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We sought to determine whether detection of cartilage invasion (CI) by computed tomography predicts oncologic outcomes after primary total laryngectomy.Retrospective cohort study comparing oncologic outcomes between radiologic versus pathologic diagnosis.Assessment of clear CI versus gestalt CI resulted in 84% versus 48% specificity, 90.9% versus 80.3% positive predictive value (PPV), 60.6% versus 80.3% sensitivity, 44.7% versus 48% negative predictive value (NPV), respectively. Disease-free survival (DFS) was similar between cT4a and cT3/cT2 patients (p = 0.87). DFS trended towards superiority among pT3/pT2 versus pT4a patients (p = 0.18). DFS was similar among patients with CI on radiologist gestalt versus no CI (p = 0.94). Histologically confirmed CI was associated with a hazard ratio (HR) of 1.46 (p = 0.27), gestalt CI 1.13 (p = 0.70), and clear CI 1.61 (p = 0.10) for DFS.Gestalt determination of CI results in high sensitivity but low specificity, while clear determination of CI results in moderate sensitivity and high specificity.

The incidence of anal squamous cell carcinoma (ASCC) has been increasing, particularly in populations with HIV. Human papillomavirus (HPV) is the causal factor in 85% to 90% of ASCCs, but few studies evaluated HPV genotypes and integrations in relation to genomic alterations in ASCC. Using whole-exome sequence data for primary (n = 56) and recurrent (n = 31) ASCC from 72 patients, we detected HPV DNA in 87.5% of ASCC, of which HPV-16, HPV-18, and HPV-6 were detected in 56%, 22%, and 33% of HIV-positive (n = 9) compared with 83%, 3.2%, and 1.6% of HIV-negative cases (n = 63), respectively. Recurrent copy-number variations (CNV) involving genes with documented roles in cancer included amplification of PI3KCA and deletion of APC in primary and recurrent tumors; amplifications of CCND1, MYC, and NOTCH1 and deletions of BRCA2 and RB1 in primary tumors; and deletions of ATR, FANCD2, and FHIT in recurrent tumors. DNA damage response genes were enriched among recurrently deleted genes in recurrent ASCCs (P = 0.001). HPV integrations were detected in 29 of 76 (38%) ASCCs and were more frequent in stage III–IV versus stage I–II tumors. HPV integrations were detected near MYC and CCND1 amplifications and recurrent targets included NFI and MUC genes. These results suggest HPV genotypes in ASCC differ by HIV status, HPV integration is associated with ASCC progression, and DNA damage response genes are commonly disrupted in recurrent ASCCs.Implications:These data provide the largest whole-exome sequencing study of the ASCC genomic landscape to date and identify HPV genotypes, integrations, and recurrent CNVs in primary or recurrent ASCCs.

Supplemental Table S1. Clinical characteristics and outcomes by HIV status. Supplemental Table S2. HPV integration sites detected in patient WXS data. Supplemental Table S3. Curated list of 981 cancer-related genes considered in this study.

Supplemental Table S4. Functional ontology enrichment of genes within recurrent CNVs in all ASCC tumors, primary ASCC tumors, and recurrent or metastatic ASCC tumors

Supplemental Figure S1. HPV-18 genome coverage in ASCC. Supplemental Figure S2. Copy number variation in 81 ASCCs.

Other Supporting Colleagues from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs ∼US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age ≤40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]

Supplementary Table 1 Legends and References from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Supplementary Table 1 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Supplementary Table 2 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Key Points A dust devil frequency of occurrence of between 1.3 and 3.4 dust devils km−2 sol−1 was derived from MEDA-RDS observations for the first 365 sols, displaying the maximum activity at around noon and increasing as we move from spring into summer We find an average dust devil diameter of 29 m (or a median diameter of 25 m) and maximum and minimum diameters of 132 ± 63.4 m and 5.6 ± 5.5 m Dust devil migration directions are in agreement with the MEDA background wind direction measurements The Mars Environmental Dynamics Analyzer, onboard the Perseverance rover, is a meteorological station that is operating on Mars and includes, among other sensors, the radiometer Radiation and Dust Sensor (RDS). From RDS irradiance observations, a total of 374 dust devils (DDs) were detected for the first 365 sols of the mission (Ls = 6°–182°), which along with wind and pressure measurements, we estimated a DD frequency of formation at Jezero between 1.3 and 3.4 DD km−2 sol−1 (increasing as we move from spring into summer). This frequency is found to be smaller than that estimated at the Spirit or Pathfinder landing sites but much greater than that derived at InSight landing site. The maximum in DD frequency occurs between 12:00 and 13:00 local true solar time, which is when the convective heat flux and lower planetary boundary layer IR heating are both predicted to peak in Jezero crater. DD diameter, minimum height, and trajectory were studied showing (a) an average diameter of 29 m (or a median of 25 m) and a maximum and minimum diameter of 132 ± 63.4 and 5.6 ± 5.5 m; (b) an average minimum DD height of 231 m and a maximum minimum-height of 872 m; and (c) the DD migration direction is in agreement with wind measurements. For all the cases, DDs decreased the UV irradiance, while at visible or near-IR wavelengths both increases and decreases were observed. Contrary to the frequency of formation, these results indicate similar DD characteristics in average for the studied period. This work has been funded by the Spanish Ministry of Economy and Competitiveness, through the projects no. ESP2014-54256-C4-1-R (also -2-R, -3-R and -4-R); Ministry of Science, Innovation and Universities, projects no. ESP2016-79612-C3-1-R (also -2-R and -3-R); Ministry of Science and Innovation/State Agency of Research (10.13039/501100011033), projects no. ESP2016-80320-C2-1-R, RTI2018-098728-B-C31 (also -C32 and -C33), RTI2018-099825-B-C31. RH and ASL were supported by the Spanish project PID2019-109467GB-I00 funded by MCIN/AEI/10.13039/50110001103 and by Grupos Gobierno Vasco IT1742-22. The US co-authors performed their work under sponsorship from NASA’s Mars 2020 project, from the Game Changing Development programme within the Space Technology Mission Directorate and from the Human Exploration and Operations Directorate. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). G.M. acknowledges JPL funding from USRA Contract Number 1638782. ML is supported by contract 15-712 from Arizona State University and 1607215 from Caltech-JPL. Peerreview

International audience; Two >130-meter-diameter impact craters formed on Mars during the later half of 2021. These are the two largest fresh impact craters discovered by the Mars Reconnaissance Orbiter since operations started 16 years ago. The impacts created two of the largest seismic events (magnitudes greater than 4) recorded by InSight during its 3-year mission. The combination of orbital imagery and seismic ground motion enables the investigation of subsurface and atmospheric energy partitioning of the impact process on a planet with a thin atmosphere and the first direct test of martian deep-interior seismic models with known event distances. The impact at 35°N excavated blocks of water ice, which is the lowest latitude at which ice has been directly observed on Mars.

We characterize vortex and dust devils (DDs) at Jezero from pressure and winds obtained with the Mars Environmental Dynamics Analyzer (MEDA) instrument on Mars 2020 over 415 Martian days (sols) (Ls = 6°–213°). Vortices are abundant (4.9 per sol with pressure drops >0.5 Pa correcting from gaps in coverage) and they peak at noon. At least one in every five vortices carries dust, and 75% of all vortices with Δp > 2.0 Pa are dusty. Seasonal variability was small but DDs were abundant during a dust storm (Ls = 152°–156°). Vortices are more frequent and intense over terrains with lower thermal inertia favoring high daytime surface-to-air temperature gradients. We fit measurements of winds and pressure during DD encounters to models of vortices. We obtain vortex diameters that range from 5 to 135 m with a mean of 20 m, and from the frequency of close encounters we estimate a DD activity of 2.0–3.0 DDs km−2 sol−1. A comparison of MEDA observations with a Large Eddy Simulation of Jezero at Ls = 45° produces a similar result. Three 100-m size DDs passed within 30 m of the rover from what we estimate that the activity of DDs with diameters >100 m is 0.1 DDs km−2sol−1, implying that dust lifting is dominated by the largest vortices in Jezero. At least one vortex had a central pressure drop of 9.0 Pa and internal winds of 25 ms−1. The MEDA wind sensors were partially damaged during two DD encounters whose characteristics we elaborate in detail. The authors are very grateful to the entire Mars 2020 science operations team. The authors would also like to thank Lori Fenton and an anonymous reviewer for many suggestions that greatly improved the manuscript. This work was supported by Grant PID2019-109467GB-I00 funded by MCIN/AEI/10.13039/501100011033/ and by Grupos Gobierno Vasco IT1742-22 and by the Spanish National Research, Development and Innovation Program, through the Grants RTI2018-099825-B-C31, ESP2016-80320-C2-1-R, and ESP2014-54256-C4-3-R. Baptiste Chide is supported by the Director's Postdoctoral Fellowship from the Los Alamos National Laboratory. M. Lemmon is supported by contract 15-712 from Arizona State University and 1607215 from Caltech-JPL. R. Lorenz was supported by JPL contract 1655893. Germán Martínez acknowledges JPL funding from USRA Contract Number 1638782. A. Munguira was supported by Grant PRE2020-092562 funded by MCIN/AEI and by “ESF Investing in your future.” A. Vicente-Retortillo is supported by the Spanish State Research Agency (AEI) Project No. MDM-2017-0737 Unidad de Excelencia “María de Maeztu”-Centro de Astrobiología (INTA-CSIC), and by the Comunidad de Madrid Project S2018/NMT-4291 (TEC2SPACE-CM). Part of the research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). Finnish researchers acknowledge the Academy of Finland Grant 328 310529. Researchers based in France acknowledge support from the CNES for their work on Perseverance.

OBJECTIVE. To describe technical aspects and surgical outcomes of endoscopic resection and mucosal reconstitution with epidermal grafting (ie, the Maddern procedure) in the treatment of idiopathic subglottic stenosis. STUDY DESIGN. Medical record abstraction. SETTING. Johns Hopkins Hospital. METHODS. Retrospective series of 9 adults with idiopathic subglottic stenosis who underwent the Maddern procedure by a single surgeon over a 5-year period. Prespecified outcomes included (1) perioperative outcomes (Clavien-Dindo grade 4/5 complications, need for staged tracheostomy, hospital length of stay), (2) postoperative outcomes (peak expiratory flow rate [PEFR], need for subsequent airway surgery, tracheostomy at follow-up), and (3) patient-reported quality-of-life outcomes (Clinical COPD Questionnaire, Voice Handicap Index–10, Eating Assessment Tool–10, and 12-Item Short Form Version 2). Wilcoxon matched-pairs signed rank test and Kaplan-Meier analysis were performed. RESULTS. There were no Clavien-Dindo grade 4/5 complications; 2 patients required unplanned staged tracheostomy; and the median length of stay was 3 days. Following endoscopic resection and stent removal, a median of 2 laser resurfacing procedures were required. Two patients developed recurrent stenosis requiring cricotracheal resection (CTR). There were significant improvements in PEFR, Clinical COPD Questionnaire, and Voice Handicap Index–10, without significant difference in Eating Assessment Tool–10. The 12-Item Short Form Version 2 approximated the population norm. Kaplan-Meier analysis demonstrated significant improvement in time to surgery after the final laser resurfacing. CONCLUSION. The Maddern procedure has a low complication rate and offers durable physiologic improvement in PEFR, limiting need for additional procedures. Risks included need for CTR salvage, temporary tracheostomy, phlegm accumulation, and laryngospasm. It is a surgical option for patients with short dilation intervals who prefer to avoid the risks of CTR.

Nerves in bone play well‐established roles in pain and vasoregulation and have been associated with progression of skeletal disorders, including osteoporosis, fracture, arthritis, and tumor metastasis. However, isolation of the region‐specific mechanisms underlying these relationships is limited by our lack of quantitative methods for neuroskeletal analysis and precise maps of skeletal innervation. To overcome these limitations, we developed an optimized workflow for imaging and quantitative analysis of axons in and around the bone, including validation of Baf53b‐Cre in concert with R26R‐tdTomato (Ai9) as a robust pan‐neuronal reporter system for use in musculoskeletal tissues. In addition, we created comprehensive maps of sympathetic adrenergic and sensory peptidergic axons within and around the full length of the femur and tibia in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Three distinct patterns of periosteal innervation (termed type I, II, III) were defined at sites that are important for bone pain, bone repair, and skeletal homeostasis. For the first time, our results establish a gradient of bone marrow axon density that increases from proximal to distal along the length of the tibia and define key regions of interest for neuroskeletal studies. Lastly, this information was related to major nerve branches and local maps of specialized mechanoreceptors. This detailed mapping and contextualization of the axonal subtypes innervating the skeleton is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

The incidence of anal squamous cell carcinoma (ASCC) has been increasing, particularly in populations with HIV. Human papillomavirus (HPV) is the causal factor in 85% to 90% of ASCCs, but few studies evaluated HPV genotypes and integrations in relation to genomic alterations in ASCC. Using whole-exome sequence data for primary (n = 56) and recurrent (n = 31) ASCC from 72 patients, we detected HPV DNA in 87.5% of ASCC, of which HPV-16, HPV-18, and HPV-6 were detected in 56%, 22%, and 33% of HIV-positive (n = 9) compared with 83%, 3.2%, and 1.6% of HIV-negative cases (n = 63), respectively. Recurrent copy-number variations (CNV) involving genes with documented roles in cancer included amplification of PI3KCA and deletion of APC in primary and recurrent tumors; amplifications of CCND1, MYC, and NOTCH1 and deletions of BRCA2 and RB1 in primary tumors; and deletions of ATR, FANCD2, and FHIT in recurrent tumors. DNA damage response genes were enriched among recurrently deleted genes in recurrent ASCCs (P = 0.001). HPV integrations were detected in 29 of 76 (38%) ASCCs and were more frequent in stage III–IV versus stage I–II tumors. HPV integrations were detected near MYC and CCND1 amplifications and recurrent targets included NFI and MUC genes. These results suggest HPV genotypes in ASCC differ by HIV status, HPV integration is associated with ASCC progression, and DNA damage response genes are commonly disrupted in recurrent ASCCs. Implications: These data provide the largest whole-exome sequencing study of the ASCC genomic landscape to date and identify HPV genotypes, integrations, and recurrent CNVs in primary or recurrent ASCCs.

Objectives: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. Methods: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. Results: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. Conclusions: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Organ preservation (OP) treatment for advanced laryngeal cancer has increased compared to primary total laryngectomy. Our study compares oncologic and functional outcomes between these approaches.Retrospective cohort study.Single tertiary care institution.Retrospective review of patients receiving primary total laryngectomy or OP for laryngeal cancer between 1/1/2000 and 12/31/2018.A total of 118 patients received primary total laryngectomy and 119 received OP. Overall survival was similar between total laryngectomy and OP. When stratified by T stage, disease-free survival was worse among T3 patients receiving OP versus total laryngectomy. In T3 patients, 28 OP patients experienced local recurrence (28.9%) compared to 3 total laryngectomy patients (7.1%; p 0.01). In total, 20 OP patients with local recurrence received salvage surgery. These patients had similar overall survival to patients who underwent initial total laryngectomy (TL). About 14 OP patients with local recurrence did not receive salvage surgery. About 89 (75.4%) TL patients achieved normal diet as compared to 64 (53.8%) OP patients (p 0.001). In TL patients, 106 (89.8%) received primary or secondary tracheoesophageal-prosthesis, 82 (77.4%) of whom achieved completely understandable speech.There was no difference in survival by treatment in T4 patients, possibly because of strict patient selection. However, disease-free survival was worse in T3 patients receiving OP, likely due to a high local recurrence rate. Approximately 40% of patients with local recurrence were not eligible for salvage laryngectomy. TL patients had comparable swallowing and speech outcomes with OP patients.3 Laryngoscope, 2022.

The sixth Coupled Model Intercomparison Project (CMIP6) constitutes the latest update on expected future climate change based on a new generation of climate models. To extract reliable estimates of future warming and related uncertainties from these models, the spread in their projections is often translated into probabilistic estimates such as the mean and likely range. Here, we use a model weighting approach, which accounts for the models' historical performance based on several diagnostics as well as model interdependence within the CMIP6 ensemble, to calculate constrained distributions of global mean temperature change. We investigate the skill of our approach in a perfect model test, where we use previous-generation CMIP5 models as pseudo-observations in the historical period. The performance of the distribution weighted in the abovementioned manner with respect to matching the pseudo-observations in the future is then evaluated, and we find a mean increase in skill of about 17 % compared with the unweighted distribution. In addition, we show that our independence metric correctly clusters models known to be similar based on a CMIP6 “family tree”, which enables the application of a weighting based on the degree of inter-model dependence. We then apply the weighting approach, based on two observational estimates (the fifth generation of the European Centre for Medium-Range Weather Forecasts Retrospective Analysis – ERA5, and the Modern-Era Retrospective analysis for Research and Applications, version 2 – MERRA-2), to constrain CMIP6 projections under weak (SSP1-2.6) and strong (SSP5-8.5) climate change scenarios (SSP refers to the Shared Socioeconomic Pathways). Our results show a reduction in the projected mean warming for both scenarios because some CMIP6 models with high future warming receive systematically lower performance weights. The mean of end-of-century warming (2081–2100 relative to 1995–2014) for SSP5-8.5 with weighting is 3.7 ∘C, compared with 4.1 ∘C without weighting; the likely (66%) uncertainty range is 3.1 to 4.6 ∘C, which equates to a 13 % decrease in spread. For SSP1-2.6, the weighted end-of-century warming is 1 ∘C (0.7 to 1.4 ∘C), which results in a reduction of −0.1 ∘C in the mean and −24 % in the likely range compared with the unweighted case.

The Earth System Model Evaluation Tool (ESMValTool), a community diagnostics and performance metrics tool for evaluation and analysis of Earth system models (ESMs), is designed to facilitate a more comprehensive and rapid comparison of single or multiple models participating in the Coupled Model Intercomparison Project (CMIP). The ESM results can be compared against observations or reanalysis data as well as against other models including predecessor versions of the same model. The updated and extended version (v2.0) of the ESMValTool includes several new analysis scripts such as large-scale diagnostics for evaluation of ESMs as well as diagnostics for extreme events, regional model and impact evaluation. In this paper, the newly implemented climate metrics such as effective climate sensitivity (ECS) and transient climate response (TCR) as well as emergent constraints for various climate-relevant feedbacks and diagnostics for future projections from ESMs are described and illustrated with examples using results from the well-established model ensemble CMIP5. The emergent constraints implemented include constraints on ECS, snow-albedo effect, climate–carbon cycle feedback, hydrologic cycle intensification, future Indian summer monsoon precipitation and year of disappearance of summer Arctic sea ice. The diagnostics included in ESMValTool v2.0 to analyze future climate projections from ESMs further include analysis scripts to reproduce selected figures of chapter 12 of the Intergovernmental Panel on Climate Change's (IPCC) Fifth Assessment Report (AR5) and various multi-model statistics.

In recent years, the OpenNotes movement and other changes in healthcare have driven institutions to make medical records increasingly transparent. As patients have begun to question and request changes to their Problem Lists, clinicians have come to face the ever more frequent challenge of discerning which changes to make and which to refuse. Now clinicians and patients together choose the list of problems that represent the patient’s current state of health and illness. As the physician’s role slides closer to consultant and the medical paternalism of the twentieth century falls further into the background of our technology-infused present, who holds the power of delineating a patient’s clinical identity? This paper examines the ethical and practical dimensions of this question and proposes a research agenda that aims to answer it. Such explorations are essential to ensuring that the physician remains relevant to patient’s notions of health, illness, intervention, and healing.

Background The prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART. Methods This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry. Results Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3–4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations. Conclusions These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting., Depression is a major challenge for people with human immunodeficiency virus (HIV). Adults with depressive symptoms had lower neuroactive steroid metabolites than those without depressive symptoms, highlighting the importance of hypothalamic-pituitary-adrenal axis dysregulation in HIV-infected adults with depression.

Educational games are employed to teach a variety of scientific skills and concepts. We evaluated Pest Quest, a co-operative tabletop game designed to teach about Integrated Pest Management. In it, students worked together to protect a farm from insect pests by scouting and making sound treatment decisions. We gave students in an introductory, nonmajors entomology course assessments of their Integrated Pest Management knowledge and attitudes toward agriculture before and after playing a digital port of the game. We also administered a postgame survey to gauge students’ opinions and feelings about the game. Pest Quest proved engaging and accessible, with students enjoying the game and having the impression it helped them learn. However, this conclusion was not captured in our assessments. We provide access to physical and digital versions of Pest Quest and suggestions for more effective implementation in entomology and agriculture classrooms.

Listeria monocytogenes (Lm) es una bacteria gram positiva considerada oportunista. Afecta particularmente a embarazadas, neonatos, ancianos e inmunocomprometidos y puede ocasionar un amplio espectro de manifestaciones clínicas que van desde un síndrome febril a una enfermedad invasiva grave que incluye bacteriemias, sepsis, meningitis y meningoencefalitis. Se presenta el caso de un paciente adulto masculino con antecedentes de hipertensión, psoriasis, cirrosis y diabetes tipo II insulinodependiente, que ingresó a terapia intensiva del Hospital J. M. Cullen con cuadro febril, astenia, excitación psicomotriz y desorientación temporo espacial asociada a rigidez de nuca. Se tomaron muestras de sangre, orina y LCR para cultivo, y se le indicó tratamiento empírico con ceftriaxona y vancomicina. En la coloración de Gram del LCR y de las muestras de hemocultivo se observó la presencia de bacilos positivos. En los cultivos se desarrollaron colonias pequeñas y grisáceas que se identificaron mediante método automatizado Phoenix 100 (BD) y pruebas fenotípicas convencionales como Lmq. Frente a este resultado se rotó la medicación a ampicilina y gentamicina. El paciente evolucionó favorablemente y una vez finalizado el tratamiento fue dado de alta sin secuelas. Se destaca la importancia de realizar una anamnesis exhaustiva y sospechar bacterias poco frecuentes como Listeria monocytogenes, que pueden originar fallas de tratamiento con la terapia empírica inicial.

Aim The Shouldice procedure is a layered reconstruction of the posterior wall in inguinal hernia repair and currently the preferred method if the layers of the abdominal wall are of good quality, the wish of the patient for a non-mesh repair and if a mesh method is not possible or available. The correct performance of the reconstruction of the posterior wall is essential part of the operation. Material and Methods A life educational video was made with the four-layer reconstruction in detail. The first layer of the reconstruction starts at the medial corner and the conjoint tendon is sutured to the caudal flap of the transversalis fascia using a continuous non resorbable suture. The second layer of the reconstruction is made by approximating the cranial flap of the transversalis fascia and the posterior part of the inguinal ligament. The third layer starts at the level of the deep internal inguinal ring and approximates the lower border of the internal oblique muscle with the inguinal ligament. The fourth and final layer approximates the internal oblique muscle again with the inguinal ligament. Results The four-layer reconstruction after splitting the transversalis fascia is shown in detail since treatment of the hernia sac is like the other techniques. Conclusions The instructional video can be used for the resident training as a start in a hernia course followed by the execution on a model before the actual execution on a patient.

Background Overviews of systematic reviews (SR) summarise and appraise the quality of research relevant for evidence-based decision-making. ‘A Measurement Tool to Assess Systematic Reviews' (AMSTAR 2) is a valid and moderately reliable appraisal instrument with 16 items that can be used to derive the overall confidence rating (OCR). OCR (high, moderate, low or critically low) can be derived based on the original algorithm with 7/9 critical/non-critical items. We aimed to assess the methods for deriving OCR in overviews of SRs of clinical interventions. Methods Our cross-sectional study was conducted using 45 overviews of SRs with at least 20 AMSTAR 2 appraisals selected by two authors from a title/abstract search for ‘AMSTAR 2' in Medline, Epistemonikos and CINAHL in 09/2020. One author coded the data. OCR methods and outcomes were compared using descriptive and univariate statistics. Results The 45 overviews were published in 2018-2020 by 2-16 authors. The overviews appraised on average 44 SRs (range: 20-158). OCRs of 1.412 SRs were derived in 41 overviews (91%). OCR were derived according to the original algorithm (22; 54%), own algorithm (9; 22%), unspecified algorithm (9; 22%) or AMSTAR 2 website (1; 2%). The OCR were high (190; 13%), moderate (182; 13%), low (267, 19%) or critically low (773; 55%). The original algorithm was more likely to generate the critically low+low ratings than either own algorithms (OR = 2.28, 95% CI [1.66-3.13]) or unclear algorithms (OR = 3.78 [2.81-5.09]). Conclusions High quality SRs are needed for making public health decisions. AMSTAR 2 assigns mostly low and critically low OCR to SRs in various clinical areas. These SRs should not be relied on as a source of accurate evidence. Furthermore, our results show that SR reporting guidelines need to be better followed and that AMSTAR 2 users should explicitly report their OCR methods. Key messages The methodological quality of the majority of systematic reviews (SRs) in various clinical fields is disappointing, highlighting the requirement for better adherence to reporting guidelines. There is a need for improvement on reporting how AMSTAR 2 is applied in overviews of SRs.

BACKGROUND/AIM Head and neck cancers are often treated with extended courses of radiotherapy (RT), which may prove excessively toxic for frail patients. Split course RT (SCRT) delivers two courses of RT separated by 4-6 weeks, personalizing treatment intensity based on response. In this study, we present our updated experience using this technique. PATIENTS AND METHODS From a single institution database, we identified patients considered for SCRT. For patients undergoing a second course of RT, cumulative incidence of locoregional recurrence (LRR) and overall survival (OS) are reported. RESULTS A total of 98 patients were included, of whom seventy-five percent underwent a second course of RT. The most common fractionation was 30 Gy in 10 fractions for each course, with a median cumulative dose of 60 Gy. In those undergoing a second course of RT, median OS was 9.7 months and cumulative incidence of LRR at 6, 12, and 24 months was 17.0%, 23.1%, and 29.4%, respectively. CONCLUSION SCRT offers an attractive treatment paradigm to personalize radiation intensity based on patient tolerance, while maintaining reasonable safety and efficacy in those unfit for standard full course RT.

Bone marrow adipocytes accumulate with age and in diverse disease states. However, their origins and adaptations in these conditions remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, by analyzing bone and adipose tissues in the lipodystrophic ‘fat-free’ mouse, we define a novel, secondary adipogenesis pathway that relies on the recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress in the fat-free mouse model, resulting in the expansion of bone marrow adipocytes specialized for lipid storage with compromised lipid mobilization and cytokine expression within regions traditionally devoted to hematopoiesis. This finding further distinguishes bone marrow from peripheral adipocytes and contributes to our understanding of bone marrow adipocyte origins, adaptations, and relationships with surrounding tissues with age and disease.

Background Rare locations of hernias, as well as primary ventral hernias under certain circumstances (cirrhosis, dialysis, rectus diastasis, subsequent pregnancy), might be technically challenging. The aim was to identify situations where the treatment strategy might deviate from routine management. Methods The guideline group consisted of surgeons from the European and Americas Hernia Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in formulating the recommendations. The Scottish Intercollegiate Guidelines Network (SIGN) critical appraisal checklists were used to evaluate the quality of full‐text papers. A systematic literature search was performed on 1 May 2018 and updated 1 February 2019. The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was followed. Results Literature was limited in quantity and quality. A majority of the recommendations were graded as weak, based on low quality of evidence. In patients with cirrhosis or on dialysis, a preperitoneal mesh repair is suggested. Subsequent pregnancy is a risk factor for recurrence. Repair should be postponed until after the last pregnancy. For patients with a concomitant rectus diastasis or those with a Spigelian or lumbar hernia, no recommendation could be made for treatment strategy owing to lack of evidence. Conclusion This is the first European and American guideline on the treatment of umbilical and epigastric hernias in patients with special conditions, including Spigelian and lumbar hernias. All recommendations were weak owing to a lack of evidence. Further studies are needed on patients with rectus diastasis, Spigelian and lumbar hernias., This guideline addresses the treatment of umbilical and epigastric hernias in clinically challenging situations (cirrhosis, dialysis, subsequent pregnancy, rectus diastasis), as well as the treatment of Spigelian and primary lumbar hernias. Emphasises the need for better evidence

Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in the brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV- controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, CHOP, CASP1, WARS) gene expression changes are associated with decreased energy metabolism (SREBF1, SREBF2, PARK2, TXNIP) and oligodendrocyte myelin production (MAG, MOG), leading to white matter dysfunction. Machine learning identified a 15-gene signature predictive of HIV status that was validated in an independent cohort. No specific gene expression patterns were associated with NCI. These findings suggest therapies that decrease chronic inflammation while protecting mitochondrial function may help to preserve white matter integrity in older HIV+ individuals.

Author(s): Lorenz, David R; Mukerji, Shibani S; Misra, Vikas; Uno, Hajime; Gelman, Benjamin B; Moore, David J; Singer, Elyse J; Morgello, Susan; Gabuzda, Dana | Abstract: ObjectivePeople with human immunodeficiency virus (HIV) (PWH) have increased prevalence of multimorbidity and frailty at younger ages compared to the general population. This study investigated individual and combinatorial effects of neuropsychiatric and medical comorbidities as predictors of frailty in PWH.DesignAnalysis of data from the National NeuroAIDS Tissue Consortium, a longitudinal observational cohort.Methods524 PWH over age 40 were classified using Fried's Frailty criteria. Twelve comorbidities were documented from longitudinal data and associations between individual and co-occurring comorbidities with frailty were assessed using weighted network and logistic regression analyses.ResultsAt frailty assessment between 2015-2020, median age was 61 years, 76% were male, 94% were on ART, 73% had two or more comorbidities, 24% were frail, and 52% were prefrail. Among individual comorbidities, highest odds of frailty were in participants with depressive symptoms (adjusted odds ratio [aOR], 95% confidence interval [CI] 3.48 [2.22-5.46]]), followed by bone disease and COPD (2.47 [1.28-4.72] and 2.13 [1.36-3.34], respectively). Among co-occurring comorbidities, highest odds of frailty were in participants having depressive symptoms with diabetes, hypertension, or obesity (aORs [95% CIs] 5.29 [2.32-12.08], 5.21 [2.65-10.40], 4.85 [2.39-9.95], respectively), cognitive impairment with diabetes or renal disease, (2.81 [1.38-5.68] and 2.53 [1.26-5.03], respectively), renal disease with cardiovascular disease (2.81 [1.32-6.01]), and diabetes with obesity (2.76 [1.39-5.45]).ConclusionsCo-occurrence of depressive symptoms, cognitive impairment, diabetes, or renal disease with other medical conditions substantially increases odds of frailty in older PWH. Identifying and treating these comorbidities may help to reduce functional decline with aging in PWH.

BACKGROUND: People with HIV (PWH) have increased frailty risk at younger ages compared with the general population. Multimorbidity is associated with frailty, yet effects of specific comorbidities on transition to frailty in PWH are unknown. SETTING: Prospective study of 219 PWH age 45 years or older in the National NeuroAIDS Tissue Consortium. METHODS: Frailty status was categorized using Fried frailty phenotype criteria. Comorbidities [bone disease, cardiovascular disease, cerebrovascular disease, liver disease, renal disease, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, obesity, cancers, neuropsychiatric conditions] were assessed from longitudinal data. Associations between baseline comorbidities and transition to frailty within 30 months were analyzed using Kaplan-Meier and Cox regression models. Grip strength was assessed using mixed-effects models. RESULTS: At baseline, the median age was 61 years, 73% were male 98% were on antiretroviral therapy, 29% had ≥3 comorbidities, 27% were robust, and 73% were pre-frail. Cerebrovascular disease, diabetes, and COPD were independent predictors of transition to frailty within 30 months in models adjusted for age, sex, and multimorbidity (≥3 additional comorbidities) [hazard ratios (95% confidence intervals) 2.52 (1.29 to 4.93), 2.31 (1.12 to 4.76), and 1.82 (0.95 to 3.48), respectively]. Furthermore, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity was associated with substantially increased frailty hazards compared with multimorbidity alone (hazard ratios 4.75-7.46). Cerebrovascular disease was associated with decreased baseline grip strength (P = 0.0001), whereas multimorbidity, diabetes, and COPD were associated with declining grip strength (P < 0.10). CONCLUSIONS: In older PWH, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity is associated with substantially increased risk of becoming frail within 30 months. Interventions targeting these comorbidities may ameliorate frailty and age-related functional decline in PWH.

SUMMARYBone marrow adipocytes (BMAs) accumulate with age and in diverse disease states. However, their age- and disease-specific origins and adaptations remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, we identified a novel, bone marrow-specific adipogenesis pathway using the AdipoqCre+/DTA+ ‘fat free’ mouse (FF), a model in which Adipoq-Cre drives diphtheria toxin-induced cell death in all adiponectin-expressing cells. Adiponectin is highly expressed by BMAs, peripheral adipocytes, and a subset of bone marrow stromal progenitor cells with preadipocyte-like characteristics. Consistent with this, FF mice presented with uniform depletion of peripheral white and brown adipose tissues, in addition to loss of BMAs in canonical locations such as the tail vertebrae. However, unexpectedly, a distinctly localized subset of BMAs accumulated with age in FF mice in regions such as the femoral and tibial diaphysis that are generally devoid of bone marrow adipose tissue (BMAT). Ectopic BMAs in FF mice were defined by increased lipid storage and decreased expression of cytokines including hematopoietic support factor Cxcl12 and adipokines adiponectin, resistin, and adipsin. FF BMAs also displayed resistance to lipolytic stimuli including cold stress and β3-adrenergic agonist CL316,243. This was associated with reduced expression of adrenergic receptors and monoacylglycerol lipase. Global ablation of adiponectin-expressing cells regulated bone accrual in an age- and sex-dependent manner. High bone mass was present early in life and this was more pronounced in females. However, with age, both male and female FF mice had decreased cortical thickness and mineral content. In addition, unlike BMAs in healthy mice, expansion of ectopic BMAs in FF mice was inversely correlated with cortical bone volume fraction. Subcutaneous fat transplant and normalization of systemic metabolic parameters was sufficient to prevent ectopic BMA expansion in FF mice but did not prevent the initial onset of the high bone mass phenotype. Altogether, this defines a novel, secondary adipogenesis pathway that relies on recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress, resulting in expansion of BMAs specialized for lipid storage with compromised lipid mobilization and endocrine function within regions traditionally devoted to hematopoiesis. Our findings further distinguish BMAT from peripheral adipose tissues and contribute to our understanding of BMA origins and adaptation with age and disease.

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic &beta, cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and &beta, cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on &beta, cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human &beta, cell compensation in function and mass expansion. In this study, we investigated the action of metformin on &beta, cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited &beta, cell glucose-stimulated insulin secretion in vitro, stimulation of &beta, cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, &beta, cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress &beta, cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on &beta, cell function or cell mass and, instead, early metformin treatment may help protect &beta, cells from exhaustion and decompensation.

Background: Marijuana smoke contains some of the same toxicants present in tobacco smoke. Marijuana smoking is prevalent among HIV+ individuals, but few studies have characterized smoke-related toxicants or associated health outcomes in exclusive marijuana users. Methods: This longitudinal study included 245 participants over age 40 (76% HIV+). 33 plasma and 28 urine metabolites of nicotine, ∆-9-trans-tetrahydrocannabinol, polycyclic aromatic hydrocarbons, and volatile organic compounds were assayed by liquid or gas chromatography/mass spectrometry. Exposures and health outcomes were assessed from surveys and medical records. Findings: At baseline, 18% of participants were marijuana-only smokers, 20% tobacco-only smokers, and 24% dual marijuana-tobacco smokers (median (IQR) age 53 (47–60) years, 78% male, 54% white race). Marijuana smoking was independently associated with elevated plasma naphthalenes, 2-hydroxyfluorene sulfate, 4-vinylphenol sulfate, and o-cresol sulfate (p