Endoscopic closure techniques of bariatric surgery complications: a meta-analysis.

BACKGROUND: Leaks following bariatric surgery, while rare, are potentially fatal due to risk of peritonitis and sepsis. Anastomotic leaks and gastro-gastric fistulae following Roux-En-Y gastric bypass (RYGB) as well as staple line leaks after sleeve gastrectomy have historically been treated multimodally with surgical drainage, aggressive antibiotic therapy, and more recently, endoscopically. Endoscopic clipping using over-the-scope clips and endoscopic suturing are two of the most common approaches used to achieve full thickness closure. METHODS: A systematic literature search was performed in PubMed to identify articles on the use of endoscopic clipping or suturing for the treatment of leaks and fistulae following bariatric surgery. Studies focusing on stents, and those that incorporated multiple closure techniques simultaneously, were excluded. Literature review and meta-analysis were performed with the PRISMA guidelines. RESULTS: Five studies with 61 patients that underwent over-the-scope clip (OTSC) closure were included. The pooled proportion of successful closure across the studies was 81.1% (95% CI 67.3 to 91.7). The successful closure rates were homogeneous (I2 = 39%, p = 0.15). Three studies with 92 patients that underwent endoscopic suturing were included. The weighted pooled proportion of successful closure across the studies was shown to be 22.4% (95% CI 14.6 to 31.3). The successful closure rates were homogeneous (I2 = 0%, p = 0.44). Three of the studies, totaling 34 patients, examining OTSC deployment reported data for reintervention rate. The weighted pooled proportion of reintervention across the studies was 35.0% (95% CI 11.7 to 64.7). We noticed statistically significant heterogeneity (I2 = 68%, p = 0.04). One study, with 20 patients examining endoscopic suturing, reported rate of repeat intervention 60%. CONCLUSION: Observational reports show that patients managed with OTSC were more likely to experience healing of their defect than those managed with endoscopic suturing. Larger controlled studies comparing different closure devices for bariatric leaks should be carried out to better understand the ideal endoscopic approach to these complications.

Farnesol brain transcriptomics in CNS inflammatory demyelination.

BACKGROUND: Farnesol (FOL) prevents the onset of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). OBJECTIVE: We examined the transcriptomic profile of the brains of EAE mice treated with daily oral FOL using next-generation sequencing (RNA-seq). METHODS: Transcriptomics from whole brains of treated and untreated EAE mice at the peak of EAE was performed. RESULTS: EAE-induced mice, compared to naïve, healthy mice, overall showed increased expression in pathways for immune response, as well as an increased cytokine signaling pathway, with downregulation of cellular stress proteins. FOL downregulates pro-inflammatory pathways and attenuates the immune response in EAE. FOL downregulated the expression of genes involved in misfolded protein response, MAPK activation/signaling, and pro-inflammatory response. CONCLUSION: This study provides insight into the molecular impact of FOL in the brain and identifies potential therapeutic targets of the isoprenoid pathway in MS patients.

The immunomodulatory roles of the gut microbiome in autoimmune diseases of the central nervous system: Multiple sclerosis as a model.

The gut-associated lymphoid tissue is a primary activation site for immune responses to infection and immunomodulation. Experimental evidence using animal disease models suggests that specific gut microbes significantly regulate inflammation and immunoregulatory pathways. Furthermore, recent clinical findings indicate that gut microbes' composition, collectively named gut microbiota, is altered under disease state. This review focuses on the functional mechanisms by which gut microbes promote immunomodulatory responses that could be relevant in balancing inflammation associated with autoimmunity in the central nervous system. We also propose therapeutic interventions that target the composition of the gut microbiota as immunomodulatory mechanisms to control neuroinflammation.

Farnesol induces protection against murine CNS inflammatory demyelination and modifies gut microbiome.

Farnesol is a 15­carbon organic isoprenol synthesized by plants and mammals with anti-oxidant, anti-inflammatory, and neuroprotective activities. We sought to determine whether farnesol treatment would result in protection against murine experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis (MS). We compared disease progression and severity in C57BL/6 mice treated orally with 100 mg/kg/day farnesol solubilized in corn oil to corn-oil treated and untreated EAE mice. Farnesol significantly delayed the onset of EAE (by ~2 days) and dramatically decreased disease severity (~80%) compared to controls. Disease protection by farnesol was associated with a significant reduction in spinal cord infiltration by monocytes-macrophages, dendritic cells, CD4+ T cells, and a significant change in gut microbiota composition, including a decrease in the Firmicutes:Bacteroidetes ratio. The study suggests FOL could protect MS patients against CNS inflammatory demyelination by partially modulating the gut microbiome composition.

PRX9 and PRX40 Are Extensin Peroxidases Essential for Maintaining Tapetum and Microspore Cell Wall Integrity during Arabidopsis Anther Development.

Pollen and microspore development are essential steps in the life cycle of all land plants that generate male gametes. Within flowering plants, pollen development occurs inside of the anther. Here, we report the identification of two class III peroxidase-encoding genes, PEROXIDASE9 (PRX9) and PRX40, that are genetically redundant and essential for proper anther and pollen development in Arabidopsis (Arabidopsis thaliana). Arabidopsis double mutants devoid of functional PRX9 and PRX40 are male sterile. The mutant anthers display swollen, hypertrophic tapetal cells and pollen grains, suggesting disrupted cell wall integrity. These phenotypes lead to nearly 100%-penetrant pollen degeneration upon anther maturation. Using immunochemical and biochemical approaches, we show that PRX9 and PRX40 likely cross-link extensins to contribute to tapetal cell wall integrity during anther development. This work suggests that PRX9 and PRX40 encode Arabidopsis extensin peroxidases and highlights the importance of extensin cross-linking during pollen development.

New complementary perspectives for inpatient physical function assessment: matched clinician-report and patient-report short form measures from the PROMIS adult physical function item bank.

PURPOSE: To develop two item content-matched, precise, score-level targeted inpatient physical function (PF) short form (SF) measures: one clinician-reported, one patient-reported. Items were derived from PROMIS PF bank content; scores are reported on the PROMIS PF T-score metric. METHODS: The PROMIS PF item bank was reviewed for content measuring lower-level PF status (T-scores 10-50) with high item set score-level reliability (≥ 0.90). Selected patient-reported (PR) items were also edited to function as clinician-reported (CR) items. Items were reviewed by clinicians and field tested; responses were assessed for meeting PROMIS measure development standards. New CR and PR items were calibrated using patient responses to the original PROMIS PF items as anchoring data. SFs were constructed, based on content and precision. RESULTS: Nine PROMIS PF items were candidates for CR and PR inpatient PF assessment; three new items were written to extend content coverage. An inpatient sample (N = 515; 55.1% female; mean age = 66.2 years) completed 12 PR items and was assessed by physical therapists (using 12 CR items). Analyses indicated item sets met expected measure development standards. Twelve new CR and three new PR items were linked to the PROMIS PF metric (raw score r = 0.73 and 0.90, respectively). A 5-item CR SF measure was constructed; score-level reliabilities were ≥ 0.90 for T-scores 13-45. A 5-item PR SF measure was assembled, mirroring CR SF content. CONCLUSIONS: Two item content-matched SFs have been developed for clinician and patient reporting and are an effective, efficient means of assessing inpatient PF and offer complementary perspectives.

Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.

BACKGROUND: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Offspring of parents who were separated and not speaking to one another have reduced resistance to the common cold as adults.

Exposure to parental separation or divorce during childhood has been associated with an increased risk for physical morbidity during adulthood. Here we tested the hypothesis that this association is primarily attributable to separated parents who do not communicate with each other. We also examined whether early exposure to separated parents in conflict is associated with greater viral-induced inflammatory response in adulthood and in turn with increased susceptibility to viral-induced upper respiratory disease. After assessment of their parents' relationship during their childhood, 201 healthy volunteers, age 18-55 y, were quarantined, experimentally exposed to a virus that causes a common cold, and monitored for 5 d for the development of a respiratory illness. Monitoring included daily assessments of viral-specific infection, objective markers of illness, and local production of proinflammatory cytokines. Adults whose parents lived apart and never spoke during their childhood were more than three times as likely to develop a cold when exposed to the upper respiratory virus than adults from intact families. Conversely, individuals whose parents were separated but communicated with each other showed no increase in risk compared with those from intact families. These differences persisted in analyses adjusted for potentially confounding variables (demographics, current socioeconomic status, body mass index, season, baseline immunity to the challenge virus, affectivity, and childhood socioeconomic status). Mediation analyses were consistent with the hypothesis that greater susceptibility to respiratory infectious illness among the offspring of noncommunicating parents was attributable to a greater local proinflammatory response to infection.

Moving towards a Network of Autonomous UAS Atmospheric Profiling Stations for Observations in the Earth's Lower Atmosphere: The 3D Mesonet Concept.

The deployment of small unmanned aircraft systems (UAS) to collect routine in situ vertical profiles of the thermodynamic and kinematic state of the atmosphere in conjunction with other weather observations could significantly improve weather forecasting skill and resolution. High-resolution vertical measurements of pressure, temperature, humidity, wind speed and wind direction are critical to the understanding of atmospheric boundary layer processes integral to air-surface (land, ocean and sea ice) exchanges of energy, momentum, and moisture; how these are affected by climate variability; and how they impact weather forecasts and air quality simulations. We explore the potential value of collecting coordinated atmospheric profiles at fixed surface observing sites at designated times using instrumented UAS. We refer to such a network of autonomous weather UAS designed for atmospheric profiling and capable of operating in most weather conditions as a 3D Mesonet. We outline some of the fundamental and high-impact science questions and sampling needs driving the development of the 3D Mesonet and offer an overview of the general concept of operations. Preliminary measurements from profiling UAS are presented and we discuss how measurements from an operational network could be realized to better characterize the atmospheric boundary layer, improve weather forecasts, and help to identify threats of severe weather.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

Dispositional Affect Moderates the Stress-Buffering Effect of Social Support on Risk for Developing the Common Cold.

OBJECTIVE: The aim was to examine whether trait positive and negative affect (PA, NA) moderate the stress-buffering effect of perceived social support on risk for developing a cold subsequent to being exposed to a virus that causes mild upper respiratory illness. METHOD: Analyses were based on archival data from 694 healthy adults (Mage = 31.0 years, SD = 10.7 years; 49.0% female; 64.6% Caucasian). Perceived social support and perceived stress were assessed by self-report questionnaire and trait affect by aggregating responses to daily mood items administered by telephone interview across several days. Subsequently, participants were exposed to a virus that causes the common cold and monitored for 5 days for clinical illness (infection + objective signs of illness). RESULTS: Two 3-way interactions emerged-Support × Stress × PA and Support × Stress × NA. The nature of these effects was such that among persons with high trait PA or low trait NA, greater social support attenuated the risk of developing a cold when under high but not low perceived stress; this stress-buffering effect did not emerge among persons with low trait PA or high trait NA. CONCLUSIONS: Dispositional affect might be used to identify individuals who may be most responsive to social support and support-based interventions.

Basal salivary cortisol secretion and susceptibility to upper respiratory infection.

The immunosuppressive effects of glucocorticoids (GCs) are well-established. However, whether the net effect of GC-elicited alterations in immune function is sufficient to influence a clinically relevant outcome in healthy adults has yet to be shown. The aim of the present study was to investigate whether inter-individual differences in basal salivary cortisol production are associated with increased risk and severity of infection and subsequent illness following experimental exposure to a virus that causes the common cold. The present analyses combine archival data from three viral-challenge studies. Participants were 608 healthy adults, aged 18 to 55 years (49.2% female; 65.8% white), who each completed a three-day saliva collection protocol; was subsequently exposed to a virus that causes the common cold; and monitored for 5 days for objective signs of infection (presence of challenge virus in nasal secretions) and clinical illness (mucus weight, mucociliary clearance time). Basal cortisol production (operationalized as the calculated area-under-the-curve averaged across the 3 days) showed a graded association with infection risk, with those producing higher levels of cortisol being at greater risk. Cortisol also showed a continuous association with duration of viral shedding, an indicator of viral replication and continuing infection, such that higher cortisol concentrations predicted more days of shedding. Cortisol was not, however, related to severity of objective illness. These findings are the first to demonstrate in healthy adults an association between basal cortisol production and an objectively measured and clinically relevant infectious disease outcome.

Resolution of Otitis Media With Effusion in Children With Cleft Palate Followed Through Five Years of Age.

OBJECTIVE: To describe the temporal pattern of otitis media with effusion (OME) resolution for a cohort of nonsyndromic cleft palate children enrolled before palatoplasty and followed through 5 years of age. DESIGN: This is a prospective, longitudinal study of the time course for OME resolution in infants and children with palatal clefts. SETTING: Cleft Palate Craniofacial Center of a tertiary care pediatric hospital. PARTICIPANTS: This study included 52 children with cleft palate (29 boys, 45 white, Veau 1 through 4) who had a Furlow-type palatoplasty between 10 and 24 months of age performed by one of six surgeons. INTERVENTIONS: Standard cleft palate management was supplemented with study visits to the research clinic pre- and postpalatoplasty and then yearly to 6 years of age for assessments of middle ear status by interval history, otoscopy, and tympanometry. MAIN OUTCOME MEASURE: The main outcome measure was age at otitis media resolution defined as the age in years at the first in a sequence of "disease-free" diagnoses not interrupted or followed by any other diagnosis. RESULTS: The cumulative percent OME resolution for ears/children at ages <1, 1, 2, 3, 4, 5 years was 4.1/4.4, 14.3/10.9, 31.6/21.7, 45.9/37.0, 56.1/50.0, and 70.4/60.9%. OME resolution followed a simple linear time curve with slopes of 13.5% (confidence interval [CI] = 12.2% to 14.8%, r(2) = .99) and 11.9% (CI = 10.1% to 13.6%, r(2) = .99) resolutions per year for ears and children, respectively. CONCLUSIONS: There is a natural, age-related pattern of resolution for persistent OME that affects most infants and young children with cleft palate that is not affected by palatoplasty.

Self-Rated Health in Healthy Adults and Susceptibility to the Common Cold.

OBJECTIVES: To explore the association of self-rated health (SRH) with host resistance to illness after exposure to a common cold virus and identify mechanisms linking SRH to future health status. METHODS: We analyzed archival data from 360 healthy adults (mean [standard deviation] age = 33.07 [10.69] years, 45.6% women). Each person completed validated questionnaires that assessed SRH (excellent, very good, good, fair, poor), socioemotional factors, and health practices and was subsequently exposed to a common cold virus and monitored for 5 days for clinical illness (infection and objective signs of illness). RESULTS: Poorer SRH was associated in a graded fashion with greater susceptibility to developing clinical illness (good/fair versus excellent: odds ratio = 3.21, 95% confidence interval = 1.47-6.99; very good versus excellent: odds ratio = 2.60, 95% confidence interval = 1.27-5.32), independent of age, sex, race, prechallenge immunity (specific antibody), body mass, season, education, and income. Greater illness risk was not attributable to infection, but to increased likelihood of developing objective signs of illness once infected. Poorer SRH also correlated with poorer health practices, increased stress, lower positive emotions, and other socioemotional factors. However, none of these (alone or together) accounted for the association between SRH and host resistance. Additional data (separate study) indicated that history of having colds was unrelated to susceptibility and hence also did not account for the SRH link with immunocompetence. CONCLUSIONS: Poorer SRH is associated with poorer immunocompetence, possibly reflecting sensitivity to sensations associated with premorbid immune dysfunction. In turn, poorer immune function may be a major contributing mechanism linking SRH to future health.

Does hugging provide stress-buffering social support? A study of susceptibility to upper respiratory infection and illness.

Perceived social support has been hypothesized to protect against the pathogenic effects of stress. How such protection might be conferred, however, is not well understood. Using a sample of 404 healthy adults, we examined the roles of perceived social support and received hugs in buffering against interpersonal stress-induced susceptibility to infectious disease. Perceived support was assessed by questionnaire, and daily interpersonal conflict and receipt of hugs were assessed by telephone interviews on 14 consecutive evenings. Subsequently, participants were exposed to a virus that causes a common cold and were monitored in quarantine to assess infection and illness signs. Perceived support protected against the rise in infection risk associated with increasing frequency of conflict. A similar stress-buffering effect emerged for hugging, which explained 32% of the attenuating effect of support. Among infected participants, greater perceived support and more-frequent hugs each predicted less-severe illness signs. These data suggest that hugging may effectively convey social support.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1ß, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

A method to assess the accuracy of sonotubometry for detecting Eustachian tube openings.

Sonotubometry is a simple test for Eustachian tube (ET) opening during a maneuver. Different sonotubometry configurations were suggested to maximize test accuracy, but no method has been described for comparing sonotubometry test results with those for a definitive measure of ET opening. Here, we present such a method and exemplify is use by an accuracy assessment of a simple sonotubometry configuration. A total of 502 data-sequences from 168 test sessions in 103 adult subjects were analyzed. For each session, subjects were seated in a pressure chamber and relative middle ear over- and under-pressures created by changing chamber pressure. At each pressure, the test sequence of bilateral tympanometry, bilateral sonotubometry while the subject swallowed twice, and bilateral tympanometry was done. Tympanometric data were expressed as the fractional gradient equilibrated (FGE) by swallowing and sonotubometric signals were analyzed to record the shape of detected sound signals. Tympanometric and sonotubometric tubal opening assignments were analyzed by cross-correlation. For the data sequences with FGE = 0 (n = 32) evidencing no tubal opening and one (n = 249) evidencing definitive tubal opening, detection of a sonotubometry sound signal during a swallow had a sensitivity and specificity of 74.2 and 65.6 % for identifying ET openings and an accuracy of 73.3 % for assigning ET opening/non-opening by swallowing. Measures of sound signal shape were significantly different between those groups. This protocol allows a sonotubometry accuracy assessment for detecting ET openings. For the test configuration used, accuracy was moderate, but this should improve as more sophisticated sonotubometry test configurations are evaluated.

Childhood environments and cytomegalovirus serostatus and reactivation in adults.

Childhood adversity, defined in terms of material hardship or physical or emotional maltreatment has been associated with risk for infection with cytomegalovirus (CMV) among children and adolescents, and with CMV reactivation in children and adults. The present study examined whether different dimensions of childhood experience-those pertaining to socioeconomic status (SES), physical environment, or family relationships-relate differentially to CMV serostatus and reactivation during adulthood. Participants were 140 healthy adults, aged 18-55years (41% female; 64% white). Childhood environments were assessed retrospectively and included family SES (parental housing tenure); childhood neighborhood environment (urban residence; physical conditions; safety; and social atmosphere); residential exposures (parental smoking and physical condition of home); and family relationships (parental divorce; warmth; harmony; dysfunction; parental bonding). Approximately 39% (n=53) of participants were CMV+. In individual analyses controlling for age, sex, race, body mass, current adult SES and smoking status, fewer years of parental home ownership, having a parent who smoked, and living in a poorly maintained or unsafe neighborhood each were associated with greater odds of infection with CMV. By comparison, in individual analyses limited to CMV+ participants, less family warmth, less harmony, greater dysfunction, and suboptimal parental bonding each were related to higher antibody levels, independent of the aforementioned covariates. Findings were not attributable to current adult perceptions of psychological stress or relative levels of emotional stability. These results suggest that different types of childhood adversity may be associated with differential effects on CMV infection and latency.

Gut microbiota in multiple sclerosis and animal models.

Multiple sclerosis (MS) is a chronic central nervous system (CNS) neurodegenerative and neuroinflammatory disease marked by a host immune reaction that targets and destroys the neuronal myelin sheath. MS and correlating animal disease models show comorbidities, including intestinal barrier disruption and alterations of the commensal microbiome. It is accepted that diet plays a crucial role in shaping the microbiota composition and overall gastrointestinal (GI) tract health, suggesting an interplay between nutrition and neuroinflammation via the gut-brain axis. Unfortunately, poor host health and diet lead to microbiota modifications that could lead to significant responses in the host, including inflammation and neurobehavioral changes. Beneficial microbial metabolites are essential for host homeostasis and inflammation control. This review will highlight the importance of the gut microbiota in the context of host inflammatory responses in MS and MS animal models. Additionally, microbial community restoration and how it affects MS and GI barrier integrity will be discussed.