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Pectus excavatum is the most common congenital anomaly of the chest wall. Surgical management of this problem has evolved to encompass many modifications of Dr Ravitch's initial groundbreaking repair to include the insertion of mesh, metal struts, and bars to bolster the repair through open and minimally invasive approaches. This report presents a case of right ventricular outflow tract obstruction from a dislodged pectus bar after a modified Ravitch procedure. The presentation, diagnosis, and management of this exceedingly rare complication are described, and the discussion also provides clinical pearls and inspiration for future research directions that are based on this experience.

Early life sleep disruption (ELSD) has been shown to have long lasting effects on social behavior in adult prairie voles (Microtus ochrogaster), including impaired expression of pair bond behavior during partner preference testing (e.g., reduced huddling with a pair bonded partner). However, due to the limitations of manual behavior tracking, the behavioral effects of ELSD across the entire time course of pair bond formation have not yet been described, hindering our ability to trace mechanisms. Here, we used computer vision to precisely track multiple behaviors during opposite-sex cohabitation of prairie voles. Male-female pairs were allowed to interact through a mesh divider in the home cage for 72 h, providing variables of body direction, distance-to-divider, and locomotion speed, with temporal resolution as high as the video frame rate (20-25 Hz). We found that control males displayed periodic, stereotyped patterns of body orientation towards females during pair bond formation. In contrast, ELSD males showed reduced duration and ultradian periodicity of these body orientation behaviors towards females. Furthermore, in both sexes, ELSD altered stereotypical spatial and temporal patterns of locomotion seen in control animals that typically varied across days of cohabitation and light/dark periods. This study highlights the utility of computer vision in deep characterization of subtle behaviors and allows a more comprehensive behavioral assessment of the profound and persistent effects of ELSD on later life social behavior. Our findings may shed light on causal mechanisms underlying human neurodevelopmental disorders featuring sleep disruption and social deficits, such as autism spectrum disorder.

Early life experiences are crucial for proper organization of excitatory synapses within the brain, with outsized effects on late-maturing, experience-dependent regions such as the medial prefrontal cortex (mPFC). Previous work in our lab showed that early life sleep disruption (ELSD) from postnatal days 14–21 in the highly social prairie vole results in long lasting impairments in social behavior. Here, we further hypothesized that ELSD alters glutamatergic synapses in mPFC, thereby affecting cognitive flexibility, an mPFC-dependent behavior. ELSD caused impaired cued fear extinction (indicating cognitive inflexibility), increased dendritic spine density, and decreased glutamate immunogold-labeling in vesicular glutamate transporter 1 (vGLUT1)-labeled presynaptic nerve terminals within mPFC. Our results have profound implications for neurodevelopmental disorders in humans such as autism spectrum disorder that also show poor sleep, impaired social behavior, cognitive inflexibility, as well as altered dendritic spine density and glutamate changes in mPFC, and imply that poor sleep may cause these changes.

Real-time tracking of neurotransmitter levels in vivo has been technically challenging due to the low spatiotemporal resolution of current methods. Since the imbalance of cortical excitation/inhibition (E:I) ratios are associated with a variety of neurological disorders, accurate monitoring of excitatory and inhibitory neurotransmitter levels is crucial for investigating the underlying neural mechanisms of these conditions. Specifically, levels of the excitatory neurotransmitter L-glutamate, and the inhibitory neurotransmitter GABA, are assumed to play critical roles in the E:I balance. Therefore, in this work, a flexible electrochemical microsensor is developed for real-time simultaneous detection of L-glutamate and GABA. The flexible polyimide substrate was used for easier handling during implantation and measurement, along with less brain damage. Further, by electrochemically depositing Pt-black nanostructures on the sensor's surface, the active surface area was enhanced for higher sensitivity. This dual neurotransmitter sensor probe was validated under various settings for its performance, including in vitro, ex vivo tests with glutamatergic neuronal cells and in vivo test with anesthetized rats. Additionally, the sensor's performance has been further investigated in terms of longevity and biocompatibility. Overall, our dual L-glutamate:GABA sensor microprobe has its unique features to enable accurate, real-time, and long-term monitoring of the E:I balance in vivo. Thus, this new tool should aid investigations of neural mechanisms of normal brain function and various neurological disorders.

Early postnatal experiences are important for shaping the development of the stress response and may contribute to the later emergence of alcohol use disorders. We have previously found that early life sleep disruption impairs social development and alters GABA neurons in the brain of adult prairie voles, a socially monogamous rodent that displays natural ethanol preference in the laboratory. However, it is unclear whether these effects on social behavior are due, in part, to overall anhedonia and/or altered behavioral response to stress. To address this question, litters containing prairie vole pups were sleep disrupted by gentle cage agitation for 7 consecutive days from postnatal days (P) 14 to 21 (early life sleep disruption, or ELSD group) or allowed to sleep undisturbed (Control). Adult voles underwent a 2-bottle choice ethanol drinking procedure integrated with a single session of footshocks. Ethanol intake after footshock was measured as well as c-Fos immunoreactivity in the lateral and central amygdala. ELSD animals showed increased ethanol consumption and increased neural activity in these amygdala regions after footshock compared to control animals. There were no differences in baseline ethanol drinking prior to exposure to a stressor. These results suggest that early life sleep disruption in prairie voles does not produce anhedonia but can have long-lasting effects on stress reactivity. In addition to shaping species-typical social behavior, early life sleep may be important in the development of stress induced ethanol consumption and the activation of limbic pathways associated with stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Traumatic Brain Injury (TBI) is a highly prevalent and serious public health concern. Most cases of TBI are mild in nature, yet some individuals may develop following-up persistent disability. The pathophysiologic causes for those with persistent postconcussive symptoms are most likely multifactorial and the underlying mechanism is not well understood, although it is clear that sleep disturbances feature prominently in those with persistent disability. The sleep electroencephalogram (EEG) provides a direct window into neuronal activity during an otherwise highly stereotyped behavioral state, and represents a promising quantitative measure for TBI diagnosis and prognosis. With the ever-evolving domain of machine learning, deep convolutional neural networks, and the development of better architectures, these approaches hold promise to solve some of the long entrenched challenges of personalized medicine for uses in recommendation systems and/or in health monitoring systems. In particular, advanced EEG analysis to identify putative EEG biomarkers of neurological disease could be highly relevant in the prognostication of mild TBI, an otherwise heterogeneous disorder with a wide range of affected phenotypes and disability levels. In this work, we investigate the use of various machine learning techniques and deep neural network architectures on a cohort of human subjects with sleep EEG recordings from overnight, in-lab, diagnostic polysomnography (PSG). An optimal scheme is explored for the classification of TBI versus non-TBI control subjects. The results were promising with an accuracy of ∼95% in random sampling arrangement and ∼70% in independent validation arrangement when appropriate parameters were used using a small number of subjects (10 mTBI subjects and 9 age- and sex-matched controls). We are thus confident that, with additional data and further studies, we would be able to build a generalized model to detect TBI accurately, not only via attended, in-lab PSG recordings, but also in practical scenarios such as EEG data obtained from simple wearables in daily life.

Sensory gating , the ability to suppress sensory information of irrelevant stimuli, is affected in several neuropsychiatric diseases , notably schizophrenia and autism . It is currently unclear how these deficits interact with other hallmark symptoms of these disorders, such as social withdrawal and difficulty with interpersonal relationships. The highly affiliative prairie vole (Microtus ochrogaster) may be an ideal model organism to study the neurobiology underlying social behavior. In this study, we assessed unimodal acoustic sensory gating in male and female prairie voles using the prepulse inhibition (PPI) paradigm, whereby a lower amplitude sound (prepulse) decreases the startle response to a high amplitude sound (pulse) compared to the high amplitude sound alone. Prairie voles showed evidence of PPI at all prepulse levels compared to pulse alone, with both males and females showing similar levels of inhibition. However, unlike what has been reported in other rodent species, prairie voles did not show a within-session decrease in startle response to the pulse alone, nor did they show a decrease in startle response to the pulse over multiple days, highlighting their inability to habituate to startling stimuli (short- and long-term). When contrasted with a cohort of male wildtype C57Bl/6J mice that underwent a comparable PPI protocol, individual voles showed significantly higher trial-by-trial variability as well as longer latency to startle than mice. The benefits and caveats to using prairie voles in future sensory gating experiments are discussed.

L-glutamate is the most abundant neurotransmitter (NT) in the human brain and is involved in essentially all activities of the central nervous system. Variations in its availability have also been linked to neuronal disorders such as secondary mechanisms in traumatic spinal cord injury. Compared to conventional assays, electrochemical sensors have been an area of interest in NT measurement due to their favorable sensitivity as well as high temporal and spatial resolution. In this work, a highly sensitive, L-glutamate specific, amperometric electrochemical sensor was developed by cost-effective electrodeposition of nanostructured platinum black (Pt-black) on platinum substrates, which increases the active surface area for sensing. A self-referencing site was integrated in order to increase the signal-to-noise ratio (SNR). After further applying m-phenylenediamine dihydrochloride as a size exclusion layer, we demonstrated good sensitivity and selectivity for the miniaturized prototypes. These devices can be further developed for implantable biosensors for in vivo dynamic measurement and evaluation.

BACKGROUND Frozen section is a standard of care procedure during thoracic surgery when an immediate diagnosis is needed. An alternative procedure is intraoperative cytology. Video-assisted thoracic surgery is currently widely used for thoracic surgical procedures. The aim of this study was to assess intraoperative cytology together with frozen section for accuracy, turnaround time, and total response time during video-assisted thoracic surgery. METHODS We included patients having video-assisted thoracic surgery between August 2018 and February 2019 at our institution. A cytopathologist and a surgical pathologist independently performed intraoperative cytology and frozen sections, respectively. Final histologic diagnosis was the reference standard. Intraoperative cytology, frozen section turnaround, and total response times were analyzed. RESULTS A total of 52 specimens from 27 patients were included. The intraoperative cytology correlated with final histology in 98% of cases. Frozen section correlated with final histology in 100% of cases. Intraoperative cytology turnaround and total response times were equal (mean, 4.35 minutes; range, 2-15 minutes). Mean frozen section turnaround and response times were 26.2 minutes (range, 9-61 minutes) and 36.7 minutes (range, 16-90 minutes), respectively. We found a statistically significant difference between intraoperative cytology and frozen section turnaround time and total response times (P < .001). CONCLUSIONS This study highlights that intraoperative cytology could be as accurate as frozen section and considerably faster during video-assisted thoracic surgery (P < .001). Total response time could potentially be used as a quality metric for video-assisted thoracic surgery.

327 Background: In the CROSS trial, neoadjuvant chemoradiotherapy (CRT) prior to surgery for esophageal (E) and gastroesophageal junction (GEJ) cancers was found to improve survival. However, 10-year data did not show benefit in reducing isolated distant metastases. Addition of full-dose induction chemotherapy (CT) prior to CRT could provide early systemic disease control in addition to enhanced local control. We evaluated induction CT with FOLFOX followed by CRT and surgery in patients with E/GEJ cancers. Methods: This single-arm, phase II clinical trial investigated trimodality therapy in clinically staged II/III resectable cancers of the E/GEJ (NCT03110926). Treatment schedule was: 6 weeks of mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) followed by 5.5 weeks of CRT with weekly paclitaxel and carboplatin and 41.4-45 Gy of radiation (RT) and surgery. Primary endpoint was 2-year relapse-free survival (RFS) measured from time of surgery to date of first recurrence or death and was calculated by the Kaplan-Meier method. Overall survival (OS) and key pathologic findings were secondary outcomes. Results: In total, 41 patients enrolled with mean age of 63.1 years; 78% were male. Almost all (95%) were adenocarcinoma. Median duration of follow-up was 2.08 years. Most primary tumors were located in the GE junction (68.3%). Treatment was well tolerated: 95% patients completed all FOLFOX cycles, 98% received the pre-specified RT dose, and 36 of 41 (87.7%) went on to have surgery (1 elected observation after complete clinical response). R0 resection occurred in 97% of those that went on to have surgery. At least partial pathologic response was found in 30 of 36 (83.3%); 8 of 36 (22%, CI 10.1-39.2%) had a pathologic complete response (pCR) and 20 of 36 (55%) had pCR or near-complete response (NCR). At the time of analysis, 2-year RFS was 71.5% (CI 52.1-84.2) and the median RFS was 3.1 years; median OS was not reached. At time of follow-up, 85% (17 of 20) of those with NCR and PCR were relapse-free. Conclusions: Our study demonstrates a high treatment completion rate when FOLFOX was administered prior to CRT and surgery for E/GEJ cancers. Almost all patients had R0 resection and over half had NCR or pCR response. Short-term follow-up RFS and OS demonstrate promising efficacy for this approach in a sample almost exclusively of adenocarcinoma tumors. Strategies to implement induction FOLFOX or FLOT either with or without CRT should continue to be explored in larger studies. Clinical trial information: NCT03110926.

Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

Introduction Lymph node sampling by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the state of art procedure for staging the mediastinum and hilar regions in lung cancer patients. Our experience of implementing the real-time cytopathology intervention (RTCI) process for intraoperative EBUS-TBNAs is presented. This study is aimed to describe in detail the RTCI process for EBUS-TBNAs, and assess its utility and diagnostic yield before and after its implementation in parallel to conventional rapid on-site evaluation (c-ROSE). Methods A retrospective review of all EBUS-TBNAs between July 2016 and July 2017 at the University of Rochester Medical Center was performed. Final diagnoses, patient clinical data, and number of non-diagnostic samples (NDS) were reviewed. The numbers of NDS obtained from EBUS-TBNAs with no cytology assistance (NCA), with RTCI and with c-ROSE were analysed. Results Non-diagnostic lymph node samples were found in 20 out of 116 (17%), three out of 114 (2.6%) and 33 out of 286 (11.5%) cases with NCA, RTCI and c-ROSE, respectively. Application of statistical analysis revealed significant difference in the NDS between the groups of cases in the operating room with NCA and RTCI (P = .005). The different settings and variables between the cases performed using RTCI in the operating room and those assisted with c-ROSE in the bronchoscopy suite preclude legitimate comparison. Conclusion Our results indicate that the use of RTCI could yield a significantly low proportion of NDS when assisting EBUS-TBNA of mediastinal and hilar lymph node for lung cancer patients enhancing the diagnostic efficiency of the procedure.

Study Objectives. Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) commonly cooccur. Approaches to research and treatment of these disorders have been segregated, despite overlapping symptomology. We and others have hypothesized that comorbid TBI + PTSD generates worse symptoms than either condition alone. We present a mouse model of comorbid TBI + PTSD to further explore this condition. Methods. A mouse model of TBI + PTSD was generated using the single prolonged stress (SPS) protocol in combination with the controlled cortical impact (CCI) protocol. This resulted in four experimental groups: control, TBI, PTSD, and TBI + PTSD. Behavioral phenotyping included gait analysis, contextual fear conditioning, acoustic startle response, and prepulse inhibition. Results. Mice in the TBI + PTSD group showed a significantly impaired gait compared to their counterparts with TBI alone as well as control mice. Mice in the TBI + PTSD group showed significantly impaired contextual fear recall compared to controls. Prepulse inhibition testing revealed intact acoustic startle and auditory sensory gating. Conclusions. These results indicate that SPS paired with CCI in mice produces unique behavioral impairments in gait and fear recall that are not present in either condition alone. Further studies are underway to examine additional behavioral, physiological, and pathological phenotypes in this combined model of TBI + PTSD.

Introduction Sleep disturbances are common in elderly patients and may contribute to disease progression in certain populations (e.g., Alzheimer’s Disease). Light therapy is a simple and cost-effective intervention to improve sleep. Primary barriers to light therapy are 1) poor acceptability to use of devices and 2) inflexibility of current devices to deliver beyond a fixed spectrum and throughout the entirety of the day. However, dynamic, tunable lighting integrated into the native home lighting system can maximize short-wavelength light in the morning and minimize short-wavelength light in the evening, thus entraining circadian rhythms and treating sleep disturbances, and overcome these limitations. We determined the feasibility of implementing a whole-home tunable lighting system as a potential sleep intervention. Methods Tunable LED lights were installed throughout the homes of healthy older adults already enrolled in an existing study with embedded home assessment platforms (ORCATECH study; n=4 subjects in n=3 homes). In ORCATECH, continuous data on room location, activity, sleep, and general health parameters are collected at minute-to-minute resolution over months to years of participation. This single arm longitudinal design collected participants’ light usage in addition to ORCATECH outcome measures. Primary outcomes for this pilot study included the feasibility and patient acceptability. Exploratory outcomes were sleep metrics (sleep time, latency, efficiency), mobility (room transitions and actigraphy), and overall health indices (weekly body weight, self-report general health questionnaires) both pre- and post-intervention. Results Two subjects terminated the study citing technical difficulties with the lights and a preference for brighter illumination. Of the remaining 2 participants, sleep metrics were explored over a 12-month period spanning pre- and post-installation of lights. Nightly duration in bed was compared with minute-to-minute room entry data and actigraphy with high inter-measure reliability. Conclusion These data support that tunable whole-home lighting systems are reasonably acceptable and feasibly implemented using an automated platform for continuous data collection. Quantification of sleep over long periods of time is robust and reliable in the home environment of elderly subjects. These results will inform implementation of future large-scale lighting intervention studies in patients at risk for developing Alzheimer’s Disease. Support (if any) Hartford Gerontological Center Interprofessional Award, Pacific Northwest National Laboratory, OHSU ORCATECH

Introduction Sleep problems are common in humans with post-traumatic stress disorder (PTSD). Rapid eye movement (REM) sleep is involved in processing emotional memories; it is often disrupted in those with PTSD, and may be related to increased anxiety. Single prolonged stress (SPS) is a protocol used to model PTSD in rats, however little is known about how this model impacts sleep in mice. Prior research suggests SPS produces short term disturbances in REM sleep and increases in anxiety-like behavior, but further validation of this model is needed to understand how SPS impacts sleep and anxiety-like behaviors in mice specifically, as they have greater potential for transgenic manipulation Methods C57BL6/J mice underwent a SPS protocol in which they were tube-restrained for 2 hours, followed by a 15 minute forced swim in a group, ether exposure until loss of consciousness, and 10 days of social isolation. Following SPS, mice were tested for anxiety-like behavior in a light-dark box and sleep was measured from surgically implanted EEG and EMG leads. Time spent in wake, REM sleep, and non-REM sleep was quantified for 24 continuous hours in SPS and Control mice. Results There were no significant effects of SPS on the amount of time spent in any vigilance state, or in sleep-wake transitions. However, SPS-exposed mice showed significantly more anxiety-like behavior. EEG power spectra were analyzed in relevant frequency bands during each sleep state, and exploratory analyses were conducted Conclusion Minimal effects on sleep macroarchitecture were seen in mice 10 days after SPS. It is possible that sleep disturbances seen immediately after trauma exposure (such as in prior studies in rats) may have diminished over time. Further studies will need to include additional timepoints and analysis of sleep microarchitecture following SPS, and in other mouse models of PTSD, in order to more comprehensively examine changes in sleep. Support (if any) VA CDA #IK2 BX002712, Portland VA Research Foundation, Medical Research Foundation

Introduction A bidirectional relationship exists between sleep disruption and neuropathology in Alzheimer’s disease (AD). The sleep electroencephalogram (EEG) is a highly stereotyped, direct neurophysiological window into brain function; prior studies have identified abnormalities in EEG slow waves in early AD. EEG coherence across channels during sleep, a normally highly coherent brain state, could be an indicator of network coordination across brain regions. Accordingly, altered slow wave coherence during sleep may be an early indicator of cognitive decline. Methods EEG was collected during an attended overnight polysomnogram (PSG) from a community-based cohort of older subjects (n=44, average age = 71), approximately 25% of whom met criteria for mild cognitive impairment or early AD. Files were exported to EDF and a slow wave peak detector was implemented in MATLAB to count the number of slow wave oscillations, with automated artifact rejection, across 6 EEG leads standard for PSG (C3, C4, F3, F4, O1, and O2). Slow wave coherence was inferred when slow waves occurred in temporal synchrony across channels within 100 ms. Results Subjects with cognitive impairment showed significantly reduced total sleep time and time spent in rapid eye movement (REM) sleep compared to age-matched controls. EEG slow wave coherence was reliably quantified during wake, non-REM stages N1, N2, N3, and REM vigilance states as well as during transition periods between sleep stages. Using this algorithm, specific signatures of slow wave propagation during sleep were identified, including increased variability in slow wave activity and coherence, that appeared more prominent in subjects with impaired cognition. Conclusion EEG slow wave coherence during sleep and wake states can be calculated by applying automated algorithms to PSG data, and may be associated with cognitive impairment. Support (if any) NIH R01 AG059507

Sleep complaints are an early clinical symptom of neurodegenerative disorders. Patients with Parkinson's disease (PD) experience sleep disruption (SD). The objective of this study was to determine if preexisting, chronic SD leads to a greater loss of tyrosine hydroxylase (TH) within the striatum and the substantia nigra following chronic/progressive exposure with the neurotoxin, 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice underwent chronic SD for 4 weeks, then injected with vehicle (VEH) or increasing doses of MPTP for 4 weeks. There was a significant decrease in the plasma corticosterone levels in the MPTP group, an increase in the SD group, and a return to the VEH levels in the SD+MPTP group. Protein expression levels for TH in the striatum (terminals) and substantia nigra pars compacta (dopamine [DA] cell counts) revealed up to a 78% and 38% decrease, respectively, in the MPTP and SD+MPTP groups compared to their relevant VEH and SD groups. DA transporter protein expression increased in the striatum in the MPTP versus VEH group and in the SN/midbrain between the SD+MPTP and the VEH group. There was a main effect of MPTP on various gait measures (e.g., braking) relative to the SD or VEH groups. In the SD+MPTP group, there were no differences compared to the VEH group. Thus, SD, prior to administration of MPTP, has effects on serum corticosterone and gait but more importantly does not potentiate greater loss of TH within the nigrostriatal pathway compared to the MPTP group, suggesting that in PD patients with SD, there is no exacerbation of the DA cell loss.

Despite its apparent adaptive advantages, past research has found that greater familiarity and/or familial relatedness of a social demonstrator does not enhance social learning in the social transmission of food preference paradigm. This finding runs counter to research examining the effects of demonstrator characteristics in fear-mediated social learning paradigms, in which increased familiarity and/or relatedness of a demonstrator promotes higher rates of learning in observer rats. In our first experiment, we were able to corroborate the finding that increased familiarity/relatedness to the demonstrator does not enhance acquisition of a socially transmitted food preference. Furthermore, on examination of the social behavior between observers and their demonstrators during the acquisition of a socially transmitted food preference, no analogous relationship between social contact and expression of the learned preference was observed. In our second experiment, we provide further evidence that familiarity/relatedness may enhance the social acquisition of a fear response to an otherwise neutral auditory cue and demonstrate that this effect is not solely the result of increased social contact between the observer and their demonstrator during acquisition. Despite similar levels of post-cue contact in both observer types, a positive correlation was observed between post-cue social contact and expression of a socially acquired fear behavior when the observer was familiar/related to their demonstrator but not novel/unrelated. These findings both validate previous research on the role of familiarity/relatedness in these two social learning paradigms and provide further behavioral evidence that unique social mechanisms may serve to mediate the social transmission of fear.

Traumatic experiences early in life can contribute to the development of mood and anxiety disorders that manifest during adolescence and young adulthood. In young rats exposed to acute fear or stress, alterations in neural development can lead to enduring behavioral abnormalities. Here, we used a modified extinction intervention (retrieval+extinction) during late adolescence (post-natal day 45 [p45]), in rats, to target auditory Pavlovian fear associations acquired as juveniles (p17 and p25). The effects of adolescent intervention were examined by assessing freezing as adults during both fear reacquisition and social transmission of fear from a cagemate. Rats underwent testing or training at three time points across development: juvenile (p17 or p25), adolescent (p45), and adult (p100). Retrieval+extinction during late adolescence prevented social reinstatement and recovery over time of fears initially acquired as juveniles (p17 and p25, respectively). Adolescence was the only time point tested here where retrieval+extinction prevented fear recall of associations acquired 20+ days earlier.

Acquiring information about stimuli that predict danger, through either direct experience or inference from a social context, is crucial for individuals’ ability to generate appropriate behaviors in response to threats. Utilizing a modified demonstrator–observer paradigm (fear conditioning by proxy) that allows for free interaction between subjects, we show that social dominance hierarchy, and the interactive social behaviors of caged rats, is predictive of social fear transmission, with subordinate rats displaying increased fear responses after interacting with a fear-conditioned dominant rat during fear retrieval. Fear conditioning by proxy conserves some of the pathways necessary for direct fear learning (e.g., lateral amygdala) but is unique in that it requires regions necessary for emotional regulation (e.g., anterior cingulate cortex), making this paradigm an important tool for evaluating learning and behavior in the laboratory setting. Electronic supplementary material The online version of this article (doi:10.1007/s10071-016-1013-2) contains supplementary material, which is available to authorized users.

Sleep is critical for proper sensory and social development in young prairie voles, an affiliative and monogamous rodent species., Across mammals, juveniles sleep more than adults, with rapid eye movement (REM) sleep at a lifetime maximum early in life. One function of REM sleep may be to facilitate brain development of complex behaviors. Here, we applied 1 week of early-life sleep disruption (ELSD) in prairie voles (Microtus ochrogaster), a highly social rodent species that forms lifelong pair bonds. Electroencephalographic recordings from juvenile voles during ELSD revealed decreased REM sleep and reduced γ power compared to baseline. ELSD impaired pair bond formation and altered object preference in adulthood. Furthermore, ELSD increased GABAergic parvalbumin immunoreactivity in the primary somatosensory cortex in adulthood, a brain region relevant to both affected behaviors. We propose that, early in life, sleep is crucial for tuning inhibitory neural circuits and the development of species-typical affiliative social behavior.

We describe a method of social fear transmission to a discrete auditory cue in freely behaving rats. Extending beyond traditional observer/demonstrator paradigms, rats are allowed to physically interact and integrate cues from all sensory modalities. In the protocol described in this article, "observer" rats experience social fear conditioning through a proxy cage mate that serves as a "demonstrator" during retrieval of a cued fear memory. We find that a specific auditory cue can come to elicit fear expression in an animal with no foot shock experience simply by interacting with a conspecific expressing a conditioned response in the presence of an otherwise benign stimulus. In this "fear conditioning by proxy" paradigm, we have demonstrated that some, but not all, rats display conditioned responding (e.g., freezing) to a cue after interacting with a cage mate during fear memory retrieval. The amount of freezing exhibited by this fear conditioned "by proxy" rat 24 hr after learning critically depends on social influences, including social relationships and social interactions during learning. © 2018 by John WileySons, Inc.

We examined the enduring effects of predictable versus unpredictable fear conditioning early in life on memory and relearning in adulthood. At postnatal Day 17 or 25 (P17 or P25), rats either remained naive, or were fear conditioned using paired (predictable) or unpaired (unpredictable) presentations of white noise and foot shocks. At 2 months of age (adulthood), each group was fear conditioned (or reconditioned) with either paired or unpaired training, and then was tested for fear extinction the next day. Initial findings replicate previous work from our lab and others, demonstrating a difference in adult memory retention based on age of acquisition. Specifically, rats that received paired conditioning at P25, but not P17, show increased freezing to the cue when tested in adulthood. We further show that paired as well as unpaired conditioning at P17 potentiates paired conditioning in adulthood; however, paired, but not unpaired, conditioning at P25 potentiates paired and unpaired conditioning in adulthood. These findings suggest that early predictable versus unpredictable aversive learning at P17 or P25 differentially modulate memory retention and future learning. (PsycINFO Database Record

Safety margins in pulmonary metastasectomy are not yet well defined. We hypothesize that histological subtype, size of the lesion and local growth characteristics must be taken into consideration during metastasectomy. This study was conducted to examine and classify growth patterns at resection margins and define the relationships between aggressive local growth, metastasis size and local recurrence to direct metastasectomy.Histologic sections of pulmonary metastases were prospectively collected and haematoxylin-eosin stains were systematically evaluated and classified by their pattern of lung tissue infiltration. Logistic regression was used to model the association between the subgroups of colorectal, renal cell and epithelial cancers and melanomas and sarcomas.From 183 patients, 412 lung specimens were removed, which contained 459 pulmonary metastases. We found that 58% of all lesions had microscopic signs of aggressive local dissemination. The metastases showed histology-specific patterns of local growth: sarcoma was associated with pleural infiltration; colorectal metastases with interstitial spread and aerogenous spread of floating cancer cell clusters; and melanoma with perivascular growth and with lymph vessel involvement. Aggressive patterns of growth had an increasing probability of around 3% for each additional millimetre of metastasis diameter. Local intrapulmonary recurrence was significantly more common in association with interstitial growth and pleural penetration as well as safety margins 7 mm.Approximately 40% of all lung metastases have a smooth surface and might be resected with small margins. Growth characteristics within the lung differ with the histologic subtype and safety margins should generally increase with the size of the metastasis.

Pairing a neutral cue (e.g., a tone) with an inherently aversive unconditioned stimulus (US; e.g., a footshock) creates an associative memory such that later presentations of the now conditioned stimulus alone elicit a conditioned fear response (e.g., freezing). This direct associative learning is only one technique through which individuals can learn about potential threats. However, the convenient design and robust responses makes direct fear conditioning the most frequently used paradigm in the research of fear and anxiety disorders. Fear can also be acquired from a social context, such as observing the fear expression of a conspecific or witnessing another animal during a dangerous encounter. The extent to which nonprimate laboratory animals engage in learning strategies based on vicarious experience is remarkably scantily characterized. Recently, attempts to determine the conditions that allow the social transmission of fear in laboratory rodents have gained traction, with results and interpretations varying to a great degree. Utilizing a modified demonstrator–observer paradigm that allows free interaction between subjects—fear conditioning by proxy—we explore the ability of rats to learn an associative fear response vicariously. Here, we review how certain individual traits in the current situational state of the subjects may either facilitate or impede learning in this social fear-conditioning paradigm and discuss how fear conditioning by proxy learning relates to empathy seen in humans.

Background The current American Joint Committee on Cancer Seventh Edition (AJCC7) pathologic staging for esophageal adenocarcinoma (EAC) is derived from data assessing the outcomes of patients having undergone esophagectomy without neoadjuvant treatment and has unclear significance in patients who have received multimodality therapy. Lymph nodes with evidence of neoadjuvant treatment effect without residual cancer cells may be observed and are not traditionally considered in pathologic reports, but may have prognostic significance. Methods All patients who underwent esophagectomy after completing neoadjuvant therapy for EAC at our institution between 2006 and 2012 were reviewed. Slides of pathologic specimens were reexamined for locoregional treatment-response nodes lacking viable cancer cells but with evidence of acellular mucin pools, central fibrosis, necrosis, or calcifications suggesting prior tumor involvement. Kaplan-Meier survival functions were estimated, and Cox proportional hazards regression models were used to compare staging models. Results Ninety patients (82 men) underwent esophagectomy after neoadjuvant therapy for EAC (mean age, 61.8 ± 8.9 years). All patients received preoperative chemotherapy, and 50 patients also underwent preoperative radiotherapy. Median Kaplan-Meier survival was 55.6 months, and 5-year survival was 35% (95% confidence interval, 19% to 62%). A total of 100 treatment-response nodes were found in 38 patients. For patients with limited nodal disease (62 ypN0-N1), the presence of treatment-response nodes was associated with significantly worse survival ( p = 0.03) compared with patients lacking such nodes. Adjusting for patient age and AJCC7 pathologic stage showed the presence of treatment-response nodes significantly increased the risk of death (hazard ratio, 2.7; 95% confidence interval, 1.1 to 6.9; p = 0.04). When stage-adjusted survival was modeled, counting treatment-response nodes as positive nodes offered a better model fit than ignoring them. Conclusions Treatment-response lymph nodes detected from esophagectomy specimens in patients having undergone neoadjuvant chemotherapy or combined chemoradiation for EAC provide valuable prognostic information, particularly in patients with limited nodal disease. The current practice of considering lymph nodes lacking viable cancer cells, but with evidence of tumor necrosis, as pathologically negative likely results in understaging. Future efforts at revising the staging system for EAC should consider incorporating treatment-response lymph nodes in the analysis.

The detection of gastroesophageal reflux (GERD) via pH testing is the key component of the evaluation of patients considered for antireflux surgery. Two common pH testing systems exist, a multichannel, intraluminal impedance-pH monitoring (MII-pH) catheter, and wireless (Bravo®) capsule; however, discrepancies between the two systems exist. In patients with atypical symptoms, MII-pH catheter is often used preferentially. We aimed to elucidate the magnitude of this discrepancy and to assess the diagnostic value of MII-pH and the Bravo wireless capsule in a population of patients with mixed respiratory and typical symptoms. The study population consisted of 66 patients tested with MII-pH and Bravo pH testing within 90 days between July 2009 and 2013. All patients presented with laryngo-pharyngo-respiratory (LPR) symptoms. Patient demographics, symptomatology, manometric and endoscopic findings, and pH monitoring parameters were analyzed. Patients were divided into four comparison groups: both pH tests positive, MII-pH negative/Bravo positive, MII-pH positive/Bravo negative, and both pH tests negative. Nearly half of the patients (44 %) had discordant pH test results. Of these, 90 % (26/29) had a negative MII-pH but positive Bravo study. In this group, the difference in the DeMeester score was large, a median of 29.3. These patients had a higher BMI (28.5 vs. 26.1, p = 0.0357), were more likely to complain of heartburn (50 vs. 23 %, p = 0.0110), to have a hiatal hernia, (85 vs. 53 %, p = 0.0075) and a structurally defective lower esophageal sphincter (LES, 85 vs. 58 %, p = 0.0208). In patients with LPR symptoms, we found a high prevalence of discordant esophageal pH results, most commonly a negative MII-pH catheter and positive Bravo. As these patients exhibited characteristics consistent with GERD (heartburn, defective LES, hiatal hernia), the Bravo results are likely true. A 24-h MII-pH catheter study may be inadequate to diagnose GERD in this patient population.

Fear conditioning is widely employed to examine the mechanisms that underlie dysregulations of the fear system. Various manipulations are often used following fear acquisition to attenuate fear memories. In rodent studies, freezing is often the main output measure to quantify ‘fear’. Here, we developed data-driven criteria for defining a standard benchmark that indicates remission from conditioned fear and for identifying subgroups with differential treatment responses. These analyses will enable a better understanding of individual differences in treatment responding. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

Background Five-year survival after the surgical treatment of esophageal cancer has traditionally been reported to be as low as 15%. More recently, the improvement of clinical staging involving PET/CT and the introduction of neoadjuvant chemo-radiation have each altered the survival outcomes of patients with this lethal disease. The impact of these factors on survival trends has not been well described in literature. The aim of this study was to analyze the survival trends after esophagectomy for esophageal adenocarcinoma at a high-volume center. Methods The study population consisted of 471 consecutive patients undergoing esophagectomy for esophageal adenocarcinoma at a university-based medical center between January 1, 2000 and July 31, 2017. Clinical variables were collected for three groups based on the date of esophagectomy and were compared (Group 1: 2000–2004, Group 2: 2005–2011, Group 3: 2012–2017). Survival was compared via the Kaplan-Meier (KM) method. Results The 471 patients had a median age of 64.0 years (range 27.0–86.2) and 395/471 (84%) were male. Dysphagia (282/471, 60%), heartburn (63/471, 13%) and chest pain (29/471, 6%) were the most common presenting symptoms. The majority of the patients underwent transhiatal esophagectomy (n = 279, 59.1%) and en-bloc esophagectomy (n = 85, 18.0%). Staging with PET/CT was utilized in 316/471 patients (67%) with 6% of Group 1, 76% of Group 2 and 100% of Group 3, P Conclusion This analysis reveals an improvement in 5-year survival after esophagectomy from 30% to 47% over the past two decades. Similarly, 10-year survival has improved from 23% to 37%. The evolution of better clinical staging and advancements in neoadjuvant therapy likely played a vital role in these trends. In contrast to the earliest cohort, PET/CT is now routinely utilized in the staging of esophageal cancer. Further, other than those with early stage disease, all patients are currently evaluated for neoadjuvant chemo-radiation. Notably, the 5-year survival rate for the most recent cohort (2012–2017) approaches 50% and would likely be higher if patients with esophageal adenocarcinoma treated endoscopically were included. Improvements in staging and treatment paradigms for esophageal adenocarcinoma have resulted in significant progress towards cure. Disclosure All authors have declared no conflicts of interest.

e15580 Background: Trimodality treatment (tx) with neoadjuvant chemoradiation (CRT) followed by esophagectomy is standard tx for locally advanced EGJ cancer. Post-operatively, there is no strong consensus about role of routine surveillance imaging. At the University of Rochester, patients (pts) have surveillance CT scans every 4-6 months (mos) for the first 2 years post-esophagectomy and every 6-12 mos for the next 3 years. Methods: Pts were identified who underwent esophagectomy for T1-T3 EGJ cancer between January 2011 and December 2015 at our institution. Objectives were to describe the impact of timing and methods of recurrence detection (MoRD) on patient outcomes. Recurrence-free (RFS) and overall survival (OS) were graphed via the Kaplan-Meier method. Results: 138 pts underwent esophagectomy for EGJ cancer: 107 (77.5%) were male, median age was 64, and 116 patients (84.1%) had adenocarcinoma. 112 pts (81.2%) had neoadjuvant CRT. The entire cohort’s median OS was 38.4 mos. 68 pts (49.3%) relapsed with a median RFS of 20.0 mos. Recurrence was detected by routine imaging in 36 pts (52.9%), imaging triggered by symptoms in 27 pts (39.7%), and symptoms alone in 5 pts (7.4%). Post-relapse median OS was 2.3 mos when detected based on symptoms alone, 5.0 mos when detected by imaging triggered by symptoms, and 13.7 mos when detected by routine scans (log-rank p = 0.041). There was no significant association between baseline patient/tumor characteristics or pathologic response and MoRD . 53 patients (77.9%) received salvage/palliative tx with a median of 2 tx (IQR = 1). There was no significant association between MoRD and number of salvage/palliative tx. Conclusions: 49.3% of pts relapsed after esophagectomy for EGJ cancer, consistent with current literature. Almost half of relapses were detected based on symptoms despite routine imaging. Increased OS for pts with relapse detected by routine scans is likely related to lead time bias, but may also be related to increased tx intensity or less aggressive tumors. MoRD did not have a measurable impact on number of lines of post-relapse tx. Prospective randomized trials are needed to determine real benefit of regular surveillance scans among EGJ cancer survivors.

32 Background: Trimodality treatment with neoadjuvant chemoradiation (CRT) followed by surgery is a standard treatment for esophageal/GEJ (E/GJ) cancers. Following esophagectomy, there is no strong consensus about optimal surveillance and routine imaging. At our institution, patients have surveillance CT scans every 4-6 months for the first 2 years post-surgery and every 6-12 months for the next 3 years. Methods: An IRB-approved chart review was performed identifying patients who underwent surgical resection for locally advanced E/GJ cancer between January 2011 and December 2015 at the University of Rochester. Study objectives were to describe timing of and methods used to detect recurrence as well as their impact on patient outcomes. Recurrence-free (RFS) and overall survival (OS) were graphed via the Kaplan-Meier method. Results: 138 patients underwent surgical resection for E/GJ cancer during the study period: 107 (77.5%) were male, median age was 64, and 116 patients (84.1%) had adenocarcinoma. 111 patients (80.4%) received neoadjuvant CRT. Median OS for entire cohort was 43.4 months. 65 patients (47.1%) relapsed with a median RFS of 19.8 months. Recurrence was detected by routine imaging in 34 patients (52.3%), imaging triggered by symptoms in 25 patients (38.5%), and symptoms alone in 6 patients (9.2%). Median OS post-relapse was 1.5 months when detected based on symptoms alone, 5.0 months when detected by imaging triggered by symptoms, and 13.5 months when detected by routine scans (Log-rank p = 0.046). There were no significant associations between baseline patient /tumor characteristics and subsequent method of recurrence detection. Conclusions: 47.1% of patients suffered relapse after trimodality therapy for E/GJ cancer, consistent with published literature. Almost half of these were detected based on symptoms despite routine imaging. Increased OS for patients with relapse detected by routine scans is likely related to lead time bias, but may be related to increased treatment intensity, or due to less aggressive tumors. Prospective randomized trials are needed to determine the true benefit of regular surveillance scans among esophageal cancer survivors.

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a foot-shock) leads to associative learning such that the tone alone will elicit a conditioned response (e.g., freezing). Individuals can also acquire fear from a social context, such as through observing the fear expression of a conspecific. In the current study, we examined the influence of kinship/familiarity on social transmission of fear in female rats. Rats were housed in triads with either sisters or non-related females. One rat from each cage was fear conditioned to a tone CS+ shock US. On day two, the conditioned rat was returned to the chamber accompanied by one of her cage mates. Both rats were allowed to behave freely, while the tone was played in the absence of the foot-shock. The previously untrained rat is referred to as the fear-conditioned by-proxy (FCbP) animal, as she would freeze based on observations of her cage-mate's response rather than due to direct personal experience with the foot-shock. The third rat served as a cage-mate control. The third day, long-term memory tests to the CS were performed. Consistent with our previous application of this paradigm in male rats (Bruchey et al. in Behav Brain Res 214(1):80-84, 2010), our results revealed that social interactions between the fear conditioned and FCbP rats on day two contribute to freezing displayed by the FCbP rats on day three. In this experiment, prosocial behavior occurring at the termination of the cue on day two was significantly greater between sisters than their non-sister counterparts, and this behavior resulted in increased freezing on day three. Our results suggest that familiarity and/or kinship influences the social transmission of fear in female rats.

Background Current diagnostic techniques establishing gastroesophageal reflux disease as the underlying cause in patients with respiratory symptoms are poor. Our aim was to provide additional support to our prior studies suggesting that the association between reflux events and oxygen desaturations may be a useful discriminatory test in patients presenting with primary respiratory symptoms suspected of having gastroesophageal reflux as the etiology. Methods Thirty-seven patients with respiratory symptoms, 26 with typical symptoms, and 40 control subjects underwent simultaneous 24-h impedance–pH and pulse oximetry monitoring. Eight patients returned for post-fundoplication studies. Results The median number (interquartile range) of distal reflux events associated with oxygen desaturation was greater in patients with respiratory symptoms (17 (9–23)) than those with typical symptoms (7 (4–11, p

Purpose Patients with pulmonary metastases (PM) from soft-tissue sarcomas (STS) have historically been treated with surgery and/or chemotherapy. Since 2001, we have treated PM with stereotactic body radiation therapy (SBRT). We postulated that SBRT for PM from STS would yield excellent local control (LC) and overall survival (OS). Methods and Materials Fifty-two patients with PM from STS, diagnosed between 1990 and 2006 at the University of Rochester, were retrospectively reviewed. Most patients received multimodality treatment comprising of surgery, chemotherapy, and/or radiation. SBRT used the Novalis ExacTrac patient positioning platform, vacuum bag immobilization, and relaxed end-expiratory breath hold techniques. Results Leiomyosarcoma (23%), malignant fibrous histiocytoma (19%), and synovial sarcoma (15%) were the most common histologies. Forty-eight percent initially presented with PM, whereas 52% developed PM at a median of 0.7 (0.3–7.3) years after initial diagnosis. Median follow-up from diagnosis of PM was 0.9 (0.3–7.3) years. Fifteen patients underwent SBRT to 74 lesions. Median number of lesions treated was 4 (1–16) per patient and 3.5 (1–6) per session. Preferred dose and fractionation was 50 Gy in 5 Gy fractions. Three-year LC was 82%. No patients experienced Grade ≥3 toxicity. Median OS was 2.1 (0.8–11.5) years for patients treated with SBRT, and 0.6 (0.1–7.8) years for those who never received SBRT (p = 0.002). Conclusions SBRT provides excellent LC of PM and may extend OS. SBRT should be considered for all patients with PM from STS, particularly those who are not surgical candidates. Further investigation is warranted to establish criteria for the use of SBRT for STS patients with PM.

Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response (‘darting’) that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes. DOI: http://dx.doi.org/10.7554/eLife.11352.001, eLife digest Animals can respond to fear in a variety of ways, such as by standing still (freezing), or rapidly escaping from an apparent threat. Freezing is the most common measure of fear that has been used in research studies. However, since the vast majority of these experiments have used male animals, it is not clear if freezing is a sufficient measure of fear in females. To address this question, Gruene et al. analyzed different types of fear responses in large groups of male and female rats. The experiments used a technique called cued fear conditioning, which pairs a sound with a mild electrical shock to a foot. When rats learn that the sound predicts the shock, the sound alone causes them to produce a fear response. However, if the sound is then played repeatedly without a footshock, the rats learn to become less fearful of the sound in another learning process called “extinction”. The experiments found that females were four times more likely than males to display fear in the form of rapid movements (referred to as “darting”). Animals that displayed darting were also less likely to freeze in response to the sound cue, which suggests that darting may represent an alternative fear strategy that is more common in females. During a subsequent extinction test, females that darted also displayed quicker reductions in both types of fear responses, which suggests that darting might be an active coping response that promotes long term reductions in fear. Gruene et al.’s findings suggest that there are differences in the ways that males and females respond in fear of a threatening stimulus, and highlight the importance of analyzing a variety of fear responses in experiments. The next steps will be to understand the biological basis of the darting response in female rats. DOI: http://dx.doi.org/10.7554/eLife.11352.002