Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease's multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS's pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease's complexity and the multifaceted approach required for its study and management.

Wildfire Smoke Exposure Is Associated with Adverse Respiratory Events under General Anesthesia in At-risk Pediatric Patients.

BACKGROUND: Increasing wildfire activity worldwide has led to exposure to poor air quality and numerous detrimental health impacts. This study hypothesized an association between exposure to poor air quality from wildfire smoke and adverse respiratory events under general anesthesia in pediatric patients. METHODS: This was a single-center retrospective double-cohort study examining two significant wildfire events in Northern California. Pediatric patients presenting for elective surgery during periods of unhealthy air quality were compared with those during periods of healthy air quality. The primary exposure, unhealthy air, was determined using local air quality sensors. The primary outcome was the occurrence of an adverse respiratory event under anesthesia. Secondary analysis included association with other known risk factors for adverse respiratory events. RESULTS: A total of 625 patients were included in the analysis. The overall risk of a respiratory complication was 42.4% (265 of 625). In children without a history of reactive airway disease, the risk of adverse respiratory events did not change during unhealthy air periods (102 of 253, 40.3%) compared with healthy air periods (95 of 226, 42.0%; relative risk 0.96 [0.77 to 1.19], P = 0.703). In children with a history of reactive airway disease, the risk of adverse respiratory events increased from 36.8% (25 of 68) during healthy air periods to 55.1% (43 of 78) during periods with unhealthy air (1.50 [1.04 to 2.17], P = 0.032). The effect of air quality on adverse respiratory events was significantly modified by reactive airways disease status (1.56 [1.02 to 2.40], P = 0.041). CONCLUSIONS: Pediatric patients with underlying risk factors for respiratory complications under general anesthesia had a greater incidence of adverse respiratory events during periods of unhealthy air quality caused by wildfire smoke. In this vulnerable patient population, postponing elective anesthetics should be considered when air quality is poor.

Memory for diverse faces in a racially attentive context.

Two experiments assessed how racial ambiguity and racial salience moderates the cross-race effect (CRE). In experiment 1, White and Black participants studied and identified the race of Asian, Black, Latino, and White faces that varied in ethnic typicality (high or low ET). For White participants, the CRE was larger when comparing high-ET White faces to high-ET other-race faces than low-ET other-race faces. Black participants showed a similar CRE reduction by ethnic typicality, but also showed a less prevalent CRE than White participants. Experiment 2 replicated experiment 1 procedures, but without the race identification task and only with White participants. Experiment 2 findings were comparable to experiment 1. Furthermore, experiment 2 showed a noticeably smaller CRE on Black faces than experiment 1, eliciting questions about increased racial salience amplifying the CRE. Results' general implications and the conceptual roots that indirectly link the CRE and racism will be discussed.

Ring Expansion of 1-Indanones to 2-Halo-1-naphthols as an Entry Point to Gilvocarcin Natural Products.

Herein, we describe a two-step ring expansion of 1-indanones to afford 2-chloro/bromo-1-naphthols (32 examples). The developed method shows broad functional group tolerance, benefits from mild reaction conditions, and enables rapid access to the tetracyclic core of gilvocarcin natural products. The orthogonally functionalized products allow for selective postmodifications as exemplified in the total synthesis of defucogilvocarcin M. For the selective oxidation of the chromene, a mild and regioselective oxidation protocol (DDQ and TBHP) was developed.

The Benefit of Gratitude: Trait Gratitude Is Associated With Effective Economic Decision-Making in the Ultimatum Game.

The current research investigated the role of gratitude in economic decisions about offers that vary in fairness yet benefit both parties if accepted. Participants completed a trait/dispositional gratitude measure and then were randomly assigned to recall either an event that made them feel grateful (i.e., induced gratitude condition) or the events of a typical day (i.e., neutral condition). After the gratitude induction task, participants played the ultimatum game (UG), deciding whether to accept or reject fair offers (i.e., proposer: responder ratio $5:5) and unfair offers (i.e., proposer: responder ratios of $9:1, $8:2, or $7:3) from different proposers. Results showed that trait gratitude was positively correlated with respondents' acceptance of unfair offers. However, experimentally induced momentary gratitude did not influence acceptance of unfair offers. The trait or disposition to be grateful involves the enduring capacity across different types of situations and benefactors to see the good that is present, even when that benefit is small. Accordingly, dispositional gratitude - but not momentarily induced gratitude - was associated with a greater propensity to accept even the small benefits within unfair offers which otherwise pose barriers to making the effective economic decision of accepting offers regardless of their relative size.

Anesthesiology Residency Training and the Anesthesia Toolbox: Five Years of Experience With a Collaboratively Developed Peer-Reviewed e-Learning System.

The Internet is a source of professional self-education for medical students and residents. Unfortunately, much of the content discovered through search engines is of insufficient quality for professional education. The Anesthesia Toolbox (AT) was developed to provide online peer-reviewed educational resources for anesthesiology trainees and faculty. Since 2014, AT has developed 24 curricula, 822 content items, and 3238 quiz questions. As of March 2020, 64 anesthesiology residency programs in the United States subscribed to the AT (41% of total). Since the onset of the pandemic in March, AT has added 25 programs (28% increase) and gained 1156 users (26% increase).

Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. METHODS: Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. RESULTS: Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. CONCLUSIONS: Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.

Resection of a Posterior Mediastinal Mass in a 4-Year-Old Child Complicated by Difficult Airway Management and Emergent Use of Extracorporeal Membrane Oxygenation.

Literature on posterior mediastinal masses is limited. Furthermore, they have traditionally been described to pose lower cardiopulmonary risks compared with anterior mediastinal masses. Studies on posterior mediastinal masses are even more limited in the pediatric population. We present a case of a large posterior mediastinal mass in a 4-year-old child who presented with extremely difficult airway management during endobronchial intubation due to severe external compression that led to use of an adapted airway management technique with a rigid airway exchanger for lung isolation. Due to the pathology of the mass, a tracheal tear was encountered during surgical dissection and the patient required emergent venovenous extracorporeal membrane oxygenation to allow for successful airway repair and complete resection of the mass.

Use of Remifentanil for Open in utero Fetal Myelomeningocele Repair Maintains Uterine Relaxation with Reduced Volatile Anesthetic Concentration.

INTRODUCTION: Open fetal repair of myelomeningocele (MMC) is an option for prenatally diagnosed spina bifida. Historically, high-dose volatile anesthetic was used for uterine relaxation but is associated with fetal cardiovascular depression. We examined the impact of administering a supplemental remifentanil infusion on the concentration of inhaled anesthetic required for intraoperative uterine relaxation. METHODS: We retrospectively analyzed 22 consecutive patients who underwent open fetal MMC repair with desflurane anesthesia from 2014 to 2018. The anesthetic protocol was modified to include high-dose opioid with remifentanil in 2016. We examined intraoperative end-tidal desflurane concentrations, vasopressor use, incidence of umbilical artery Doppler abnormalities, and incidence of preterm labor and delivery. RESULTS: Patients (n = 11) who received desflurane and remifentanil (Des/Remi) were compared to patients (n = 11) who received desflurane (Des) alone. Intraoperatively, the maximum end-tidal desflurane required to maintain uterine relaxation was lower in the Des/Remi group (7.9 ± 2.2% vs. 13.1 ± 1.2%, p < 0.001). The mean phenylephrine infusion rate was also lower in the Des/Remi group (36 ± 14 vs. 53 ± 10 mcg/min, p = 0.004). DISCUSSION: Use of opioid with supplemental remifentanil was associated with lower volatile anesthetic dosing and decreased vasopressor use; fetal outcomes were not different. Remifentanil may allow for less volatile anesthetic use while maintaining adequate uterine relaxation.

Exposure to incivility hinders clinical performance in a simulated operative crisis.

BACKGROUND: Effective communication is critical for patient safety. One potential threat to communication in the operating room is incivility. Although examined in other industries, little has been done to examine how incivility impacts the ability to deliver safe care in a crisis. We therefore sought to determine how incivility influenced anaesthesiology resident performance during a standardised simulation scenario of occult haemorrhage. METHODS: This is a multicentre, prospective, randomised control trial from three academic centres. Anaesthesiology residents were randomly assigned to either a normal or 'rude' environment and subjected to a validated simulated operating room crisis. Technical and non-technical performance domains including vigilance, diagnosis, communication and patient management were graded on survey with Likert scales by blinded raters and compared between groups. RESULTS: 76 participants underwent randomisation with 67 encounters included for analysis (34 control, 33 intervention). Those exposed to incivility scored lower on every performance metric, including a binary measurement of overall performance with 91.2% (control) versus 63.6% (rude) obtaining a passing score (p=0.009). Binary logistic regression to predict this outcome was performed to assess impact of confounders. Only the presence of incivility reached statistical significance (OR 0.110, 95% CI 0.022 to 0.544, p=0.007). 65% of the rude group believed the surgical environment negatively impacted performance; however, self-reported performance assessment on a Likert scale was similar between groups (p=0.112). CONCLUSION: Although self-assessment scores were similar, incivility had a negative impact on performance. Multiple areas were impacted including vigilance, diagnosis, communication and patient management even though participants were not aware of these effects. It is imperative that these behaviours be eliminated from operating room culture and that interpersonal communication in high-stress environments be incorporated into medical training.

Enhanced Memory for Fair-Related Faces and the Role of Trait Anxiety.

The current research examined whether fair consideration-a social norm that people inherently prefer to confirm-would modulate face recognition. Each neutral face was associated with fair or unfair offers via an economic decision task, the Ultimatum Game (UG) task. After the UG, participants were asked to identify the faces of proposers who made different offers. Enhanced memory was observed for fair-related compared to unfair-related faces. Furthermore, high trait anxiety was associated with reduced memory for fair-related faces. These results were further confirmed by signal detection theory. The current research provided initial evidence that people showed enhanced memory for faces that made fair offers from the economic decision task, and that high trait anxiety was associated with reduced fair-related memory. Possible neural mechanisms and the implication in economic and social situations have been discussed.

Public Perceptions on the Influence of Diet and Kidney Stone Formation.

Introduction: Public awareness regarding the influence of diet on kidney stones is unknown. We sought to evaluate such perceptions among an unselected community cohort. Materials and Methods: A survey was created to assess perception of beverages/foods on risk of kidney stone formation. Surveys were distributed to attendees of a State Fair. Participants were categorized to determine the effect of stone history on prevention knowledge (no prior stone vs prior stone). Results: Seven hundred fifty-three participants completed the survey, including 264 (35%) with a prior stone. Participants with prior stones were less likely to believe stones were preventable compared to those without (56% vs 65%, p = 0.01). Appropriate perceptions regarding influence of diet on stones were highest for water (>90% of participants) and cola/salt/red meat (>50%). Fewer than half of respondents correctly identified the influence of the remaining 14 substances. On multivariable analysis, stone formers were more likely to correctly identify the influence of lemonade (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.32-3.31), nuts (OR 2.60; 95% CI 1.60-4.23), and spinach (OR 5.06; 95% CI 2.89-8.86), but less likely to identify the influence of coffee (OR 0.43; 95% CI 0.23-0.82) and red meat (OR 0.52; 95% CI 0.23-0.59). Conclusion: Patients with prior stones hold different attitudes regarding the influence of certain foods and drinks on stone formation relative to the public. Such attitudes are not always correct, and as a group they are less likely to believe in dietary stone prevention. Such findings may indicate confusion among stone formers and highlight an opportunity for improved dietary counseling.

Development of a Classification Scheme for Examining Adverse Events Associated with Medical Devices, Specifically the DaVinci Surgical System as Reported in the FDA MAUDE Database.

OBJECTIVE: To examine the Manufacturer and User Facility Device Experience Database (MAUDE) database to capture adverse events experienced with the Da Vinci Surgical System. In addition, to design a standardized classification system to categorize the complications and machine failures associated with the device. SUMMARY BACKGROUND DATA: Overall, 1,057,000 DaVinci procedures were performed in the United States between 2009 and 2012. Currently, no system exists for classifying and comparing device-related errors and complications with which to evaluate adverse events associated with the Da Vinci Surgical System. METHODS: The MAUDE database was queried for events reports related to the DaVinci Surgical System between the years 2009 and 2012. A classification system was developed and tested among 14 robotic surgeons to associate a level of severity with each event and its relationship to the DaVinci Surgical System. Events were then classified according to this system and examined by using Chi-square analysis. RESULTS: Two thousand eight hundred thirty-seven events were identified, of which 34% were obstetrics and gynecology (Ob/Gyn); 19%, urology; 11%, other; and 36%, not specified. Our classification system had moderate agreement with a Kappa score of 0.52. Using our classification system, we identified 75% of the events as mild, 18% as moderate, 4% as severe, and 3% as life threatening or resulting in death. Seventy-seven percent were classified as definitely related to the device, 15% as possibly related, and 8% as not related. Urology procedures compared with Ob/Gyn were associated with more severe events (38% vs 26%, p < 0.0001). Energy instruments were associated with less severe events compared with the surgical system (8% vs 87%, p < 0.0001). Events that were definitely associated with the device tended to be less severe (81% vs 19%, p < 0.0001). CONCLUSIONS: Our classification system is a valid tool with moderate inter-rater agreement that can be used to better understand device-related adverse events. The majority of robotic related events were mild but associated with the device.

The cross-race effect in face recognition memory by bicultural individuals.

Social-cognitive models of the cross-race effect (CRE) generally specify that cross-race faces are automatically categorized as an out-group, and that different encoding processes are then applied to same-race and cross-race faces, resulting in better recognition memory for same-race faces. We examined whether cultural priming moderates the cognitive categorization of cross-race faces. In Experiment 1, monoracial Latino-Americans, considered to have a bicultural self, were primed to focus on either a Latino or American cultural self and then viewed Latino and White faces. Latino-Americans primed as Latino exhibited higher recognition accuracy (A') for Latino than White faces; those primed as American exhibited higher recognition accuracy for White than Latino faces. In Experiment 2, as predicted, prime condition did not moderate the CRE in European-Americans. These results suggest that for monoracial biculturals, priming either of their cultural identities influences the encoding processes applied to same- and cross-race faces, thereby moderating the CRE.

Accessing low-oxidation state taxanes: is taxadiene-4(5)-epoxide on the taxol biosynthetic pathway?

We have shown for the first time that taxadiene (3) can be epoxidised in a regio- and diastereoselective manner to provide taxadiene-4(5)-epoxide (12) as a single diastereoisomer, and that this epoxide can be rearranged to give taxa-4(20),11(12)-dien-5α-ol (4). Furthermore, the epoxide 12 rearranges under acidic conditions to give taxa-4(20),11(12)-dien-5α-ol (4), the known bridged ether OCT (5) and the new oxacyclotaxane (OCT2) 15. Contrary to previous speculation, taxadiene-4(5)-epoxide (12) is susceptible to rearrangement when exposed to an ironIII porphyrin, and these observations justify consideration of epoxide 12 as a chemically competent intermediate on the taxol biosynthetic pathway.

Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level.

Ezrin is a key regulator of cancer metastasis that links the extracellular matrix to the actin cytoskeleton and regulates cell morphology and motility. We discovered a small-molecule inhibitor, NSC305787, that directly binds to ezrin and inhibits its function. In this study, we used a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS-MS)-based proteomic approach to identify ezrin-interacting proteins that are competed away by NSC305787. A large number of the proteins that interact with ezrin were implicated in protein translation and stress granule dynamics. We validated direct interaction between ezrin and the RNA helicase DDX3, and NSC305787 blocked this interaction. Downregulation or long-term pharmacological inhibition of ezrin led to reduced DDX3 protein levels without changes in DDX3 mRNA. Ectopic overexpression of ezrin in low-ezrin-expressing osteosarcoma cells caused a notable increase in DDX3 protein levels. Ezrin inhibited the RNA helicase activity of DDX3 but increased its ATPase activity. Our data suggest that ezrin controls the translation of mRNAs preferentially with a structured 5' untranslated region, at least in part, by sustaining the protein level of DDX3 and/or regulating its function. Therefore, our findings suggest a novel function for ezrin in regulation of gene translation that is distinct from its canonical role as a cytoskeletal scaffold at the cell membrane.

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists.

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD7.4 <5.3 and CLND solubility >116 µg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD7.4 (2.4), high LE (0.43), and solubility (152 µg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.

Imagination perspective affects ratings of the likelihood of occurrence of autobiographical memories.

Two experiments tested and confirmed the hypothesis that when the phenomenological characteristics of imagined events are more similar to those of related autobiographical memories, the imagined event is more likely to be considered to have occurred. At Time 1 and 2-weeks later, individuals rated the likelihood of occurrence for 20 life events. In Experiment 1, 1-week after Time 1, individuals imagined 3 childhood events from a first-person or third-person perspective. There was a no-imagination control. An increase in likelihood ratings from Time 1 to Time 2 resulted when imagination was from the third-person but not first-person perspective. In Experiment 2, childhood and recent events were imagined from a third- or first-person perspective. A significant interaction resulted. For childhood events, likelihood change scores were greater for third-person than first-person perspective; for recent adult events, likelihood change scores were greater for first-person than third-person perspective, although this latter trend was not significant.