Decision-making Considerations in Revisional Bariatric Surgery.

OBJECTIVE: With drastic variations in bariatric practices, consensus is lacking on an optimal approach for revisional bariatric surgeries. MATERIALS AND METHODS: The authors reviewed and consolidated bariatric surgery literature to provide specific revision suggestions based on each index surgery, including adjustable gastric band (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), single anastomosis duodenal-ileal bypass with sleeve (SADI-S), one anastomosis gastric bypass (OAGB), and vertical banded gastroplasty (VBG). RESULTS: AGB has the highest weight recurrence rate and can be converted to RYGB, SG, and BPD-DS. After index SG, common surgical options include a resleeve or RYGB. The RYGB roux limb can be distalized and pouch resized in context of reflux, and the entire anatomy can be revised into BPD-DS. Data analyzing revisional surgery after a single anastomosis duodenal-ileal bypass with sleeve was limited. In patients with one anastomosis gastric bypass and vertical banded gastroplasty anatomy, most revisions were the conversion to RYGB. CONCLUSIONS: As revisional bariatric surgery becomes more common, the best approach depends on the patient's indication for surgery and preexisting anatomy.

Large retroperitoneal lymphangioma.

Abnormal cystic lymphangioma is a rare, benign tumour of lymphatic origin that often presents with subtle clinical symptoms. A man in his 20s sought medical attention for a progressively tender mass located in the right lower quadrant. Following ultrasound and CT imaging, surgical pathology confirmed the presence of abnormal cystic lymphangioma. This case is noteworthy because of the patient's young age and the retroperitoneal location. An exploratory laparotomy was performed, mitigating the risk of recurrence. In the future, if imaging identifies a cystic mass, consideration of abnormal cystic lymphangioma within the differential diagnosis is imperative. Despite its predominantly subtle symptoms and non-malignant nature, the mass effect by the abnormal cystic lymphangioma can compromise surrounding structures. Overall, clinicians confronted with a cystic mass should adopt a comprehensive diagnostic approach, encompassing abnormal cystic lymphangioma in the differential diagnosis due to its unknown and complex nature.

A dyadic longitudinal analysis of parent-adolescent inflammation trends and the role of shared socioeconomic characteristics on family inflammation.

The objective of the present study was to evaluate the interdependency of parent-adolescent inflammation trends across time and to examine whether shared family socioeconomic characteristics explained between-family differences in parents' and adolescents' risk for inflammation. A total of N = 348 families, consisting of one parent and one adolescent child, were followed every two years in a three-wave longitudinal study. Sociodemographic questionnaires were used to determine parental educational attainment and family income-to-needs ratio (INR). At each time point, parents and adolescents collected dried blood spot (DBS) samples that were assayed for circulating CRP and log-transformed prior to analysis by longitudinal dyadic models. Models revealed significant differences in parents' and adolescents' inflammation trends over time (bint = - 0.13, p < 0.001). While parental CRP levels remained relatively stable across the study period, adolescent CRP increased by approximately 38% between study waves. Parents' average CRP levels were positively correlated with adolescents' average CRP (r = 0.32, p < 0.001), but parental change in CRP over time was not significantly related to change in adolescents' CRP over time. Family dyads with higher parental educational attainment had lower average CRP (b = -0.08, p = 0.01), but parental education did not predict change in dyads' inflammation over time. Study findings suggest that shared family socioeconomic characteristics contribute to baseline similarities in parents' and adolescents' inflammation and potentially point to adolescence as a period of inflammatory change where youth may diverge from parental inflammation trends.

Rapid detection of viable microbes with 5-cyano-2,3-di-(p-tolyl)tetrazolium chloride and 5(6)-carboxyfluorescein diacetate using a fibre fluorescence spectroscopy system.

AIMS: To assess the efficacy of two commercially available viability dyes, 5-cyano-2,3-di-(p-tolyl)tetrazolium chloride (CTC) and 5(6)-carboxyfluorescein diacetate (CFDA), in reporting on viable cell concentration and species using an all-fibre fluorometer. METHODS AND RESULTS: Four bacterial species (two Gram-positive and two Gram-negative) commonly associated with food poisoning or food spoilage (Escherichia coli, Salmonella enterica, Staphylococcus aureus, and Bacillus cereus) were stained with CTC or CFDA and the fibre fluorometer was used to collect full fluorescence emission spectra. A good correlation between concentration and fluorescence intensity was found for Gram-negative bacteria between 107 and 108 colony-forming units (CFU) ml-1. There was no correlation with concentration for Gram-positive bacteria; however, the information in the CTC and CFDA spectra shows the potential to distinguish Gram-negative cells from Gram-positive cells, although it may simply reflect the overall bacterial metabolic activity under staining conditions from this study. CONCLUSIONS: The limit of detection (LoD) is too high in the dip-probe approach for analysis; however, the development of an approach measuring the fluorescence of single cells may improve this limitation. The development of new bacteria-specific fluorogenic dyes may also address this limitation. The ability to differentiate bacteria using these dyes may add value to measurements made to enumerate bacteria using CTC and CFDA.

Associations between emotion reactivity to daily interpersonal stress and acute social-evaluative stress during late adolescence.

Emotion reactivity refers to the intensity of changes in positive and negative emotion following a stimulus, typically studied with respect to daily stressors (e.g., arguments, demands) or laboratory stressors, including the Trier Social Stress Test (TSST). Yet, it is unclear whether emotion reactivity to daily and to laboratory stressors are related. The present study examined whether greater emotion reactivity to daily stressors (i.e., arguments, demands) is associated with greater reactivity to the TSST. Late adolescents (N = 82; Mage = 18.35, SD = 0.51, range 17-19; 56.1% female; 65.9% Latine, 34.2% European American) reported whether they experienced arguments and demands with friends, family, and individuals at school and their negative and positive emotion nightly for 15 days. They also completed the TSST, a validated paradigm for eliciting social-evaluative threat, and reported their emotion at baseline and immediately post-TSST. Multilevel models examined whether daily and laboratory emotion reactivity were related by testing whether the daily associations between arguments and demands with emotion differed by emotion reactivity to the TSST. Individuals with greater positive emotion reactivity (i.e., greater reductions in positive emotion) and greater negative emotion reactivity to the TSST showed greater positive emotion reactivity to daily demands. Emotion reactivity to the TSST was not significantly related to emotion reactivity to arguments. Findings provide preliminary evidence that emotion reactivity to the TSST relates to some aspects of daily emotion reactivity, with relations differing depending on type of daily stressor and valence of emotion. Results contextualise the implications of emotion reactivity to the TSST for daily stress processes.

Low early life socioeconomic status and susceptibility to the common cold in adulthood: The moderating role of negative affective reactivity.

OBJECTIVE: Socioeconomic disadvantage during childhood and adolescence is associated with higher risk for many physical health problems, including infectious disease, throughout the lifespan. Greater negative affective (NA) reactivity has shown similar links to greater risk for physical health conditions and altered patterns of biological functioning associated with acute respiratory infection as socioeconomic disadvantage; yet their interactive effects on physical health outcomes have not been examined. Thus, the present study examined whether NA reactivity accentuated the link between early socioeconomic disadvantage and susceptibility to the common cold. METHOD: Participants were 212 adults (42% female, 18-55 years old) who completed measures of childhood socioeconomic status (SES; parental home ownership) and were subsequently exposed to a virus that causes the common cold. Participants then remained quarantined for 5 days, during which multiple indicators of viral infection and clinical illness were assessed. Before and after quarantine, participants completed a laboratory stress task to assess NA reactivity. RESULTS: NA reactivity moderated the relationship between parental home ownership and clinical cold diagnosis in adulthood (b = -0.11, p = .018), such that fewer years of parental home ownership was associated with increased odds for developing a cold only among adults who had greater NA reactivity (OR = 0.89, 95% confidence interval, CI [0.82, 0.96]), but not among those who had lower NA reactivity (OR = 1.01, 95% CI [0.94, 1.09]). CONCLUSIONS: These findings suggest that how individuals negatively react to psychosocial stressors in adulthood may exacerbate the impact of childhood SES on acute infection susceptibility. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exploring the Experiences and Perceptions of Adults With Spinal Cord Injury or Disease Aged 50 Years or Older on Participation in Sports.

Background: Sports are physical activities that provide physical, psychological, and social benefits for individuals with spinal cord injury/disease (SCI/D). However, most sports research has been completed on individuals with SCI/D who are aged >50 years, even though the majority of people with SCI/D are aged >50 years. Despite substantial evidence supporting sports for older adults not living with a disability, there is currently no research examining the impact of sports for adults with SCI/D aged ≥50 years. Objectives: To explore the perceptions and experiences of individuals with SCI/D aged 50 years or older who participate in sports in the community. Methods: Fifteen adults with SCI/D aged ≥50 years who participated in community-based sports were interviewed. Interviews were audio-recorded and transcribed verbatim. Conventional content analysis was applied to the data. Results: The overarching theme identified was that sports are fun and adaptable physical activities that have the potential to optimize physical, psychological, and social health in all people with SCI/D, regardless of age. Within this overarching theme, six categories surfaced: (1) importance of participating in sports later in life, (2) prioritizing health over performance, (3) uncertainties about participating in sports later in life, (4) reflections on participating in sports later in life, (5) beliefs on alternative sports involvement, and (6) advice for other aging adults with SCI/D considering sports. Conclusion: Sports are perceived to provide physical, psychological, and social benefits for individuals with SCI/D aged 50 years or older. Findings will inform the development of future adaptive sports programs for older individuals with SCI/D.

Do all roads lead to Rome? A retrospective analysis on surgical technique in sleeve gastrectomy.

BACKGROUND: New York University Langone Health has three accredited bariatric centers, with 10 different bariatric surgeons. This retrospective analysis compares surgeon techniques in laparoscopic or robotic sleeve gastrectomy (SG) to identify associations with perioperative morbidity and mortality. METHODS: All adults who underwent SG between 2017 and 2021 at NYU Langone Health were evaluated via EMR and MBSAQIP 30-day data. We also surveyed all 10 bariatric surgeons and compared their techniques and total adverse outcomes. Bleeding, SSI, mortality, readmission, and reoperation were specifically sub-analyzed via logistic regression. RESULTS: 86 (2.77%) out of 3,104 patients who underwent SG encountered an adverse event. Lower adverse outcomes were observed with a laparoscopic approach, 40-Fr bougie, buttressing, not oversewing the staple line, using hemostatic agents, stapling 3-cm from pylorus, and no routine UGI series. Lower bleeding rates were observed in a laparoscopic approach, 40-Fr bougie, buttressing, not oversewing the staple line, using hemostatic agents, stapling 3-cm from pylorus, no routine UGI series, and not proceeding with SG if hiatal hernia is present. Lower SSI rates were observed with ViSiGi™ bougie, no hemostatic agents, and routine EGD. Lower readmission rates were observed with 40-Fr bougie, buttressing, not oversewing, and stapling 3-cm from pylorus. Hemostatic agents had higher reoperation rates. It was not feasible to test for mortality given the low incidence. CONCLUSION: Certain surgical techniques in SG among our bariatric surgeons had a significant effect on the rates of adverse outcomes, bleeding, readmission, reoperation, and SSI. Our findings warrant further investigation into these techniques via multivariate regression or prospective design. LIMITATIONS: This study was limited by its retrospective and univariate design. We did not account for interaction. The sample size was small, and follow-up of 30 days was relatively short. We did not include patient characteristics in the model or control for surgeon skill.

Do all roads lead to Rome?: A retrospective analysis on surgical technique in Roux-en-Y gastric bypass.

BACKGROUND: New York University Langone Health has three accredited bariatric centers, with altogether ten different bariatric surgeons. This retrospective analysis compares individual surgeon techniques in laparoscopic or robotic Roux-en-Y gastric bypass (RYGB) to identify potential associations with perioperative morbidity and mortality. METHODS: All adult patients who underwent RYGB between 2017 and 2021 at NYU Langone Health campuses were evaluated via electronic medical records and MBSAQIP 30-day follow-up data. We surveyed all ten practicing bariatric surgeons to analyze the relationship between their techniques and total adverse outcomes. Bleeding, SSI, mortality, readmission, and reoperation were specifically sub-analyzed via logistic regression. RESULTS: 54 (7.59%) out of 711 patients who underwent laparoscopic or robotic RYGB encountered an adverse outcome. Lower adverse outcomes were observed with laparoscopic approach, creating the JJ anastomosis first, flat positioning, division of the mesentery, Covidien™ laparoscopic staplers, gold staples, unidirectional JJ anastomosis, hand-sewn common enterotomy, 100-cm Roux limb, 50-cm biliopancreatic limb, and routine EGD. Lower bleeding rates were observed with flat positioning, gold staples, hand-sewn common enterotomy, 50-cm biliopancreatic limb, and routine EGD. Lower readmission rates were observed in laparoscopic, flat positioning, Covidien™ staplers, unidirectional JJ anastomosis, and hand-sewn common enterotomy. Gold staples had lower reoperation rates. Otherwise, there was no statistically significant difference in SSI. CONCLUSION: Certain surgical techniques in RYGB within our bariatric surgery group had significant effects on the rates of total adverse outcomes, bleeding, readmission, and reoperation. Our findings warrant further investigation into the aforementioned techniques via multivariate regression models or prospective study design. LIMITATIONS: This study was limited by the inherent nature of its retrospective and univariate statistical design. We did not account for the interaction between techniques. The sample size of surgeons was small, and follow-up of 30 days was relatively short. We did not include patient characteristics in the model or control for surgeon skill.

Implementation of Multimodal Pain Protocol Associated With Opioid Use Reduction in Trauma Patients.

INTRODUCTION: Many trauma centers have adopted multimodal pain protocols (MMPPs) to provide safe and effective pain control. The objective was to evaluate the association of a protocol on opioid use in trauma patients and patient-reported pain scores. METHODS: This was a retrospective review of adult trauma patients admitted from 7/1-9/30/2018 to 7/1-9/30/2019 at an urban academic level 1 trauma center. The MMPP consisted of scheduled nonopioid medications implemented on July 1, 2019. Patients were stratified by level of care upon admission, intensive care unit (ICU) or floor, and by injury severity score (ISS) (ISS < 16 or ISS ≥ 16). Pain scores, opioid, and nonopioid analgesic medication use were compared for the hospital stay or first 30 d. RESULTS: Seven hundred ninety eight patients were included with a mean age of 54 ± 22 y and 511 (64.0%) were men. Demographic and clinical characteristics between those in the pre-MMP (n = 404) and post-MMPP (n = 394) groups were not different. The average pain scores were not different between the two groups (3.7 versus 3.8, P = 0.44), but patients in the post-MMPP group received 36% less morphine milliequivalents (109.6 versus 70; P < 0.0001). The MMPP had the largest effect on patients admitted to the ICU regardless of injury severity. ICU patients with ISS ≥ 16 had the greatest reduction in morphine milliequivalents (174.6 versus 84.4; P < 0.0001). The use of nonopioid analgesics was significantly increased in all groups. CONCLUSIONS: A MMPP is associated with a reduction of opioids and increase in nonopioid analgesics with no difference in patient-reported pain scores.

Low subjective social status is associated with daily selection of fewer healthy foods and more high-fat/high sugar foods.

Socioeconomic status has been related to poorer eating behaviors, potentially due to feeling of lower status relative to peers. Despite experimental evidence that temporarily feeling of lower status can contribute to greater caloric intake, it remains unclear how feeling of lower social status relate to eating behavior in daily life. This study aimed to test whether lower subjective social status (SSS)-the feeling of having relatively lower social status-in American society and relative to college peers were related to daily food selection. A sample of 131 young adults (Mage = 20.3, SD = 0.8; 60% female; 46% Latinos; 34% European American; 15% Asian American; 5% of other ethnicities) reported their SSS in society and in college and completed 15 daily reports regarding the number of daily servings they had of fruits, vegetables, fried foods, fast foods, desserts, and sugary drinks. Multilevel models with days nested within individuals were used to test whether low SSS in society or college related to daily food intake. Next, we examined whether associations were driven by young adults' perceived stress and daily stressors. Analyses controlled for age, gender, ethnicity, family and personal income, and parents' education to test the unique associations between subjective status and food intake. Whereas SSS in society was not related to food intake, young adults with lower SSS in their college consumed fewer daily servings of healthy foods and more daily servings of high-fat/high-sugar foods. Although lower college SSS was related to greater perceived stress, perceived stress and daily stressors were consistently unrelated to daily food intake. Findings suggested that lower SSS in local environments (e.g., college) may impact young adults' daily food choices through processes beyond heightened stress.

Resting respiratory sinus arrhythmia is related to emotion reactivity to social-evaluative stress.

BACKGROUND: Higher resting parasympathetic nervous system activity, as indexed by respiratory sinus arrhythmia (RSA), has been considered a marker of emotion regulatory capacity and is consistently related to better mental health. However, it remains unclear how resting RSA relates to emotion reactivity to acute social-evaluative stress, a potent predictor of depression and other negative outcomes. METHOD: A sample of 89 participants (Mage = 18.36, SD = 0.51; 58.43 % female) provided measures of RSA at rest and then completed the Trier Social Stress Test, a standardized laboratory-based social-evaluative stress task that involves public speaking and mental arithmetic while being evaluated by two confederate judges. Participants reported a variety of emotions (e.g., negative emotion, positive emotion) at baseline and immediately after the stress task. RESULTS: Participants with higher resting RSA showed greater increases in negative emotion, guilt, depressive emotion, and anger, as well as greater decreases in positive emotion after the task. LIMITATION: Data were limited to a relatively small sample of late adolescents, who may be particularly responsive to social-evaluative stress compared to adults. CONCLUSIONS: Findings suggest that higher resting RSA may enhance emotion responses to social-evaluative stress in adolescents, potentially due to active engagement and responding to rather than passively viewing stimuli. Higher resting RSA may promote flexible emotion responses to the social environment, which may account for associations between higher RSA and better mental health.

Socioeconomic disadvantage, chronic stress, and proinflammatory phenotype: an integrative data analysis across the lifecourse.

Socioeconomic disadvantage confers risk for many chronic illnesses, and theories have highlighted chronic psychological stress and alterations to inflammatory processes as key pathways. Specifically, disadvantage can heighten chronic stress, which may promote a proinflammatory phenotype characterized by immune cells mounting exaggerated cytokine responses to challenge and being less sensitive to inhibitory signals. Importantly, lifecourse perspectives emphasize that such immune alterations should be more potent earlier in life during a sensitive period when bodily tissues are highly plastic to environmental inputs. However, examining these propositions is resource intensive, as they require cell-culturing approaches to model functional inflammatory activities, a wide age range, and longitudinal data. Here, we integrated data from five independent studies to create a diverse sample of 1,607 individuals (960 with longitudinal data; 8 to 64 years old; 359 Asian, 205 Black, and 151 Latino/a). Leveraging the resulting lifecourse data, rich interview assessments of disadvantage and stress, and ex vivo assessments of inflammation, we examined two questions: (1) Does chronic stress account for the link between disadvantage and proinflammatory phenotype? (2) Is there a developmental period during which inflammatory responses are more sensitive to disadvantage and chronic stress? Disadvantage was associated with higher chronic stress, which was linked with a proinflammatory phenotype cross-sectionally, longitudinally, and in terms of prospective change across 1.5 to 2 years. Consistent with the sensitive period hypothesis, the magnitude of these indirect associations was strongest in earlier decades and declined across the lifecourse. These findings highlight the importance of taking a lifecourse perspective in examining health disparities.

What is 'disability'? Exploring the conceptions of internationally educated learners in a Canadian physical therapy bridging program.

BACKGROUND: Physiotherapists' understanding of disability has direct relevance for their practices and work with disabled people. PURPOSE: To explore how physiotherapists from diverse backgrounds, cultures and social locations conceptualize disability. Understanding their conceptualizations will provide insight to determine future directions regarding disability education, in healthcare education, to optimize the quality of care and life for individuals with disabilities. METHODS: Six internationally educated physiotherapists enrolled in a Canadian physical therapy bridging program were interviewed and data were analyzed for themes. RESULTS: Participants' conceptualizations of disability were complex and a dynamic process that reflected what was 'thinkable' in relation to experience, such as with social location and in personal, professional and educational domains. This primary theme was reflected in three subthemes: 1) Professional PT acculturation shaped disability conceptualization in particular ways; 2) Medical model as the dominant way of thinking; and 3) Social model thinking was more feasible in resource rich contexts. CONCLUSION: These results reinforce the benefits of a wide exposure to different ways of conceptualizing and addressing disability within PT education to counter the dominance of the medical model and reinforce the importance of advocacy and allyship with disabled people.

The Relationship Between Family Socioeconomic Status and Adolescent Sleep and Diurnal Cortisol.

OBJECTIVE: This study aimed to investigate the associations between indices of family socioeconomic status and sleep during adolescence and to examine whether measures of hypothalamic-pituitary-adrenal (HPA) axis functioning mediate the observed associations. METHODS: A total of 350 ethnically diverse adolescents (57% female; mean [standard deviation] age wave 1 = 16.4 [0.7] years) completed a three-wave longitudinal study in which sleep and cortisol data were collected at 2-year time intervals. Sleep duration, latency, and variability were assessed via actigraphy during a period of 8 days per study wave. Salivary cortisol was collected across 3 days per study wave to assess cortisol diurnal slope, area under the curve, and the cortisol awakening response. Adolescents' caregivers reported their education levels, family income, and economic hardship. RESULTS: A greater family income-to-needs ratio was associated with longer adolescent sleep duration ( b = 2.90, p = .023), whereas greater parental education was associated with shorter sleep duration ( b = -3.70, p = .030), less sleep latency ( b = -0.74, p = .016), and less variability across days ( b = -2.06, p = .010). Diurnal cortisol slope statistically mediated the association of parental education with sleep duration ( b = -0.48, 95% confidence interval = -1.099 to -0.042), but not the association of income-to-needs ratio with sleep duration. CONCLUSIONS: Findings suggest that parental education and family resources may have unique impacts upon sleep and HPA axis functioning during the period of adolescence. Future research is needed to examine family and behavioral factors that may underlie socioeconomic status associations with adolescent sleep and HPA axis functioning.

Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder.

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.

The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.

Recent studies have demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of posttranslational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 was unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.

The Small t Antigen of JC Virus Antagonizes RIG-I-Mediated Innate Immunity by Inhibiting TRIM25's RNA Binding Ability.

JC polyomavirus (JCV), a DNA virus that leads to persistent infection in humans, is the causative agent of progressive multifocal leukoencephalopathy, a lethal brain disease that affects immunocompromised individuals. Almost nothing is currently known about how JCV infection is controlled by the innate immune response and, further, whether JCV has evolved mechanisms to antagonize antiviral immunity. Here, we show that the innate immune sensors retinoic acid-inducible gene I (RIG-I) and cGMP-AMP synthase (cGAS) control JCV replication in human astrocytes. We further identify that the small t antigen (tAg) of JCV functions as an interferon (IFN) antagonist by suppressing RIG-I-mediated signal transduction. JCV tAg interacts with the E3 ubiquitin ligase TRIM25, thereby preventing its ability to bind RNA and to induce the K63-linked ubiquitination of RIG-I, which is known to facilitate RIG-I-mediated cytokine responses. Antagonism of RIG-I K63-linked ubiquitination and antiviral signaling is also conserved in the tAg of the related polyomavirus BK virus (BKV). These findings highlight how JCV and BKV manipulate a key innate surveillance pathway, which may stimulate research into designing novel therapies.IMPORTANCE The innate immune response is the first line of defense against viral pathogens, and in turn, many viruses have evolved strategies to evade detection by the host's innate immune surveillance machinery. Investigation of the interplay between viruses and the innate immune response provides valuable insight into potential therapeutic targets against viral infectious diseases. JC polyomavirus (JCV) is associated with a lifelong, persistent infection that can cause a rare neurodegenerative disease, called progressive multifocal leukoencephalopathy, in individuals that are immunosuppressed. The molecular mechanisms of JCV infection and persistence are not well understood, and very little is currently known about the relevance of innate immunity for the control of JCV replication. Here, we define the intracellular innate immune sensors responsible for controlling JCV infection and also demonstrate a novel mechanism by which a JCV-encoded protein acts as an antagonist of the type I interferon-mediated innate immune response.

ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity.

Activation of the RIG-I-like receptors, retinoic-acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15, the mechanistic roles of which in innate immunity still remain enigmatic. In the present study, we report that ISG15 conjugation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISGylation of the caspase activation and recruitment domains of MDA5 promotes its oligomerization and thereby triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease of SARS-CoV-2, a recently emerged coronavirus that has caused the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a key immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.

Sleep disturbance and the long-term impact of early adversity.

Sleep disturbance may be a central, yet underappreciated mechanism by which early adversity has a long-term impact upon mental and physical health. The fundamental regulatory processes shaped by early adversity - neural, neuroendocrine, and immune - are also central to sleep. Sleep problems, in turn, lead to a similar constellation of chronic health problems that have been linked to early adversity. We bring together work from the fields of early adversity and sleep in order to suggest a model by which sleep disturbance plays a critical role in the far-reaching impacts of early adversity on health. Future research should employ more longitudinal designs and pay particular attention to the impact of developmental periods such as adolescence and midlife when maturational and environmental factors conspire to create a unique time of sleep disturbance. We also suggesting that intervening to minimize sleep disturbance may be a promising means by which to test the model, as well as potentially blunt the long-term impact of early adversity on health.