The current state of gastrointestinal motility evaluation in cystic fibrosis: a comprehensive literature review.

Background and Objective: As life expectancy in cystic fibrosis (CF) has increased over the years, a shift in focus toward extra-pulmonary comorbidities such as gastrointestinal (GI) disease has become a topic of particular importance. Although not well-defined in the current literature, GI dysmotility is thought to significantly contribute to GI symptomatology in the CF population. The objective of this article was to provide a comprehensive review of diagnostic modalities at the disposal of the clinician in the evaluation of patients with CF (pwCF) presenting with GI complaints. Furthermore, we aimed to highlight the available literature regarding utilization of these modalities in CF, in addition to their shortcomings, and emphasize areas within the motility literature where further research is essential. Methods: A comprehensive review of all available literature in the English language through December 1, 2022 utilizing PubMed was conducted. Our search was limited to GI motility/transit and dysmotility in pwCF. Two researchers independently screened references for applicable articles and extracted pertinent data. Key Content and Findings: Several diagnostic imaging and manometry options exist in the evaluation of dysmotility; however, the literature is lacking in high-quality, prospective studies to validate such testing in pwCF. Common symptoms experienced and diagnostic motility tools available based on segment of the GI tract as related to pwCF are explored in the current review. Shortcomings in the current literature are identified and future direction to enhance research efforts within the field of CF-related dysmotility is provided. Conclusions: The influence of CF on GI integrity and motility is far-reaching. Despite improvements in longevity and advancement of pulmonary-specific treatment strategies, further high-quality research targeting the evaluation and management of GI dysmotility in pwCF is needed.

Refractory Gastroesophageal Reflux Disease: Diagnosis and Management.

Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett's esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.

Analyzing Outcomes of Nuss and Ravitch Repair for Primary and Recurrent Pectus Excavatum in Adults.

BACKGROUND: Limited data exist for pectus excavatum repair in adults. We reviewed outcomes in adult patients undergoing Ravitch or Nuss pectus excavatum repairs to determine whether there was a statistical difference in postoperative complications and recurrence between primary and redo operations. METHODS: Patients undergoing pectus excavatum repair between 2001 and 2018 were excluded if they were receiving a concurrent unrelated operation, aged younger than 18 years, or had less than 1 year of follow-up (for recurrence analysis). Postoperative complications were recorded based on procedure type (Ravitch/Nuss) and iteration of repair (primary/redo). Continuous patient data were compared using Student t tests for variables such as age, length of stay, estimated blood loss, body mass index, and number of bars inserted. Fisher exact or χ2 tests were performed for postoperative complications and recurrence rates between groups. RESULTS: Of 290 patients, there were no significant differences in postoperative complications or recurrence rates between all Nuss repairs (n = 237; P = .59) and all Ravitch repairs (n = 53; P = .48), redo Nuss repairs (n = 53; P = .26) and Ravitch repairs (n=26; P = .99), and primary (P = .26) and redo Nuss (P = .10) repairs or primary (P = .99) and redo Ravitch (P = .99) repairs. There were significant differences in age, length of stay, follow-up, bars inserted, and estimated blood loss between all Nuss and Ravitch repairs (P < .05). CONCLUSIONS: Postoperative complication and recurrence rates were not statistically different between Nuss and Ravitch procedures of all types, suggesting either procedure may have utility in recurrent pectus excavatum. Further research may look to expand sample size and a prospective study investigating long-term outcomes.

The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe: Separating Analgesia and Anxiety.

The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.

The effect of the speed and range of motion of movement on the hyperemic response to passive leg movement.

Passive leg movement (PLM)-induced hyperemia is used to assess the function of the vascular endothelium. This study sought to determine the impact of movement speed and range of motion (ROM) on the hyperemic response to PLM and determine if the currently recommended protocol of moving the leg through a 90° ROM at 180°/sec provides a peak hyperemic response to PLM. 11 healthy adults underwent multiple bouts of PLM, in which either movement speed (60-240°/sec) or ROM (30-120° knee flexion) were varied. Femoral artery blood flow (Doppler Ultrasound) and mean arterial pressure (MAP; photoplethysmography) were measured throughout. Movement speed generally exhibited positive linear relationships with the hyperemic response to PLM, eliciting ~15-20% increase in hyperemia and conductance for each 30°/sec increase in speed (P < 0.05). However, increasing the movement speed above 180°/sec was physically difficult and seemingly impractical to implement. ROM exhibited curvilinear relationships (P<0.05) with hyperemia and conductance, which peaked at 90°, such that a 30° increase or decrease in ROM from 90° resulted in a 10-40% attenuation (P < 0.05) in the hyperemic response. Alterations in the balance of antegrade and retrograde flow appear to play a role in this attenuation. Movement speed and ROM have a profound impact on PLM-induced hyperemia. When using PLM to assess vascular endothelial function, it is recommended to perform the test at the traditional 180°/sec with 90° ROM, which offers a near peak hyperemic response, while maintaining test feasibility.

Where Do We Begin? Building Blocks to Establish a Cardiothoracic Surgery Interest Group.

BACKGROUND: With the impending shortage of cardiothoracic (CT) surgeons, much focus has been on increasing trainee interest, particularly at the medical student level. We aimed to determine the effect of participation in our Cardiothoracic Surgery Interest Group (CTSIG) on medical student attitudes regarding surgery, and especially CT surgery. METHODS: An anonymous survey was administered at two time points to the current member list of our 2015 to 2016 CTSIG and repeated for the 2016 to 2017 academic year. A set CTSIG event schedule was developed with current CT faculty and included events every 1 to 2 months. Total CTSIG membership was 101 students. Descriptive analysis was performed on quantitative data. RESULTS: Of 73 preclinical students completing both pre/postsurveys, 62% (45) were male. Postsurveys demonstrated increased interest in surgery and CT surgery as a career, which was significantly greater than those reporting no change (p < 0.01 for both). Common factors mentioned as deterrents for a CT surgery career included lifestyle, length of training, and associated personality/culture. Events hosted by the CTSIG most frequently reported as increasing interest included lunches/dinners with CT surgery faculty (89%), a "Leadership in Surgery" event (58%), and an "Intro to CT Surgery and Q/A Session" hosted by a CT surgeon (51%). CONCLUSIONS: Establishing a CTSIG that includes preset events with exposure to CT surgery by shadowing and interaction with faculty in a relaxed setting has the ability to increase preclinical interest in CT surgery. More emphasis on advocacy is needed to clear up misconceptions about CT surgery to maintain recruitment of outstanding students in our CT surgery heritage.

An unusual etiology of hyperparathyroidism: robotic-assisted resection of a giant functional intrathymic parathyroid cyst.

Parathyroid cysts (PCs) are relatively rare entities, with an even smaller proportion that functionally produce parathyroid hormone (PTH). Given associated hypercalcemia, often symptomatic, as well as potentially related osteoporosis and/or nephrolithiasis, resection of these functional cysts is often indicated. This case report details the management course for a patient who presented with primary hyperparathyroidism and was ultimately found to have a functional intrathymic PC. During initial workup, 4-dimensional computed tomography (4D-CT) of the neck demonstrated enlarged left upper and right lower parathyroid glands; however, the patient's hyperparathyroid state persisted even after bilateral neck exploration and resection of these two glands. Subsequent postoperative imaging of the mediastinum revealed a large (11 cm) thymic cyst. The patient consequently underwent uneventful robotic-assisted thoracoscopic excision of the mediastinal cyst. Intraoperative blood PTH levels dropped from 734 pg/mL preoperatively to 86 pg/nL 10 minutes following resection, consistent with surgical cure by the Miami Criteria. At two months postoperatively, the patient's serum total calcium (STC) was normal at 9.2 mg/dL. Final surgical pathology noted a 15-gram parathyroid gland, with cystic degeneration. As the robot becomes further integrated into the everyday practice of thoracic surgery, we believe this approach offers advantages over conventional video-assisted thoracoscopic surgery (VATS) for mediastinal resections. Advantages include better visualization and finer, more precise dissection, especially important in this case, given the proximity of vital structures and the small, but real, risk of parathyromatosis associated with intraoperative cyst rupture.

Unmatched Integrated Cardiothoracic Surgery Program Applicants: Where Do They End Up?

BACKGROUND: With the recent introduction of Integrated Cardiothoracic Surgery Residency Programs (IPs), limited data exist on unmatched applicants. We aimed to determine the dropout rate in individuals who applied for IP but did not match. METHODS: An online Institutional Review Board-approved survey was sent to current residents (n = 409), provided by the Thoracic Surgery Directors Association, to evaluate preferences and pathway to cardiothoracic surgery (CTS). Descriptive analysis was performed on quantitative data. Main Residency Match Data from 2008 to 2017 were collected. RESULTS: Of 250 respondents, 89 (36%) were in IPs. In the cohort, 110 (44%) applied for at least one IP, whereas only 10 of the remaining 140 CTS residents had contemplated applying. From written comments of those 140 residents, the most common reasons against applying for IP programs were (1) uncertainty of IP training/belief that general surgery offered more well-rounded training and (2) uncommitted to CTS as a medical student. Interestingly, 96% of IP residents were set on a cardiac career, whereas a larger proportion of 4/3 and traditional residents were interested in general thoracic (36%). According to the National Resident Matching Program, 147 individuals applied to IP programs from 2008 to 2011 and were unmatched. Only 20 of those individuals (14%), from our results, ended up in a CTS residency program. CONCLUSIONS: Only a small percentage of applicants that did not match to an IP from 2008 to 2011 have ended up in CTS. As IPs continue to develop and improve, the concerns brought about by current CTS residents must be addressed to attract the next generation of exceptional surgeons.

Pleiotropy in Drosophila organogenesis: Mechanistic insights from Combgap and the retinal determination gene network.

Master regulatory transcription factors cooperate in networks to shepherd cells through organogenesis. In the Drosophila eye, a collection of master control proteins known as the retinal determination gene network (RDGN) switches the direction and targets of its output to choreograph developmental transitions, but the molecular partners that enable such regulatory flexibility are not known. We recently showed that two RDGN members, Eyes absent (Eya) and Sine oculis (So), promote exit from the terminal cell cycle known as the second mitotic wave (SMW) to permit differentiation. A search for co-factors identified the ubiquitously expressed Combgap (Cg) as a novel transcriptional partner that impedes cell cycle exit and interferes with Eya-So activity specifically in this context. Here, we argue that Cg acts as a flexible transcriptional platform that contributes to numerous gene expression outcomes by a variety of mechanisms. For example, Cg provides repressive activities that dampen Eya-So output, but not by recruiting Polycomb chromatin-remodeling complexes as it does in other contexts. We propose that master regulators depend on both specifically expressed co-factors that assemble the combinatorial code and broadly expressed partners like Cg that recruit the diverse molecular activities needed to appropriately regulate their target enhancers.

Mutations that impair Eyes absent tyrosine phosphatase activity in vitro reduce robustness of retinal determination gene network output in Drosophila.

A limited collection of signaling networks and transcriptional effectors directs the full spectrum of cellular behaviors that comprise development. One mechanism to diversify regulatory potential is to combine multiple biochemical activities into the same protein. Exemplifying this principle of modularity, Eyes absent (Eya), originally identified as a transcriptional co-activator within the retinal determination gene network (RDGN), also harbors tyrosine and threonine phosphatase activities. Although mounting evidence argues for the importance of Eya's phosphatase activities to mammalian biology, genetic rescue experiments in Drosophila have shown that the tyrosine phosphatase function is dispensable for normal development. In this study, we repeated these rescue experiments in genetically sensitized backgrounds in which the dose of one or more RDGN factor was reduced. Heterozygosity for sine oculis or dachshund, both core RDGN members, compromised the ability of phosphatase-dead eya, but not of the control wild type eya transgene, to rescue the retinal defects and reduced viability associated with eya loss. We speculate that Eya's tyrosine phosphatase activity, although non-essential, confers robustness to RDGN output.

Antagonistic regulation of the second mitotic wave by Eyes absent-Sine oculis and Combgap coordinates proliferation and specification in the Drosophila retina.

The transition from proliferation to specification is fundamental to the development of appropriately patterned tissues. In the developing Drosophila eye, Eyes absent (Eya) and Sine oculis (So) orchestrate the progression of progenitor cells from asynchronous cell division to G1 arrest and neuronal specification at the morphogenetic furrow. Here, we uncover a novel role for Eya and So in promoting cell cycle exit in the second mitotic wave (SMW), a synchronized, terminal cell division that occurs several hours after passage of the furrow. We show that Combgap (Cg), a zinc-finger transcription factor, antagonizes Eya-So function in the SMW. Based on the ability of Cg to attenuate Eya-So transcriptional output in vivo and in cultured cells and on meta analysis of their chromatin occupancy profiles, we speculate that Cg limits Eya-So activation of select target genes posterior to the furrow to ensure properly timed mitotic exit. Our work supports a model in which context-specific modulation of transcriptional activity enables Eya and So to promote both entry into and exit from the cell cycle in a distinct spatiotemporal sequence.

DeepStack: Expert-level artificial intelligence in heads-up no-limit poker.

Artificial intelligence has seen several breakthroughs in recent years, with games often serving as milestones. A common feature of these games is that players have perfect information. Poker, the quintessential game of imperfect information, is a long-standing challenge problem in artificial intelligence. We introduce DeepStack, an algorithm for imperfect-information settings. It combines recursive reasoning to handle information asymmetry, decomposition to focus computation on the relevant decision, and a form of intuition that is automatically learned from self-play using deep learning. In a study involving 44,000 hands of poker, DeepStack defeated, with statistical significance, professional poker players in heads-up no-limit Texas hold'em. The approach is theoretically sound and is shown to produce strategies that are more difficult to exploit than prior approaches.

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks.

Among the mechanisms that steer cells to their correct fate during development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. In this review we discuss the key features that underlie master regulatory potency during normal and ectopic development, focusing on two examples, the retinal determination gene network (RDGN) that directs eye development in the fruit fly and the pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo. In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate. By synthesizing the in vivo evidence provided by the RDGN with the extensive mechanistic insight gleaned from the PGN, we highlight the unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. We suggest that deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts.

Peer Technical Consultant: Veteran-Centric Technical Support Model for VA Home-Based Telehealth Programs.

The increased use of personal or VA-loaned computers and mobile devices for at-home telehealth has generated a need for support from a peer technical consultant who can troubleshoot technical issues.

Distinguishing grief from depression during acute recovery from spinal cord injury.

OBJECTIVE: To examine whether grief is a psychometrically sound construct that is distinct from depression in individuals who have recently sustained a spinal cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: Inpatient rehabilitation units at 3 geographically diverse, university-affiliated medical centers. PARTICIPANTS: Patients with SCI (N=206) were recruited (163 men [79.1%]). Most patients were non-Hispanic whites (n=175 [85.0%]). Most patients sustained a cervical SCI (n=134 [64.4%]). Various injury etiologies were represented, with the majority being accounted for by falls (n=72 [31.5%]) and vehicle-related accidents (n=69 [33.5%]). The mean time since injury was 53.5±40.5 days. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An adapted version of the 12-item structured clinical interview for Prolonged Grief Disorder was used to assess symptoms of grief, and the Patient Health Questionnaire-9 was used to measure depression. Demographic and injury-related data were also collected. RESULTS: A principal component analysis (with direct oblimin rotation) of the grief measure suggested a 2-component solution. The content of items loading on the separate components suggested 2 subscales: loss (6 items; Cronbach α=.810) and trauma (6 items; Cronbach α=.823). Follow-up principal component analyses including both grief and depression measures suggested clear differentiation of grief-related loss from depression. The prevalence of clinically significant levels of grief was low (6%), and levels of depression were consistent with previous findings related to inpatient rehabilitation (23.5%). CONCLUSIONS: The items used to assess grief symptoms in patients participating in inpatient rehabilitation for recently sustained SCI appear to capture a psychometrically reliable construct that is distinct from that of depression. Research is needed on the predictive validity of early grief symptoms after SCI and the relation of grief to other psychological constructs over time.

Making meaning in a burn peer support group: qualitative analysis of attendee interviews.

There is a paucity of literature on the personal experiences of burn support group members, the members' perceived benefits of group participation, and the meaning the survivors make of the support they receive. In order to provide effective psychosocial rehabilitation services and to meet the needs of burn survivors, it is important to understand the influence a support group has on its members as well as the personal experiences of those individuals who attend these groups. The purpose of this study was to explore the experiences of burn survivors in a burn survivor support group. Six self-identified burn survivors were interviewed by using a guided in-depth interview technique to explore their experiences in the support group. Key informant interviews and group observations served to triangulate the findings from the individual interviews. The experiences of the group members coalesced around four main themes: acceptance of self, perspective change, value of community, and reciprocity. The findings demonstrated the overall perceived positive impact the support group had on psychosocial recovery. For these members, the group aided the process of adjustment through the encouragement of adaptive coping strategies and the facilitation of community and relationships. Their experiences mirrored much of the literature on psychological growth from adversity. Burn survivors reported unique opportunities that allowed them to integrate their injury into their identity within an encouraging and safe environment. Using these accounts, the authors generated clinical suggestions that may encourage similar growth in other support group settings.

Evaluation of the association between Hispanic ethnicity and disease activity and severity in a large cohort of patients with juvenile idiopathic arthritis.

To examine the association between ethnicity and disease activity in patients with juvenile idiopathic arthritis (JIA), and to determine the association of ethnicity with disease severity and disability in this population. CARRAnet, a US database containing information (collected between May 2010 and June 2011) on almost 3,000 subjects with JIA, was used. Demographic variables were compared between Hispanic patients and non-Hispanic patients. Mann-Whitney and chi-square tests were used to compare indicators of disease activity, as well as imaging evidence of joint damage, and Childhood Health Assessment Questionnaire (CHAQ) scores between ethnicities. Two linear regression models were used to determine the association of ethnicity with number of active joints in JIA, and the association between ethnicity and disability (CHAQ scores). A total of 2,704 patients with JIA (277 Hispanic; 2,427 non-Hispanic) were included. Income and health insurance coverage were higher in non-Hispanics. RF-positive polyarticular JIA, positive RF and anti-CCP, as well as use of systemic steroids were more frequent in Hispanics. Imaging evidence of joint damage was present in 32 % of the Hispanic patients compared to 24 % of the non-Hispanic patients (p = 0.008). In multivariate linear regression analyses, the number of active joints was significantly higher in Hispanics than in non-Hispanics (p = 0.03), as well as CHAQ scores (p = 0.003), after adjusting for confounders. Hispanic patients with JIA had higher disease activity than non-Hispanic patients, as well as higher disease severity and disability. Since ethnicity influences disease activity, severity, and disability, different management and treatment plans should be planned accordingly.

Glucocorticoids suppress T cell function by up-regulating microRNA-98.

OBJECTIVE: To identify microRNAs (miRNAs) in human T cells that can explain known antiinflammatory properties of steroids. METHODS: Activated human CD4+ T cells from healthy donors were exposed to 1 µM methylprednisolone (MP) in vitro and then subjected to miRNA and messenger RNA microarray analyses. Changes in expression profiles were recorded. Using quantitative polymerase chain reaction (qPCR), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), we confirmed the suppression of predicted targets, and through miRNA transfection experiments, we could suggest mechanistic links. RESULTS: We identified numerous steroid-responsive genes and miRNAs-many known and some novel-including multiple previously unknown proinflammatory genes suppressed by MP. Further studies using qPCR, flow cytometry, and ELISA demonstrated that methylprednisolone increased the expression of miRNA-98 (miR-98) and suppressed the levels of predicted targets, including interleukin-13 and 3 tumor necrosis factor receptors (TNFRs): Fas, FasL, and TNFR superfamily member 1B. Forced expression of miR-98 in T cells resulted in suppression of the same targets. CONCLUSION: The findings of this study demonstrate a link between miR-98 expression and the effects of MP and provide evidence suggesting that MP acts through miR-98 to inhibit specific proinflammatory targets. Identification of this antiinflammatory mechanism of glucocorticoids is important, since it may pave the way toward the elusive goal of dissociating adverse effects from therapeutic effects.