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Background: Atrial fibrillation (AF) ablation can lead to oesophageal thermal injuries (ETI). These are thought to be the precursor of the much rarer but frequently fatal atrio-oesophageal fistulas. Many centers performing AF ablation routinely use oesophageal temperature monitoring (ETM). This meta-analysis aims to determine the utility of ETM in preventing ETI in the context of radiofrequency catheter ablation of AF. Methods: A systematic search of PubMed, Embase databases and Cochrane registry was performed comparing ETI between ETM and non-ETM strategies in AF ablation. Data on endoscopically determined ETI, AF recurrence, procedure time and ablation time were extracted. Statistical analyses including subgroup and covariate analyses were performed using random effect model in R platform. Results: ETI were similar in both ETM (n = 864) and non- ETM groups (n = 639) (RR 1.04, 95 % CI 0.34–3.23) across 12 studies. AF recurrence was statistically similar in both groups (IRR 0.92, 95 % CI 0.73–1.17) but showed a lower trend in non-ETM group. Ablation time was numerically lower in the ETM group and procedure time was numerically higher trend in the ETM group; but they were not statistically significant. Covariate analysis found that posterior wall ablation power setting, additional linear ablation, BMI, use of GA or prophylactic PPI after ablation had no significant correlation in the incidence of ETI. Conclusion: ETM was not associated with a reduced incidence of ETI during AF ablation. Evidence supporting the routine use of ETM to reduce the risk of ETI or atrio-oesophageal fistulas is lacking.

Background: The objective of this paper is to discuss perceived clinical utility and impact on physician-patient relationship of a novel, artificial-intelligence (AI) enabled clinical decision support system (CDSS) for use in treating adults with major depression. Methods: A single arm, naturalistic follow-up study aimed at assessing the acceptability and useability of the software. Patients had a baseline appointment, followed by a minimum of two appointments with the CDSS. Study exit questionnaires and interviews were conducted to assess perceived clinical utility, impact on patient-physician relationship, and understanding and trust. 7 physicians and 17 patients, of which 14 completed, consented to participate. Results: 86 % of physicians (6/7) felt the information provided by the CDSS provided more comprehensive understanding of patient situations. 71 % (5/7) felt the information was helpful. 86 % of physicians (6/7) reported the AI/predictive model was useful when deciding treatment. 62 % of patients (8/13) reported improved care due to the tool, and 46 %(6/13) reported a significantly or somewhat improved physician-patient relationship 54 % reported no change. 71 % of physicians (5/7) and 62 % of patients (8/13) rated trusting the tool. Limitations: Small sample size and treatment changes prior to CDSS introduction limits ability to verify impact on outcomes. Conclusions: Qualitative results from 12 patient exit interviews are analyzed and presented. Findings suggest physicians perceived the tool as useful in conducting appointments and used it while deciding treatment. Physicians and patients generally found the tool trustworthy, and it may have positive effects on physician-patient relationships. (Study identifier: NCT04061642).

We read with interest the recent publication of Dinesen et al. [...]

Vitiligo is a multifaceted autoimmune depigmenting disorder affecting around 0.5 to 2.0% of individuals globally. Standardizing diagnosis and therapy tracking can be arduous, as numerous clinical evaluation methods are subject to interobserver variability and may not be validated. Therefore, there is a need for diagnostic tools that are objective, dependable, and preferably non-invasive.AimsThis systematic review provides a comprehensive overview of the non-invasive objective skin measurement methods that are currently used to evaluate the diagnosis, severity, and progression of vitiligo, as well as the advantages and limitations of each technique.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used for the systematic review. Scopus, Embase, Cochrane Library, and Web of Science databases were comprehensively searched for non-invasive imaging and biophysical skin measuring methods to diagnose, evaluate the severity of, or monitor the effects of vitiligo treatment. The risk of bias in included articles was assessed using the QUADAS-2 quality assessment scale.ResultsAn extensive literature search resulted in 64 studies for analysis, describing eight imaging techniques (reflectance confocal microscopy, computer-aided imaging analysis, optical coherence tomography, infrared photography, third-harmonic generation microscopy, multiphoton microscopy, ultraviolet light photography, and visible light/digital photograph), and three biophysical approaches (dermoscopy, colorimetry, spectrometry) used in diagnosing and assessing vitiligo. Pertinent information about functionality, mechanisms of action, sensitivity, and specificity was obtained for all studies, and insights into the strengths and limitations of each diagnostic technique were addressed. Methodological study quality was adequate; however, statistical analysis was not achievable because of the variety of methods evaluated and the non-standardized reporting of diagnostic accuracy results.ConclusionsThe results of this systematic review can enhance clinical practice and research by providing a comprehensive overview of the spectrum of non-invasive imaging and biophysical techniques in vitiligo assessment. Studies with larger sample sizes and sound methodology are required to develop verified methods for use in future practice and research.Systematic review registration(PROSPERO) database, (CRD42023395996).

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug—in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades—results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain).

Understanding the pharmacokinetics of locally-injected drugs could aid in the design of immunotherapies to maximize their therapeutic effect. Here, by evaluating different IL-2 fusion proteins, the authors show that molecular weight and matrix binding affect anti-tumor immune response and report a pharmacokinetic framework to predict response to intratumoral IL-2 therapy.

As the top predator in African ecosystems, lions have lost more than 90% of their historical range, and few countries possess strong evidence for stable populations. Translocations (broadly defined here as the capture and movement of lions for various management purposes) have become an increasingly popular action for this species, but the wide array of lion translocation rationales and subsequent conservation challenges stemming from poorly conceived or unsuitable translocations warrants additional standardized evaluation and guidance. At their best, translocations fill a key role in comprehensive strategies aimed at addressing the threats facing lions and fostering the recovery of wild populations in their historic range. At their worst, translocations can distract from addressing the major threats to wild populations and habitats, divert scarce funding from more valuable conservation actions, exacerbate conflict with humans in recipient sites, disrupt local lion demography, and undermine the genetic integrity of wild lion populations in both source and recipient sites. In the interest of developing best practice guidelines for deciding when and how to conduct lion translocations, we discuss factors to consider when determining whether a translocation is of conservation value, introduce a value assessment for translocations, and provide a decision matrix to assist practitioners in improving the positive and reducing the negative outcomes of lion translocation.

In this essay I argue that La Celestina should be read as a novel. The work is impossible to perform in a theater: it is not a drama. Neither is it a humanistic co-medy, either in form or spirit. That a novel can be written in the form of a series of letters is not controversial, even though there is no narrator. In a similar way, there is —as Cervantes explained in his introduction to his Coloquio de los perros— an implicit narrative link between the segments of dialogue in his work. La Celestina is a work of the Renaissance (not the Middle Ages), and it has always been read as a novel. It is the first great novel of the print age.

Abstract In the last decade, interest in the use of beta gallium oxide (β-Ga2O3) as a semiconductor for high power/high temperature devices and deep-UV sensors has grown. Ga2O3 has an enormous band gap of 4.8 eV, which makes it well suited for these applications. Compared to thin films, nanowires exhibit a higher surface-to-volume ratio, increasing their sensitivity for detection of chemical substances and light. In this work, we explore a simple and inexpensive method of growing high-density gallium oxide nanowires at high temperatures. Gallium oxide nanowire growth can be achieved by heating and oxidizing pure gallium at high temperatures (~ 1000 °C) in the presence of trace amounts of oxygen. This process can be optimized to large-scale production to grow high-quality, dense and long Ga2O3 nanowires. We show the results of morphological, structural, electrical and optical characterization of the β-Ga2O3 nanowires including the optical bandgap and photoconductance. The influence of density on these Ga2O3 nanowires and their properties will be examined in order to determine the optimum configuration for the detection of UV light.

BackgroundKeratoconus is a disorder characterized by progressive thinning and distortion of the cornea. If detected at an early stage, corneal collagen cross-linking can prevent disease progression and further visual loss. Although advanced forms are easily detected, reliable identification of subclinical disease can be problematic. Several different machine learning algorithms have been used to improve the detection of subclinical keratoconus based on the analysis of multiple types of clinical measures, such as corneal imaging, aberrometry, or biomechanical measurements. ObjectiveThe aim of this study is to survey and critically evaluate the literature on the algorithmic detection of subclinical keratoconus and equivalent definitions. MethodsFor this systematic review, we performed a structured search of the following databases: MEDLINE, Embase, and Web of Science and Cochrane Library from January 1, 2010, to October 31, 2020. We included all full-text studies that have used algorithms for the detection of subclinical keratoconus and excluded studies that did not perform validation. This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. ResultsWe compared the measured parameters and the design of the machine learning algorithms reported in 26 papers that met the inclusion criteria. All salient information required for detailed comparison, including diagnostic criteria, demographic data, sample size, acquisition system, validation details, parameter inputs, machine learning algorithm, and key results are reported in this study. ConclusionsMachine learning has the potential to improve the detection of subclinical keratoconus or early keratoconus in routine ophthalmic practice. Currently, there is no consensus regarding the corneal parameters that should be included for assessment and the optimal design for the machine learning algorithm. We have identified avenues for further research to improve early detection and stratification of patients for early treatment to prevent disease progression.

Background: Face masks are recommended for sterile procedures, while the data supporting this recommendation is lacking. Here we systematically review randomized control trials on mask efficacy in the operating room as a means to preventing surgical site clinical infection. Methods: PubMed, Google Scholar, Web of Science, and National Institute for Occupational Safety and Health Publications and Products were searched and articles were included if they fit the criteria of 1) randomized control trial, 2) clinical patient outcomes, 3) mask efficacy, 4) surgery setting, 5) in vivo, and 6) article was in English. Results: The results indicate no difference in surgical site infections between the operations where masks were worn versus the operations where no mask was worn. Conclusion: With such limited evidence and the great cost that accrues from purchasing face masks for all surgical staff, we hope for larger, well designed randomized control trials to evaluate the true clinical efficacy of surgical masks in the operating room.

Background: The use of facemasks for infection prevention has become widely accepted. Current recommendations include influenza patients wearing a mask in a medical setting. Here we systematically reviewed randomized control trials on mask efficacy in index influenza patients to prevent transmission. Methods: PubMed, Google Scholar, and Web of Science were searched and articles were included if they fit the criteria of 1) randomized control trial, 2) influenza, 3) mask efficacy, 4) influenza patients with masks for source control, 5) in vivo, and 6) article was in English. Results: The results point to no difference in influenza transmission between medical mask and control groups. However, there have been several attempts at explaining this finding. Conclusion: This review found there were few studies and weak supporting evidence for mask recommendations. We hope for larger, randomized control trials in the hospital setting that evaluate the efficacy of masks as a means of source control in influenza infected patients.

BackgroundApproximately two-thirds of patients with major depressive disorder do not achieve remission during their first treatment. There has been increasing interest in the use of digital, artificial intelligence–powered clinical decision support systems (CDSSs) to assist physicians in their treatment selection and management, improving the personalization and use of best practices such as measurement-based care. Previous literature shows that for digital mental health tools to be successful, the tool must be easy for patients and physicians to use and feasible within existing clinical workflows. ObjectiveThis study aims to examine the feasibility of an artificial intelligence–powered CDSS, which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural network–based individualized treatment remission prediction. MethodsOwing to the COVID-19 pandemic, the study was adapted to be completed entirely remotely. A total of 7 physicians recruited outpatients diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Patients completed a minimum of one visit without the CDSS (baseline) and 2 subsequent visits where the CDSS was used by the physician (visits 1 and 2). The primary outcome of interest was change in appointment length after the introduction of the CDSS as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semistructured interviews. ResultsData were collected between January and November 2020. A total of 17 patients were enrolled in the study; of the 17 patients, 14 (82%) completed the study. There was no significant difference in appointment length between visits (introduction of the tool did not increase appointment length; F2,24=0.805; mean squared error 58.08; P=.46). In total, 92% (12/13) of patients and 71% (5/7) of physicians felt that the tool was easy to use; 62% (8/13) of patients and 71% (5/7) of physicians rated that they trusted the CDSS. Of the 13 patients, 6 (46%) felt that the patient-clinician relationship significantly or somewhat improved, whereas 7 (54%) felt that it did not change. ConclusionsOur findings confirm that the integration of the tool does not significantly increase appointment length and suggest that the CDSS is easy to use and may have positive effects on the patient-physician relationship for some patients. The CDSS is feasible and ready for effectiveness studies. Trial RegistrationClinicalTrials.gov NCT04061642; http://clinicaltrials.gov/ct2/show/NCT04061642

ABSTRACT With great apprehension, the world is now watching the birth of a novel pandemic already causing tremendous suffering, death, and disruption of normal life. Uncertainty and dread are exacerbated by the belief that what we are experiencing is new and mysterious. However, deadly pandemics and disease emergences are not new phenomena: they have been challenging human existence throughout recorded history. Some have killed sizeable percentages of humanity, but humans have always searched for, and often found, ways of mitigating their deadly effects. We here review the ancient and modern histories of such diseases, discuss factors associated with their emergences, and attempt to identify lessons that will help us meet the current challenge.

Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.

A simple and inexpensive method for growing Ga2O3 using GaAs wafers is demonstrated. Si-doped GaAs wafers are heated to 1050 °C in a horizontal tube furnace in both argon and air ambients in order to convert their surfaces to β-Ga2O3. The β-Ga2O3 films are characterized using scanning electron micrograph, energy-dispersive X-ray spectroscopy, and X-ray diffraction. They are also used to fabricate solar blind photodetectors. The devices, which had nanotextured surfaces, exhibited a high sensitivity to ultraviolet (UV) illumination due in part to large surface areas. Furthermore, the films have coherent interfaces with the substrate, which leads to a robust device with high resistance to thermo-mechanical stress. The photoconductance of the β-Ga2O3 films is found to increase by more than three orders of magnitude under 270 nm ultraviolet illumination with respect to the dark current. The fabricated device shows a responsivity of ~292 mA/W at this wavelength.

Background Predicting clinical outcomes after cardiac resynchronization therapy (CRT) and its optimization remain a challenge. We sought to determine whether pre‐ and postimplantation QRS area (QRSarea) predict clinical outcomes after CRT. Methods and Results In this retrospective study, QRSarea, derived from pre‐ and postimplantation vectorcardiography, were assessed in relation to the primary end point of cardiac mortality after CRT with or without defibrillation. Other end points included total mortality, total mortality or heart failure (HF) hospitalization, total mortality or major adverse cardiac events, and the arrhythmic end point of sudden cardiac death or ventricular arrhythmias with or without a shock. In patients (n=380, age 72.0±12.4 years, 68.7% male) undergoing CRT over 7.7 years (median follow‐up: 3.8 years [interquartile range 2.3–5.3]), preimplantation QRSarea ≥102 μVs predicted cardiac mortality (HR: 0.36; P

A simple and inexpensive thermal oxidation process was performed to synthesize gallium oxide (Ga2O3) nanowires using Ag thin film as a catalyst at 800 °C and 1000 °C to understand the effect of the silver catalyst on the nanowire growth. The effect of doping and orientation of the substrates on the growth of Ga2O3 nanowires on single-crystal gallium arsenide (GaAs) wafers in atmosphere were investigated. A comprehensive study of the oxide film and nanowire growth was performed using various characterization techniques including XRD, SEM, EDS, focused ion beam (FIB), XPS and STEM. Based on the characterization results, we believe that Ag thin film produces Ag nanoparticles at high temperatures and enhances the reaction between oxygen and gallium, contributing to denser and longer Ga2O3 nanowires compared to those grown without silver catalyst. This process can be optimized for large-scale production of high-quality, dense, and long nanowires.

Gallium oxide (Ga2O3) is a new wide bandgap semiconductor with remarkable properties that offers strong potential for applications in power electronics, optoelectronics, and devices for extreme conditions. In this work, we explore the morphology of Ga2O3 nanostructures on different substrates and temperatures. We used silver catalysts to enhance the growth of Ga2O3 nanowires on substrates such as p-Si substrate doped with boron, 250 nm SiO2 on n-Si, 250 nm Si3N4 on p-Si, quartz, and n-Si substrates by using a thermal oxidation technique at high temperatures (~1000 °C) in the presence of liquid silver paste that served as a catalyst layer. We present the results of the morphological, structural, and elemental characterization of the Ga2O3 nanostructures. This work offers in-depth explanation of the dense, thin, and long Ga2O3 nanowire growth directly on the surfaces of various types of substrates using silver catalysts.

Water and wastewater industry leaders in Texas and throughout the United States have expressed concern over high rates of retirement eligibility and difficulties finding and attracting workers ready to fill job openings, especially for work in smaller systems. In late January 2018, the U.S. Government Accountability Office released a report on water workforce readiness and a bill was introduced in the U.S. Senate to establish a water infrastructure workforce development program. Concern over existing education of workers in water and demographic information projecting future workforce readiness are commonly cited as signaling a coming crisis for the water industry. An alignment of post-secondary training and industry needs is recommended to meet coming workforce employment requirements for Texas and the nation. A model post-secondary education pathway for water science and technology is described to support water workforce readiness. Citation: Rosen RA, Cifuentes LA, Fischer J, Marquise H, Tracy JC. 2018. Water security for Texas: a post-secondary education pathway for water workforce readiness. Texas Water Journal. 9(1):120-128. Available from: https://doi.org/10.21423/twj.v9i1.7078.

Background Experimental evidence indicates that left ventricular (LV) apical pacing is hemodynamically superior to nonapical LV pacing. Some studies have shown that an LV apical lead position is unfavorable in cardiac resynchronization therapy. We sought to determine whether an apical LV lead position influences cardiac mortality after cardiac resynchronization therapy. Methods and Results In this retrospective observational study, the primary end point of cardiac mortality was assessed in relation to longitudinal (basal, midventricular, or apical) and circumferential (anterior, lateral, or posterior) LV lead positions, as well as right ventricular (apical or septal), assigned using fluoroscopy. Lead positions were assessed in 1189 patients undergoing cardiac resynchronization therapy implantation over 15 years. After a median follow‐up of 6.0 years (interquartile range: 4.4–7.7 years), an apical LV lead position was associated with lower cardiac mortality than a nonapical position (adjusted hazard ratio: 0.74; 95% confidence interval, 0.56–0.99) after covariate adjustment. There were no differences in total mortality or heart failure hospitalization. Death from pump failure was lower with apical than nonapical positions (adjusted hazard ratio: 0.69; 95% confidence interval, 0.51–0.94). Compared with a basal position, an apical LV position was also associated with lower risk of sudden cardiac death (adjusted hazard ratio: 0.34; 95% confidence interval, 0.13–0.93). No differences emerged between circumferential LV lead positions or right ventricular positions with respect to any end point. Conclusions In recipients of cardiac resynchronization therapy, an apical LV lead position was associated with better long‐term cardiac survival than a nonapical position. This effect was due to a lower risk of pump failure and sudden cardiac death.

BackgroundIn cardiac resynchronization therapy (CRT), quadripolar (QUAD) left ventricular (LV) leads are less prone to postoperative complications than non‐QUAD leads. Some studies have suggested better clinical outcomes. Methods and ResultsClinical events were assessed in 847 patients after CRT‐pacing or CRT‐defibrillation using either QUAD (n=287) or non‐QUAD (n=560), programmed to single‐site site LV pacing. Over a follow‐up period of 3.2 years (median [interquartile range, 1.90–5.0]), QUAD was associated with a lower total mortality (adjusted hazard ratio [aHR]: 0.32, 95% confidence interval [CI], 0.20–0.52), cardiac mortality (aHR: 0.36, 95% CI, 0.20–0.65), and heart failure (HF) hospitalization (aHR: 0.62, 95% CI, 0.39–0.99), after adjustment for age, sex, New York Heart Association class, HF etiology, device type (CRT‐pacing or CRT‐defibrillation), comorbidities, atrial rhythm, medication, left ventricular ejection fraction, and creatinine. Death from pump failure was lower with QUAD (aHR: 0.33; 95% CI, 0.18–0.62), but no group differences emerged with respect to sudden cardiac death. There were no differences in implant‐related complications. Re‐interventions for LV displacement or phrenic nerve stimulation, which were lower with QUAD, predicted total mortality (aHR: 1.68, 95% CI, 1.11–2.54), cardiac mortality (aHR: 2.61, 95% CI, 1.66–4.11) and HF hospitalization (aHR: 2.09, 95% CI, 1.22–3.58). ConclusionsCRT using QUAD, programmed to biventricular pacing with single‐site LV pacing, is associated with a lower total mortality, cardiac mortality, and HF hospitalization. These trends were observed for both CRT‐defibrillation and CRT‐pacing, after adjustment for HF cause and other confounders. Re‐intervention for LV lead displacement or phrenic nerve stimulation was associated with worse outcomes.

Serum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials.Serum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists.In the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD.Serum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.

I introduce the notion of “neglect defaulting,” which labels the propensity to neglect possibilities which are ordinarily sensibly neglected. In familiar contexts we are well-tuned to recognize when to override the default. But outside the range of familiar experience — here in the artificial context of puzzles — these ordinarily benign defaults can make it difficult for even sophisticated subjects, such as readers of this note, to avoid responses which on reflection will be seen as obviously mistaken. A detail of particular importance is that, although subjects are easily prompted to take one step in the direction of reaching a sound response, the tendency to then neglect to consider that another step may be needed is remarkably strong. In each of the five examples the needed but usually neglected second step is quite trivial. Concluding remarks point to consequences for larger questions outside the range of familiar experience, in politics and other contexts out of scale with everyday experience.

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse “mutation hotspots” in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.

We studied nonpharmaceutical interventions used to mitigate the second, and most deadly, wave of the 1918–1920 influenza pandemic in the United States. We conclude that several small communities implemented potentially successful attempts at preventing the introduction of influenza.

Post-traumatic stress disorder (PTSD), Major Depressive Disorder (MDD), and Substance Use Disorder (SUD) have large public health impacts. Therefore, researchers have attempted to identify those at greatest risk for these phenotypes. PTSD, MDD, and SUD are in part genetically influenced. Additionally, genes in the glutamate and gamma-aminobutyric acid (GABA) system are implicated in the encoding of emotional and fear memories, and thus may impact these phenotypes. The current study examined the associations of single nucleotide polymorphisms in GAT1 individually, and at the gene level, using a principal components (PC) approach, with PTSD, PTSD comorbid with MDD, and PTSD comorbid with SUD in 486 combat-exposed veterans. Findings indicate that several GAT1 SNPs, as well as one of the GAT1 PCs, was associated with PTSD, with and without MDD and SUD comorbidity. The present study findings provide initial insights into one pathway by which shared genetic risk influences PTSD-MDD and PTSD-SUD comorbidities, and thus identify a high-risk group (based on genotype) on whom prevention and intervention efforts should be focused.

ABSTRACT The influenza pandemic of 1918–1919 killed approximately 50 million people. The unusually severe morbidity and mortality associated with the pandemic spurred physicians and scientists to isolate the etiologic agent, but the virus was not isolated in 1918. In 1996, it became possible to recover and sequence highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims. These viral RNA sequences eventually permitted reconstruction of the complete 1918 virus, which has yielded, almost a century after the deaths of its victims, novel insights into influenza virus biology and pathogenesis and has provided important information about how to prevent and control future pandemics.

Vaccine adverse events (VAEs) are adverse bodily changes occurring after vaccination. Understanding the adverse event (AE) profiles is a crucial step to identify serious AEs. Two different types of seasonal influenza vaccines have been used on the market: trivalent (killed) inactivated influenza vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV). Different adverse event profiles induced by these two groups of seasonal influenza vaccines were studied based on the data drawn from the CDC Vaccine Adverse Event Report System (VAERS). Extracted from VAERS were 37,621 AE reports for four TIVs (Afluria, Fluarix, Fluvirin, and Fluzone) and 3,707 AE reports for the only LAIV (FluMist). The AE report data were analyzed by a novel combinatorial, ontology-based detection of AE method (CODAE). CODAE detects AEs using Proportional Reporting Ratio (PRR), Chi-square significance test, and base level filtration, and groups identified AEs by ontology-based hierarchical classification. In total, 48 TIV-enriched and 68 LAIV-enriched AEs were identified (PRR>2, Chi-square score >4, and the number of cases >0.2% of total reports). These AE terms were classified using the Ontology of Adverse Events (OAE), MedDRA, and SNOMED-CT. The OAE method provided better classification results than the two other methods. Thirteen out of 48 TIV-enriched AEs were related to neurological and muscular processing such as paralysis, movement disorders, and muscular weakness. In contrast, 15 out of 68 LAIV-enriched AEs were associated with inflammatory response and respiratory system disorders. There were evidences of two severe adverse events (Guillain-Barre Syndrome and paralysis) present in TIV. Although these severe adverse events were at low incidence rate, they were found to be more significantly enriched in TIV-vaccinated patients than LAIV-vaccinated patients. Therefore, our novel combinatorial bioinformatics analysis discovered that LAIV had lower chance of inducing these two severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines.

Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (2 µg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz.Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains.ClinicalTrials.gov NCT00098293.

Obstructive uropathy secondary to uretero-inguinal hernia is a rare phenomenon. Two types have been described-the rarer extraperitoneal type is frequently associated with other renal anomalies. Pre-operative diagnosis is essential in order to reduce the risk of ureteric injury intra-operatively. We describe one such case.