalized microfluidic devices has further enabled innovative methods to model human brain circuitry with an unmatched level of control. Microfluidic chip devices provide several novel features as platforms to model circuit-level connectivity As a proof of concept, a five-compartment microfluidic device was developed to model a mid-brain neural circuit composed of GABAergic, glutamatergic, and dopaminergic (DA) neurons . Using dIn another study, a microfluidic chip platform modeled the hippocampal dentate gyrus (hDG)-Cornu Ammonis region 3 (CA3) circuit of schizophrenic patients . An effiA similar two-compartment microfluidic device reconstructed cortico-striatal circuits using primary neurons from a mouse model of Huntington's disease (HD). Though the main focus of this review is based on hiPSCs, this innovative system was included to emphasize the value of microfluidic systems in modeling brain circuitry. Data from this study suggested that presynaptic cortical dysfunction was both necessary and sufficient to induce pathogenic properties within post-synaptic striatal neurons, thus highlighting the critical value of these systems in providing mechanistic insights into disease pathogenesis . Throughin vivo conditions , assays could be developed to record the electrophysiological properties of brain organoids in the context of normal development or exposure to environmental factors. Further, MEAs could be utilized as functional readout tools to phenotypically profile abnormal electrical activity arising from diseased brain organoids, thereby allowing for drug screening approaches to identify potential therapies that rescue electrophysiological deficits. Additional applications for MEAs include analysis of network topological properties and functional connectivity graphs within brain organoids based on spike train data, which could be derived using information-theory based network analysis –69. AddiIn conjunction with neural circuit analysis within single brain organoids, regionally diverse brain organoids could be combined into assembloids to model long-range circuits such as those implicated in neurodevelopmental disorders and drug addiction. The same optical and electrical interface tools could then also be applied to these long-range circuit models. To further enhance the fidelity and reproducibility of assembloid-based platforms in modeling long-range circuits, microfluidic devices could segregate organoids into different compartments, while still allowing inter-compartmental projections and synaptic contacts between the separated organoids . Thus, cin vitro platforms for modeling human brain circuitry, it is critical to remember the developmental context of many neurological disorders. Some neurodevelopmental disorders may be triggered early, potentially resulting from environmental exposures in combination with a susceptible genetic makeup; common examples are cases of parenteral heavy metal    or intranganese) –78. Othenganese) –81 or thnganese) –84. New AH and MH conceived the main ideas and developed the structure of the paper. AH, MH, NM, and CM wrote the manuscript. AH prepared the figure and the table. All authors critically reviewed and approved the final manuscript 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. The handling Editor declared a past co-authorship with one of the authors MH.


Within California, older adults living in rural counties have reported higher rates of falls than urban dwelling older adults. Although many Indigenous people live in rural areas, it is unclear whether the rate of falls among Indigenous older adults is similar to that of non-indigenous older adults living in rural areas. Thus, the purpose of this study was to examine fall risk behaviors and intrinsic risk factors for falls in rural dwelling Indigenous (N = 89), and non-Indigenous (N = 68) older adults 60-95 years of age living in California. Results showed that both Indigenous and non-Indigenous older adults share similarly high fall rates, but there are a much greater number of Indigenous older adults falling multiple times a year. Moreover, fall risk behaviors and intrinsic fall risk factors were significantly different between Indigenous and non-Indigenous rural-dwelling older adults. Future studies should investigate falls and fall risk factors in different tribes/locations of Indigenous older adults to better understand whether these risk factors differ among tribes. Moreover, it would be beneficial for future studies to assess the effectiveness of fall prevention exercises on fall risk in these communities. Information gained from this study helps to inform clinicians and researchers alike about the prevalence of falls and factors contributing to falls among Indigenous older adults living in rural communities; and helps to influence decisions in the future of programs for reducing fall risk in this often neglected population.


While considerable progress has been made in studying genetic and cellular aspects of metastasis with in vitro cell culture and in vivo animal models, the driving mechanisms of each step of metastasis are still relatively unclear due to their complexity. Moreover, little progress has been made in understanding how cellular fitness in one step of the metastatic cascade correlates with ability to survive other subsequent steps. Engineered models incorporate tools such as tailored biomaterials and microfabrication to mimic human disease progression, which when coupled with advanced quantification methods permit comparisons to human patient samples and in vivo studies. Here, we review novel tools and techniques that have been recently developed to dissect key features of the metastatic cascade using primary patient samples and highly representative microenvironments for the purposes of advancing personalized medicine and precision oncology. Although improvements are needed to increase tractability and accessibility while faithfully simulating the in vivo microenvironment, these models are powerful experimental platforms for understanding cancer biology, furthering drug screening, and facilitating development of therapeutics. Metastatic progression of solid tumors can be divided into five major steps: (1) invasion of the basement membrane and cell migration; (2) intravasation into the surrounding vasculature or lymphatic system; (3) survival in the circulation; (4) extravasation from vasculature to secondary tissue; and finally, (5) colonization at secondary tumor sites .5 PDXs and primary cells obtained directly from patients are more rigorous predictors of clinical outcomes by incorporating patient-specific genomics absent from cell lines. Notably, PDXs can accurately predict clinical response to targeted cancer therapeutics.6 Although these must be maintained in immunocompromised mice long term and can be only used for a limited number of passages in vitro, the ability to assimilate primary human samples into engineered models is a significant advance over traditional animal models and microfabricated platforms.Numerous cell lines have been isolated from human or murine tumors to provide homogeneous samples that possess genomic alterations consistent with their native tissue sources.7 Tissue specimens from diagnostic surgery can be procured and manipulated to obtain primary human cells which can be immortalized for long term use by treating with human telomerase.8 Immortalized primary cells retain many traits from the primary tissue specimen while still undergoing multiple passages, and they can recapitulate cancer cell signaling and extracellular matrix (ECM) remodeling.8 The ability to incorporate primary samples into in vitro models of each metastatic stage has the potential to transform these devices into more precise and impactful predictors of clinical outcomes.With tissue banks becoming more readily available for research use, both normal and cancerous tissue samples from patients can be obtained.9 Invasion through the basement membrane is considered the differentiating step between pre-cancerous neoplasia and malignant cancer in which increased collagen deposition, fiber thickness, and linearized fiber architecture contribute to a stiffer environment.11 Cells mechanically remodel ECM through a cycle of cell protrusion and contraction, and chemically degrade the matrix using metalloproteinases as they migrate.12 In addition, cancer cell contractility and matrix stiffness create a positive feedback loop causing downstream effects on cell behavior during metastatic progression.13 As such, accurate invasion and migration models must incorporate ECM with tunable stiffness, adjustable pore size, and measurable and/or controllable degradability.Metastasis is initiated during invasion and migration where cancer cells penetrate the basement membrane and navigate as single cells or via collective means through the stromal microenvironment, respectively., in vitro tumor models rarely capture the full complexity of spatiotemporal heterogeneities inherent in tumor progression due to cell culture time scales and construct size limits. The use of organoids partly overcomes these limitations by better representing genotypic and phenotypic diversity in a structured in vitro microenvironment. These structures, derived directly from human tumor tissue samples, preserve three-dimensional architecture and patient-specific phenotypes while in culture  posts modeling various levels of substrate rigidity, and synthesized networks of tunable porosity mimic features in tumor architecture during disease progression.32 To observe confined migration in a more physiologically relevant system, collagen can be micro-molded to create tracks of tunable geometries recapitulating in vivo collagen structures  differentiation into endothelial cells which assembled into perfusable, capillary-like networks, and capturing endothelial response to different environmental biochemical and biophysical cues.43 Incorporation of patient-derived hiPSCs in platforms such as these lays the foundation for personalized characterization of tumor angiogenesis and endothelial cell response to cancer therapeutics. In addition, the hyaluronic hydrogel used in this platform has been shown to induce cell migration, and thus further modifications to this design could potentially be used to simultaneously investigate invasion and migration in a defined microenvironment.Since blood flow and interstitial pressure influence tumor angiogenesis, most microfluidic systems focus on recapitulating these in vitro. Models utilizing micromolding and bioprinting techniques have been used to fabricate endothelialized tissue constructs to visualize real-time endothelial cord formation during tubulogenesis.44 In addition, tremendous inter-tumor heterogeneity in angiogenic activity depends partly on the organ of origin and cancer subtype, due to organ-specific differences in the pro- and anti-angiogenic molecule secretion profiles of stromal cell populations.35 Thus, the development of more specific, personalized experimental systems will enable characterization of angiogenic behavior within different tumor types and for individual patients, leading to improvements in drug-screening models.Although current in vitro models contain essential features of angiogenesis, further work should be aimed at incorporating tissue-specific cell types and ECM features found at organ-specific primary tumors sites, such as recapitulating low permeability vascular beds present at the blood–brain barrier or highly permeable vascular beds of liver sinusoids.45 The tumor microenvironment provides both chemical and physical cues to induce tumor cell intravasation. For example, stiffened ECM has been correlated with increased endothelial permeability which potentially promotes tumor cell intravasation.47 Although tumor cells secrete pro-angiogenic factors influencing the vascular phenotype, vascular cells actively regulate invasion.49 Thus, co-culture models representing the complex interactions between cancer cells, endothelium, and surrounding stroma are necessary to characterize intravasation.In addition to providing nutrients, tumor vasculature also facilitates intravasation, the process by which cells infiltrate the vasculature.50 For example, one of these systems incorporating cancer, endothelial, and immune cells supports the role of macrophage-assisted intravasation correlating with clinical results.48 Thus, these platforms serve as models to examine potential immune cell involvement in intravasation.Microfluidic systems allow for the incorporation of fluid flow and are amenable to real-time imaging capability. Recently, commercially available microchannel systems were used to observe intravasation events after vascular network formation.51 Circulating tumor cells (CTC) arrest in a vessel and extravasate through two primary mechanisms: physical occlusion and adhesion after rolling (Fig. Although few cancer cells reach the circulation, even fewer survive the hemodynamic shear forces, immune stresses, and red blood cell collisions they encounter once there.ing Fig. . During 55 These platforms often employ surfaces functionalized with CTC-specific adhesion proteins or antibodies to optimize adhesion dynamics for CTCs while minimizing that of leukocytes also present in whole blood.55 Physical entrapment under flow can also be utilized to isolate CTC clusters that have been suggested to have increased metastatic potential compared to single CTCs.54 Recent work has shown that single-cell encapsulation of CTCs into microdroplets can be utilized to profile enzyme secretion.56 In addition, single-cell RNA sequencing of human patient CTCs has been optimized to assess inter- and intra-patient heterogeneity and identify potential therapeutic targets using a microfluidic platform and barcoding technique.57 As the methods to capture viable CTCs become more tractable, further probing of later stages of metastasis using isolated CTCs could provide insight into the properties of these rare but crucial cells. Engineered platforms have the potential to elucidate the changes CTCs may undergo as they transition from solid tissue to the circulation, as well as determine the properties of CTCs best suited for extravasation and colonization.Microfluidic and microtubing systems enabling the collection of both single and clustered CTCs from patient blood have contributed greatly to understanding cancer metastasis.59 and study the interactions of CTCs with neutrophils, platelets, and endothelial monolayers.62 Efforts to increase throughput have led to the development of a cone viscometer platform that interfaces with standard 96-well plates to enable more streamlined testing.63 Although cone and plate viscometers facilitate highly controlled, reproducible exposure to shear conditions, they lack relevant vessel-like architecture and do not allow for real-time imaging during shear exposure.Cone and plate viscometers are often used to expose cancer cells to physiological shear forces in cell culture medium or whole blood65 Parallel plate flow chambers can be used to assess rolling-adhesion interactions between circulating cells perfused over a substrate coated with ECM, ligands, or endothelial monolayers.67 Others assess the rolling and adhesion of cancer cells to physiologically relevant proteins using controlled perfusion through functionalized microtubing.70Numerous commercially available, relatively inexpensive platforms are used to produce shear stresses in vitro. Motorized expulsion through a needle has been used to assess cancer cell viability and conditioning after shear stress exposure.71 More complete microfluidic models can incorporate spatially defined chemokine gradients and or organ-specific cells, such as primary lung endothelial cells or osteo-differentiated bone marrow derived stem cells.74 Although numerous microfluidic platforms mimic the vasculature, CTCs can also travel through the lymphatic system. Notably, it was observed that low shear stresses mimicking lymphatic flow induced cancer cell motility while high shear stresses mimicking arterial and venous flows inhibited cell motility in a YAP1-dependent manner, highlighting the importance of selecting physiologically relevant shear stresses since different ranges can elicit divergent cell behaviors.75Microfluidic systems provide an immense degree of customization, with the ability to incorporate complex structures and dynamic flow patterns in perfused channels that can be coated with ECM or endothelial monolayers.76 For example, a microfluidic device with capillary-sized channels was used to show that CTC clusters isolated from patient blood can traverse these constrictions while remaining intact.77Tumor cell arrest during extravasation can also occur through cancer cell occlusion in capillary networks. Serial deformation and transmigration chambers in microfluidic devices have been designed to mimic constrictions in capillaries and relevant endothelial/ECM barriers that cells must bypass to transmigrate after arresting.78 To stabilize self-assembled networks, co-culturing fibroblasts segregated from endothelial cells provides the necessary paracrine signaling for network stabilization, while co-seeding with pericytes regulates vessel diameter and decreases vessel permeability.79 Although self-assembled microvascular networks do not necessarily require specialized equipment, control over network formation is limited.Recently, self-assembled perfusable microvascular networks have been developed to investigate physical occlusion and rolling-adhesion events leading to extravasation.80 Although geared towards improving tissue engineering designs, this platform could be adapted to study extravasation in capillary networks. Live-cell lithography was developed to better control cell placement for in vitro vascular network assembly.81 In this system, multiple optical tweezers are used to manipulate placement of cells in three dimensions allowing the controlled addition of pericytes, smooth muscle cells, and fibroblasts outside of the vessel. Advances like these lay the foundation for systems that better recapitulate the complexity of the tumor microenvironment. As patient CTC capture platforms improve, further incorporation of these precious clinical samples into downstream assays will be crucial towards investigation of CTC performance during subsequent stages of metastasis. If assays can be streamlined and correlated with clinical data, theranostic platforms with CTCs isolated from patient blood have the potential to improve clinical outcomes.Three-dimensional printing of carbohydrate glass sacrificial fibers can create highly controlled, multiscale, and perfusable vascular networks.82 After extravasation, cancer cells have one final task to complete: colonization of secondary sites. This process is thought to be extremely inefficient with only a minute percentage of CTCs growing into lesions.83 Metastatic niches possess cell types and ECM compatible for tumor cell survival and growth,83 including perivascular niches, spaces around blood capillaries where cancer cells can seed. Extravasation and colonization models require tissue-specific cell types, microenvironmental cues, and vascularization. Leveraging tissue engineering advancements to model metastatic sites may be key in understanding factors driving colonization as it is possible to tailor the site to isolate roles of cells types, growth factors, and ECM architectures.Following arrest within the vessel, cancer cells must extravasate from the vessel to colonize new sites. This process differs from intravasation, where cancer cells navigate tumor-modified stroma via chemotactic and durotactic gradients toward leaky, nascent vasculature without experiencing hemodynamic stressors; rather, during extravasation, the vasculature that is breached by cancer cells is healthier, and cancer cells actively experience fluid shear stresses due to blood flow.84 Osteo-differentiated mesenchymal stem cells, mineralized hydroxyapatite-incorporated ECM, and ex vivo bone scaffolds have all been shown to elicit relevant cell behavior in in vitro bone tissue models.88 Incorporation of perfusable vascular networks in these models allows for cancer cells to be flowed though, recapitulating extravasation events at the metastatic site. Bioreactors can be used to create complex, mature tissue constructs for seeding as well as to expose seeded scaffolds to tunable, physiological compressive forces to observe colonization behavior.90As bone metastasis occurs frequently in breast and prostate cancers and correlates with shortened patient prognoses, many models of metastatic colonization in bone have been created.91 Moreover, decellularization provides a scaffold that can then be re-seeded with cancer cells to examine colonization in a simplified yet physiological setting.92 Decellularization proves a powerful technique to enhance and inform tissue-engineered constructs of metastatic colonization sites and assess cancer cell-ECM interactions. LiverChip® is a commercialized microfluidic model of the hepatic niche used to observe interactions between cancer cells, hepatocytes, and non-parenchymal cells.93 Infiltration of the brain–blood barrier has been modeled by adding cancer cells to numerous permutations of co-cultures containing endothelial cells, pericytes, glial cells, astrocytes, and cancer-associated fibroblasts.98 As lung, liver, brain, and lymph node are all extremely common metastatic sites, further work should be directed towards developing more complex, physiologically relevant in vitro models for assessment of cancer cell metastatic colonization at these distinct locations.Several different models have been exploited to assess colonization in various organ systems. Decellularization of tissues including mammary fat pad, lymph node, and lungs has been used to three-dimensionally map the spatial distribution of ECM components of these tissues in health and disease.Currently, metastatic colonization assays are in their infancy relative to assays focusing on earlier stages. As colonization is the stage where metastasis gains its lethality and where confounding events like drug-resistance and dormancy often occur, it is promising as a key point of intervention. While much emphasis is placed on the personalized side of patient-specific cancer cells, understanding patient-specific, non-tumor cells in metastatic sites may help explain drug-resistance and dormancy.While in vivo models can be used to study the entirety of the cascade, the complexity and timescale of metastasis limits their utility. In vitro models successfully recapitulate individual steps in metastasis, yet few encompass more than one stage in the process.99 Specifically, microfluidic chambers containing a gut tissue-like ‘source’ seeded with colon cancer cells and a liver tissue-like ‘sink’ are connected by a perfused flow channel. In this model, cancer cells can exit the gut chamber and spread to the liver chamber. This three-dimensional construct facilitates drug-screening and visualization of metastasis, though it still lacks important features like endothelial barrier function, intravasation, and extravasation. Despite limitations, it marks one of the first steps toward an in vitro model distilling the key components representing the diverse microenvironments cancer cells encounter during metastasis.Recent work to develop a more complete metastatic platform has resulted in a microfluidic metastasis-on-a-chip model where hydrogels embedded with host tissue cells are combined with microfluidics to represent the spread of metastatic cells from primary to secondary tissue.100 However, metastasis is a dynamic, multi-step process and by simplifying models to exclude parts of the cascade, we are only gaining insight as to how well cancer cells perform specific steps out of context. Thus, it is critical that more complete models be developed so that metastasis can be observed in the correct series of events.Although there are still limitations hindering in vitro recapitulation of the full metastatic cascade, approaches that stitch together multiple sequential steps into a single assay have fewer impediments. Reductionist models that incorporate a primary tumor site and a metastatic niche site separated by ECM serve as a simplified approach to assessing metastatic potential.Engineered in vitro models have greatly expanded our understanding of cancer metastasis. Incorporation of primary cells and tissue within metastatic models provides more physiologically relevant and clinically applicable findings that often correlate with patient outcomes, aiding in drug-screening and personalized medicine to advance precision oncology. As tissue banks become more common and access to primary human samples increases, metastatic models are moving towards more faithful representations of native in vivo cell interactions and behaviors Fig. .Fig. 4Pr15With the addition of primary patient blood or tumor tissue samples into established in vitro models of the metastatic cascade, personalized characterization of metastatic cancer cell behavior is gaining tractability. Further, coupling these patient-specific assays with high-throughput drug-screening approaches could aid in optimizing patient treatment plans as well as facilitate drug discovery. For example, patient-derived organoids can serve as effective preclinical models for rapidly assessing therapeutics, shown to exhibit similar responses to chemotherapeutic drugs such as topotecan and melphalan consistent with clinical outcomes.99 Moving forward on the path towards personalized cancer theranostics, ameliorations to existing in vitro models, including the addition of patient-derived samples and integration of multiple steps of the metastatic cascade into one platform, will be essential.As microfabrication techniques and biomaterials advance, models are gaining the ability to recapitulate multiple tissue-specific microenvironments connected in a physiologically relevant manner as pioneered primarily for pharmaceutical toxicity studies. Adaptation of these systems to simulate key elements of multiple metastatic stages in sequence could provide novel insight. In addition, more comprehensive models such as the metastasis-on-a-chip model that elegantly incorporates multiple steps still lack essential components in their design, such as endothelial barriers to study intravasation and extravasation effects.Further information on research design is available in the Reporting Summary


Tasks of increasing difficulty require increasing levels of cognitive engagement from participants. The costs associated with cognitive engagement rise with age in response to normative cognitive decline. Additionally, previous studies have shown an interaction between age and task difficulty, with age differences in effort expenditure increasing along with task demands. Motivational accounts of effort allocation predict the opposite relationship, where increased task difficulty in the face of declining cognitive abilities result in disengagement among older adults, comparatively lowering their effort expenditure relative to younger adults that remain committed to the task. The current study quantitatively reviews the available literature on age and effort expenditure across tasks of increasing difficulty. An initial meta-analysis found no age differences in effort across task difficulty, but inspection of the significantly heterogeneous effect sizes indicated that measurement domain might account for some of the variance found between the effect sizes. A second, post-hoc meta-analysis was conducted, recoding effect sizes giving preference to subjective measures. Subsequent moderator variable analyses found that the combined effect of age and domain of effort measurement explained a sufficient portion of the variance across effect sizes. When using physiological measures, effort was not found to differ across task difficulty for either age group. Alternatively, when measured subjectively, effort was reported to greatly increase (>1 standard deviation) with difficulty, with a larger increase in younger adults. Results are discussed in terms of effort mobilization across adulthood and the importance of measurement domain in the interpretation of results.


Sitophilus zeamais (Motschulsky) and Prostephanus truncatus (Horn). Other insects of lesser economic importance also were observed in the visual surveys, including Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae), and Tribolium castaneum (Herbst). This study demonstrated that the use of acoustic technology with visual surveys and pitfall traps can help managers to identify and target infestations within their warehouses, enabling them to reduce postharvest losses. With most warehouses being located in relatively noisy urban or peri-urban areas, background noise considerations are being incorporated into the design of future acoustic detectors for stored pest infestations. Kenya must import grain yearly to meet consumption needs; however, if the current yearly postharvest losses of 20–30% in warehouses decreased, import costs could be reduced considerably.Grain production is an important component of food security in Kenya but due to environmental conditions that favor rapid growth of insect populations, farmers and other agricultural stakeholders face ongoing and novel challenges from crop and stored product pest insects. To assist development of methods to reduce economic losses from stored product insect pests in Kenya, acoustic, visual, and pitfall trap surveys were conducted in five grain storage warehouses. Two commercially available acoustic systems successfully detected the pests of greatest economic importance,  Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) [fall armyworm] into sub-Saharan Africa will lead to 20–50% maize yield loss , Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae) [maize weevil], Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) [red flour beetle] and Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae) [Angoumois grain moth] are the major maize pests in sub-Saharan Africa , T. castaneum, and possibly other postharvest pests have been developing resistance to phosphine  and Oryzaephilus surinamensis (Linnaeus)  [sawtoothed grain beetle].Pitfall trap counts provide sampling information about local insect populations that can be useful for pest management programs . Two of  also in . Though AEC and IMC systems provided consistent quantitative measurements. Previous research has shown, however, that among the commercially available detection systems, piezoelectric sensors have greater sensitivity to insect-produced sounds because the signals encounter less attenuation as signals traverse from the insects to the sensors across different media [The results of the visual and acoustic assessments of infestation of the 50 kg storage bags suggest that both the nt media . In addiAEC probe system than for the IMC system. Such results were in agreement with Leblanc et al. [Proximity of the insects to the sensors is known to be another important factor contributing to the sensitivity of an acoustic system to detect insect infestation. The use of waveguide probes can improve the detection range by increasing the volume of grain close enough to the sensor for detection, thus improving the accuracy of detection. In this study, the rates of insect sound bursts detected and the rate of burst impulses, were consistently greater for the c et al. , who comTo improve the sensitivity and accuracy of detection in the presence of background noise, efforts have been directed towards constructing sound-attenuating boxes lined with foam and fitted with piezoelectric sensors, an example of which is shown in . These iP. truncatus and S. zeamais pest species, which provides earlier detection. However, the effects of distance between insect and sensor on detectability noted above, as well as the considerable variation of an insect’s level of activity over time [The statistically significant correspondence between the magnitude of insect sound burst rates and counts of insects captured in the probe traps confirms that acoustic detection is a useful tool for detecting and monitoring infestations in Kenyan grain warehouses. An important benefit of acoustic systems is their identification of hidden as well as visible infestations of important ver time , and thever time , combinever time ,24 in inver time  and hermver time .It is worth noting that several cell phone sound detection apps have been developed, e.g., , some ofExperience gained from the Kenyan stored product insect acoustic detection study indicates that acoustic, visual, and pitfall trap surveys all contribute information useful for early detection and management of visible and hidden pest infestations but suggests that challenges remain in designing user-friendly acoustic systems that automatically discriminate out background noise often present in warehouses. Efforts are in progress to incorporate additional spectral and temporal pattern features of sounds produced by target insects into cost-effective acoustic detection systems. Knowledge of early infestation can assist warehouse managers in maintaining strategic grain reserves with scarce resources. Improved monitoring combined with innovations such as hermetic storage bags may enable reduced reliance on grain imports.


Facial appearance served great function in social interactions, especially for older adults in making trustworthiness judgements. Previous literatures have consistently shown that when making trustworthiness judgements older adults tended to rely more on facial cues rather than behaviors, due to declines in cognition. However, one question remains unsolved, whether older adults could make accurate trustworthiness judgements if evaluative information  is easily accessible. Sixty younger adults (YAs) and sixty older adults (OAs) were recruited, and asked to make investment decisions for different brokers in ninety-six trials. In each trial, brokers’ facial appearance (trustworthy and untrustworthy looking) and different behavioral evaluative information  were displayed simultaneously on screen to facilitate investment decisions. Brokers’ facial appearances and behaviors were set to be independent to each other. The results indicated that YAs’ and the majority of OAs’ proportions of correct investment increase, gradually reaching a stable high correction rate, although OAs needed more trials than did YAs. The findings extended prior work by suggesting that both OAs and YAs had similar abilities to distinguish different brokers according to easily accessible evaluative information. However, and surprisingly, a small subgroup of OAs (with low economic status) still had a lower correction rate even after ninety-six trials, suggesting that they could not distinguish brokers based on their evaluations at all, who might be at risk for fraud.


Second, Lindsey will introduce technological innovations used in the I-CONECT project including development of user-friendly video-chat devices, recording of audio and video data and innovative recruitment efforts. Third, Asgari will share results on how speech utterance and characteristics collected through the project could distinguish those with mild cognitive impairment from those with normal cognition using machine learning modelling approaches. Finally, Cerino and his team will show results of the study which examined whether cognitive improvements through conversation-based intervention depend on an individual’s personality, laying the groundwork for a personalized intervention trial in the future. The symposium is of interest for those who study social isolation and its prevention, the link among cognition, social isolation and personality, as well as those who focus on technology as a tool for improving well-being of older adults.Epidemiological studies have demonstrated that larger social networks or more frequent social interactions may have protective effects against cognitive decline and the incidence of dementia. Therefore, increasing social interaction could be a promising intervention for improving cognitive well-being in socially isolated older adults. We have conducted multiple NIH-funded randomized controlled trials (RCT) over 10 years, examining whether conversational interactions through webcam and internet can improve cognitive functions and enhance cognitive reserve. In this symposium, we will introduce this series of behavioral intervention trials through 4 presentations. First, Dodge will provide background and results of their previous RCT where they showed efficacy of conversational intervention on domain-specific cognitive functions and introduce the ongoing larger project called I-CONECT (


Mammalian guts harbor indigenous microbes that are integral to host health. Microbiome research using sophisticated model organisms has provided insights into intricate interactions between microbiota and host animals. However, it remains unclear how these animal-microbe associations developed. We have recently addressed this question via comparative analyses of chordates, given that complex biological systems can be resolved into ancestral and derived elements when examined in an evolutionary framework (Nat Commun 9: 3402). Results support the view that microbial colonization of the mucus layer that overlies mammalian gastrointestinal epithelium was established upon loss of ancestral chitin-based barrier immunity. Comparative approaches enable us to arrange ongoing biological processes into host natural history for better understanding of intestinal animal-microbe associations. Mammalian intestines are home to indigenous microbial communities. High-throughput sequencing approaches revealed that these microbes are taxonomically diverse and distinct from those of the surrounding environment. Omics analyses of germ-free animals, combined with manipulation of gut flora, provided growing evidence for complex cellular and molecular mechanisms that underlie reciprocal interactions between microbiota and hosts. Nonetheless, we know little about how these intimate animal-microbe associations developed. Biological systems result from a series of evolutionary processes. Thus, in principle, regardless of their complexity, they can be discriminated into ancestral and derived elements when examined in a proper biological setting. Accordingly, we have conducted comparative analyses of chordates.In animal phylogeny, chordates form a branch of deuterostomes and consist of two invertebrate groups, lancelets and tunicates, as well as vertebrates. Gill slits are a key anatomical feature of deuterostomes, which enable water flow from the mouth to the gill slits. This water flow through the pharynx was prerequisite for their particulate feeding. Invertebrate chordates further employ unique net-like structures secreted from the endostyle, a chordate-specific pharyngeal glandular organ, to establish efficient filter-feeding. Using tunicates, we addressed if this chordate lineage that feeds on environmental microbes harbors indigenous microbes in their gut space similarly to mammals.Ciona intestinalis Type A revealed that the gut space was radially compartmentalized by an unknown membranous structure. Microbes captured by filtration were confined to a luminal space enclosed by this membrane, while a peripheral space over the gut epithelium appeared almost free of bacteria. A combination of chemical and physical analyses demonstrated that the membrane was formed of multilayered, meshed chitin nanofibers embedded in a proteinaceous matrix. The chitinous membranes were secreted and delaminated from the gut epithelium. When chitin synthesis was chemically inhibited, the membrane and axenic space disappeared and food microbes directly contacted with the enterocytes, thereby causing an increased death rate of Ciona. These data showed that the endogenous chitinous membranes are essential for formation of the axenic space and contribute to gut homeostasis by acting as a physical barrier .Transmission electron microscopy of gut sections of the tunicate Ciona membrane, as these structures are framed with meshed chitin nanofibers produced by homologous chitin synthases. On the other hand, these structures have distinct matrix protein compositions. While invertebrate peritrophic matrix consists of protein with chitin-binding and/or proline-threonine-serine-domains, Ciona membranes are comprised of anti-bacterial proteins and gel-forming mucin, which is the main constituent of the mammalian mucus layer that covers the gut epithelium. Briefly, the Ciona membrane provides molecular evidence for a possible link between the invertebrate peritrophic matrix and the mammalian mucus layer, which are considered analogous, i.e. with no common descent . To test this idea, we have examined the following chordate lineages that occupy phylogenetic positions between invertebrates and mammals: a basal chordate Branchiostoma floridae (lancelet), a jawless vertebrate Eptatretus atami (hagfish), and a jawed vertebrate Oreochromis mossambicus (ray-finned fish). All these organisms possessed intestinal chitinous membranes.Similar chitinous barrier membranes have been well studied in several invertebrate lineages. So-called invertebrate peritrophic matrices structurally resemble the O. mossambicus, seemingly contradicts the common view that gut mucosal surfaces of ray-finned fish are covered with a mucus layer that is colonized by indigenous microbes as in mammals. Actually, 16S ribosomal RNA gene analysis showed the presence of indigenous microbes in the gut of O. mossambicus, but this microbial community was enclosed by chitinous membranes and was segregated from the surrounding mucus layer secreted by crypt goblet cells. In contrast, we were unable to detect chitin in the guts of mice, where gut microbiota directly interact with goblet cell-derived mucus.The finding of chitinous membranes in the ray-finned fish, In conclusion, this comparative study provides a glimpse of evolutionary changes in the intestinal mucosal surfaces of chordates. We proposed a transition from a chitin-based ancestral condition to a mucin-based derived state . Radial compartmentalization of the gut space by chitinous membrane seems to be an ancestral feature of chordates. In tunicates, filter-fed microbes transiently pass through the intestine, while being confined to the luminal space by the chitinous barrier. Ray-finned fishes retain this chitin-based barrier immunity, but viable passage of ingested microbes was prevented by bactericidal gastric juice, an invention of jawed vertebrates. This would have offered the subsequent gut space as a new ecological niche for surviving microbes. Because mammals lack the chitinous barrier, gut microbes interact directly with the surrounding goblet cell-derived mucus. Thus, it seems that chitin-based barrier immunity and its loss predated mucus colonization by indigenous gut microbiota.There are considerable variations in intestinal mucus-microbe interactions. In mice, ileum mucus is loose, yet it limits microbial access to host tissues through joint actions with diffusible molecules like RegIIIγ. Colon mucus forms two layers with the outer layer extensively colonized by microbes and the densely packed inner layer devoid of microbes. The degree of mucus penetrability varies among bacterial species. These variations can be explained in the context of regional adaptation driven by local functional demands since the onset of direct mucus-microbe interaction. Accordingly, comparative approaches enable us to arrange ongoing biological processes into host natural history to decipher the complex animal-microbe association.


This symposium examines how social and psychological factors including formal schooling, subjective memory, and neuropsychological symptoms impact cognitive function among older adults in China and the U.S. The first paper used the WHO’s Study on global AGEing and adult health Wave-1 data to examine the relationship between subjective cognitive function, perceived memory decline, and objective cognitive function among older adults in China. The results showed worse subjective cognitive function was associated with poorer working memory and verbal fluency, whereas greater perceived memory decline was associated only with poorer working memory. Furthermore, using data from the Health and Retirement Study, the second paper applied group-based trajectory modeling to assess dual trajectories of subjective memory impairment and objective cognitive decline. Four distinct dual-trajectory typologies were identified, suggesting complex co-occurring changes in subjective memory and objective cognition in older adults. The third paper characterized the trajectories of three neuropsychological symptoms  prior to dementia onset. Using data from the National Health and Aging Trends Study, the study found older adults with dementia exhibit distinct trajectory of depression before dementia onset than those without dementia. Trajectories of pain and insomnia did not differ before dementia onset. The last paper examined the effect of education on cognitive decline among lower educated older adults using data from the Longitudinal Study of Older Adults in Anhui Province, China. Results suggest that older adults with some formal schooling had slower cognitive decline; the gap in cognition between the literate and illiterate widened with age.


Interventions to improve nursing home care have been developed and tested. However readily disseminated interventions are lacking. Barriers include low staffing levels contributing to limited time for education and high turnover of direct care and administrative staff. Educational interventions must be accessible to accommodate busy staff. Meaningful outcome measures are needed and interventions must fit varied nursing home sizes, ownership, resident population, and regions. Changing Talk Online (CHATO) was adapted from the effective, yet time-intensive, Changing Talk program addressing nursing home staff communication. The original classroom-based program significantly improved staff communication with residents and resulted in subsequent reductions in resident behavioral and psychological symptoms of dementia. Strategies for marketing and recruiting nursing homes and to engage administrators and staff will be discussed as implemented in the Changing Talk Online (CHATO) R61 trial. Approaches addressing unique nursing home challenges to implementation are essential for successful dissemination to improve care.