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Importance: Characteristics of outstanding graduating surgical residents are currently undefined. Identifying these qualities may be important in guiding resident selection and resident education., Objective: To determine characteristics that are most strongly associated with being rated as an outstanding graduating surgical resident., Design, Setting, and Participants: The multi-institutional study had 3 phases. First, an expert panel developed a list of characteristics embodied by top graduating surgical residents. Second, groups of faculty from 14 US general-surgery residency programs ranked 2017 through 2020 graduates into quartiles of overall performance. Third, faculty evaluated their graduates on each characteristic using a 5-point Likert scale. Data were analyzed using Spearman rank-order correlation to identify which individual characteristics were associated with overall graduate performance. A least absolute shrinkage and selection operator (LASSO) ordinal regression was performed to select a parsimonious model to predict the outcome of overall performance rating from individual characteristic scores., Main Outcome and Measures: Surgical educators' rankings of general surgery residency graduates' overall performance., Results: Fifty faculty from 14 US residency programs with a median of 13 (range, 5-30) years of surgical education experience evaluated 297 general surgery residency graduates. Surgical educators identified 21 characteristics that they believed outstanding graduating surgical residents possessed. Two hundred ninety-seven surgical residency graduates were evaluated. Higher scores in every characteristic correlated with better overall performance. Characteristics most strongly associated with higher overall performance scores were surgical judgment (r = 0.728; P < .001), leadership (r = 0.726; P < .001), postoperative clinical skills (r = 0.715; P < .001), and preoperative clinical skills (r = 0.707; P < .001). The remainder of the characteristics were moderately associated with overall performance. The LASSO regression model identified 3 characteristics from which overall resident performance could be accurately predicted without measuring other qualities: surgical judgment (odds ratio [OR] per 1 level of 5-level Likert scale OR, 1.27; 95% CI, 1.03-1.51), leadership (OR, 1.27; 95% CI, 1.06-1.48), and medical knowledge (OR, 1.16; 95% CI, 1.01-1.33)., Conclusions and Relevance: All individual characteristics identified by surgical educators as being qualities of outstanding graduating surgical residents were positively associated with overall graduate performance. Surgical judgment and leadership skills had the strongest individual associations. Assessment of only 3 qualities (surgical judgment, leadership, and medical knowledge) were required to predict overall resident performance ratings. These findings highlight the importance of developing specific surgical judgment and leadership skills curricula and assessments during surgical residency.

Background: Retinal measurements correlate with disease progression in patients with multiple sclerosis; however, whether they associate with neurologic disease in people with controlled HIV is unknown. Using spectral domain optical coherence tomography, we evaluated retinal differences between people with HIV and HIV-negative controls and investigated clinical correlates of retinal thinning., Methods: People with HIV on antiretroviral therapy for at least 1 year and HIV-negative controls recruited from the same communities underwent spectral domain optical coherence tomography, ophthalmic examination, brain MRI, and neuropsychological testing. Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GC-IPL) thicknesses were compared between groups using analysis of covariance with relevant clinical variables as covariates. Linear regression was used to explore associations of HIV history variables, cognitive domain scores, and MRI volume measurements within the HIV group., Results: The HIV group (n = 69), with long-duration HIV infection (median time from diagnosis 19 years) and outstanding viral control have thinner retinal layers than HIV-negative controls (n = 28), after adjusting for covariates (GC-IPL: P = 0.002; RNFL: P = 0.024). The effect of HIV on GC-IPL thickness was stronger in women than in men (Women: P = 0.011; Men: P = 0.126). GC-IPL thickness is associated with information processing speed in the HIV group (P = 0.007, semipartial r = 0.309). No associations were found with retinal thinning and MRI volumes or HIV factors., Conclusions: People with HIV on antiretroviral therapy have thinning of the RNFL and GC-IPL of the retina, and women particularly are affected to a greater degree. This retinal thinning was associated with worse performance on tests of information processing speed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The COVID-19 pandemic has dramatically changed education in medical residencies with the need to transition to a virtual format. The objective of this study is to assess the adoption of a virtual format for grand rounds, M&M, and education of the surgical department., Method: A 25 question online survey was developed using Qualtrics and distributed to faculty and resident physicians in the Department of Surgery from March to April 2021., Results: Fifty four out of 79 potential respondents (68%) completed the survey. Twenty-seven out of 54 (50%) respondents stated they were more likely to be participating in another activity most of the time or always. During to in-person conferences, 20/54 (37%) of participants reported being more distracted by other activities. Forty-two out of 54 (78%) participants strongly agree that virtual conferences are more flexible with their schedule and saves them travel time. All of the faculty want conferences to continue virtually (with or without an in-person component) citing virtual conferences are more flexible with their schedule and saves travel time. However, 4/26 (15%) of residents responded not wanting to continue virtual education citing work distractions and not truly having protected time., Conclusion: As the Coronavirus 2019 (COVID-19) pandemic is continuing with new variants, the virtual education and conference format is necessary. There is overwhelming support from both residents and faculty in favor of the virtual conference format due to flexibility, ease, and convenience. However, care must be taken to make sure that resident education time is truly protected.

Background: The coronavirus 2019 (COVID-19) pandemic prompted drastic changes to residency recruitment. The majority of general surgery residency interviews for the 2020-2021 interview cycle were restructured into a virtual format. The goal of this study is to evaluate general surgery residency applicants' perception of virtual interviews., Methods: A secure, anonymous, web-based survey was developed, tested, and distributed via email to all candidates who applied to the University of California Irvine general surgery residency program for Match 2021., Results: 1239 general surgery applicants were invited after Match Day 2021 to take the survey, and 167 (13.5%) completed the survey and were included in the final analysis. Applicants received and accepted a median of 10 (Interquartile range [IQR], 5-18) and 9 (IQR, 5-15) interviews. Using a Likert scale, candidates revealed they were most satisfied with introduction and program overview (72.5%) and interactions with faculty (70.6%). Applicants were dissatisfied with pre-interview socials (66.9%) and hospital tours (66.2%). When evaluating programs, they had the most difficulty discerning program culture and resident autonomy. Most applicants (54%) were satisfied with the virtual format and 52% believed that virtual format should continue., Discussion: The majority of applicants were satisfied with virtual interviews and could foresee the format continuing in the future.

Background: HIV persistence during antiretroviral therapy (ART) is the principal obstacle to cure. Lymphoid tissue is a compartment for HIV, but mechanisms of persistence during ART and viral rebound when ART is interrupted are inadequately understood. Metabolic activity in lymphoid tissue of patients on long-term ART is relatively low, and increases when ART is stopped. Increases in metabolic activity can be detected by 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and may represent sites of HIV replication or immune activation in response to HIV replication., Methods: FDG-PET imaging will be used to identify areas of high and low metabolic uptake in lymphoid tissue of individuals undergoing long-term ART. Baseline tissue samples will be collected. Participants will then be randomized 1:1 to continue or interrupt ART via analytic treatment interruption (ATI). Image-guided biopsy will be repeated 10 days after ATI initiation. After ART restart criteria are met, image-guided biopsy will be repeated once viral suppression is re-achieved. Participants who continued ART will have a second FDG-PET and biopsies 12-16 weeks after the first. Genetic characteristics of HIV populations in areas of high and low FDG uptake will be assesed. Optional assessments of non-lymphoid anatomic compartments may be performed to evaluate HIV populations in distinct anatomic compartments., Anticipated Results: We anticipate that PET standardized uptake values (SUV) will correlate with HIV viral RNA in biopsies of those regions and that lymph nodes with high SUV will have more viral RNA than those with low SUV within a patient. Individuals who undergo ATI are expected to have diverse viral populations upon viral rebound in lymphoid tissue. HIV populations in tissues may initially be phylogenetically diverse after ATI, with emergence of dominant viral species (clone) over time in plasma. Dominant viral species may represent the same HIV population seen before ATI., Discussion: This study will allow us to explore utility of PET for identification of HIV infected cells and determine whether high FDG uptake respresents areas of HIV replication, immune activation or both. We will also characterize HIV infected cell populations in different anatomic locations. The protocol will represent a platform to investigate persistence and agents that may target HIV populations., Study Protocol Registration: Identifier: NCT05419024., Competing Interests: Author BW would like to disclose the following: Licensed Patents/Royalties: Philips and NIH have a patent licensing agreement under which NIH receives royalties, a portion of which are then given to BW. NVIDIA and NIH have a licensing agreement. NIH and Canon have a licensing agreement. BW is Principal Investigator on the following Cooperative Research & Development Agreements (CRADAs), between NIH and industry: Philips (CRADA), Philips Research (CRADA), Celsion Corp (CRADA), BTG Biocompatibles/Boston Scientific (CRADA), Siemens (CRADA), NVIDIA (CRADA), XAct Robotics (CRADA). Negotiating CRADA with ProMaxo, Tempus, Galvanize, Theromics, Imactis, Varian. The following industry partners also support research in the Center for Interventional Oncology/Dr. Wood's lab via equipment, personnel, devices and/or drugs: 3T Technologies (devices), Exact Imaging (data), Angiodynamics (equipment), Astra Zeneca (pharmaceuticals, NCI CRADA), ArciTrax (devices and equipment), Imactis (Equipment), Johnson and Johnson (equipment), Medtronic (equipment), Promaxo (equipment & personnel), Theromics (Supplies), Profound (equipment and supplies), and QT Imaging (equipment and supplies). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lau, Adan, Earhart, Seamon, Nguyen, Savramis, Adams, Zipparo, Madeen, Huik, Grossman, Chimukangara, Wulan, Millo, Nath, Smith, Ortega-Villa, Proschan, Wood, Hammoud and Maldarelli.)

Introduction: The purpose of this study was to determine whether total ankle arthroplasty (TAA) and ankle/hindfoot fusion patients receiving tranexamic acid (TXA) exhibit fewer wound complications., Methods: A retrospective review was conducted of 212 patients (217 feet) undergoing TAA (n = 72), ankle (n = 36), tibiotalocalcaneal (n = 20), pantalar (n = 1), or hindfoot fusion (ie, subtalar = 47, double = 33, and triple = 8) between 2015 and 2020 by a fellowship-trained foot and ankle surgeon at an academic medical center. Demographics, medical history, complications, and union status were compared between TXA (n = 101) and non-TXA (n = 116) cohorts. The mean follow-up was 1.24 years (range, 0.25 to 4.68)., Results: The TXA group had significantly less postoperative infections (5.9% versus 15.5%, P = 0.025). Within a subgroup analysis of ankle/hindfoot fusions, the TXA group exhibited significantly more Charcot neuroarthropathy (20.7% versus 5.7%, P = 0.006) and shorter follow-up duration (0.96 versus 1.30 years, P = 0.030); however, TXA was associated with shorter time to fusion (146 versus 202 days, P = 0.049) and fewer revision surgeries (8.6% versus 21.8%, P = 0.036). Subgroup analysis excluding feet with Charcot also demonstrated less postoperative infections (4.5% versus 14.4%, P = 0.020). Subgroup analysis of TAAs showed fewer cases of superficial infections (2.3% versus 27.6%, P = 0.002) and delayed wound healing (25.6% versus 48.3%, P = 0.047) in the TXA cohort., Discussion: TXA use in ankle/hindfoot surgery was correlated with a reduction in superficial infections and radiographic time to union. The use of TXA in TAA correlated with fewer superficial infections and cases of delayed wound healing. Thus, in addition to other areas of orthopaedics, TXA seems to be beneficial in hindfoot and ankle surgery., Data Availability and Trial Registration Numbers: All data were obtained from our institution's medical records. This study is not associated with a clinical trial., (Copyright © 2022 by the American Academy of Orthopaedic Surgeons.)

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

T cell immunity to natural SARS-CoV-2 infection may be more robust and longer lived than Ab responses. Accurate assessment of T cell responses is critical for understanding the magnitude and longevity of immunity across patient cohorts, and against emerging variants. By establishing a simple, accurate, and rapid whole blood test, natural and vaccine-induced SARS-CoV-2 immunity was determined. Cytokine release in whole blood stimulated with peptides specific for SARS-CoV-2 was measured in donors with previous PCR-confirmed infection, suspected infection, or with no exposure history ( n = 128), as well as in donors before and after vaccination ( n = 32). Longitudinal assessment of T cell responses following initial vaccination and booster vaccination was also conducted ( n = 50 and n = 62, respectively). Cytokines were measured by ELISA and multiplex array. IL-2 and IFN-γ were highly elevated in PCR-confirmed donors compared with history-negative controls, with median levels ∼33-fold and ∼48-fold higher, respectively. Receiver operating curves showed IL-2 as the superior biomarker (area under the curve = 0.9950). Following vaccination, all donors demonstrated a positive IL-2 response. Median IL-2 levels increased ∼32-fold from prevaccination to postvaccination in uninfected individuals. Longitudinal assessment revealed that T cell responses were stable up to 6 mo postvaccination. No significant differences in cytokine production were observed between stimulations with Wuhan, Delta, or Omicron peptides. This rapid, whole blood-based test can be used to make comparable longitudinal assessments of vaccine-induced T cell immunity across multiple cohorts and against variants of concern, thus aiding decisions on public health policies., (Copyright © 2022 The Authors.)

The isolation of chitin utilizing ionic liquid 1-ethyl-3-methylimidazolium acetate has been determined to result in polymer contaminated with proteins. For the first time, the proteins in chitin extracted with ionic liquid have been quantified; the protein content was found to vary from 1.3 to 1.9% of the total weight. These proteins were identified and include allergenic proteins such as tropomyosin. In order to avoid 'traditional' hydroxide-based deproteinization of chitin, which could reduce the molecular weight of the final product, alternative deproteinization strategies were attempted. Testing of the previously reported deproteinization method using aqueous K 3 PO 4 resulted in protein reduction by factors varying from 2 to 10, but resulted in significant phosphate salt contamination of the final product. Contrarily, the incorporation of GRAS (Generally Recognized as Safe) compound Polysorbate 80 into the polymer washing step provided the polymer of comparable purity with no contaminants. This study presents new options for the deproteinization of chitin that can replace traditional approaches with methods that are environmentally friendly and can produce high purity polymer.

Aim: The study aim was to evaluate the RSR 3 Screen ICA™ and 2 Screen ICA™ for detection of islet cell autoimmunity in healthy Swedish subjects and patients with newly diagnosed type 1 diabetes (T1D)., Methods: 3 Screen is designed for combined detection of autoantibodies to glutamic acid decarboxylase (GADA), to the islet antigen IA-2 (IA-2A) and to zinc transporter 8 (ZnT8A), while 2 Screen detects GADA and IA-2A. Serum samples from 100 T1D patients at onset and 200 healthy controls were studied., Results: 3 Screen achieved 93% assay sensitivity and 97.5% specificity, while 2 Screen achieved 91% assay sensitivity and 98.5% specificity. Samples were also tested in assays for individual autoantibodies. There was only one 3 Screen positive healthy control sample (0.5%) that was positive for multiple autoantibodies (IA-2A and ZnT8A). In contrast, most of the 93 3 Screen positive patients were positive for multiple autoantibodies with 72% (67/93) positive for both GADA and IA-2A and 57% (53/93) positive for three autoantibodies (GADA, IA-2A and ZnT8A). Insulin autoantibodies (IAA, measured by radioimmunoassay) were positive in 13 patients and two healthy controls., Conclusion: 3 Screen achieved high sensitivity and specificity, suitable for islet cell autoimmunity screening in a healthy population. In the case of 3 Screen positivity, further assays for GADA, IA-2A and ZnT8A are required to check for multiple autoantibody positivity, a hallmark for progression to T1D. In addition, testing for IAA in children below two years of age is warranted., (© 2022. The Author(s).)

Purpose: The radiobiological benefits afforded by spatially fractionated (GRID) radiation therapy pairs well with the dosimetric advantages of proton therapy. Inspired by the emergence of energy-layer specific collimators in pencil beam scanning (PBS), this work investigates how the spot spacing and collimation can be optimized to maximize the therapeutic gains of a GRID treatment while demonstrating the integration of a dynamic collimation system (DCS) within a commercial beamline to deliver GRID treatments and experimentally benchmark Monte Carlo calculation methods., Methods: GRID profiles were experimentally benchmarked using a clinical DCS prototype that was mounted to the nozzle of the IBA-dedicated nozzle system. Integral depth dose (IDD) curves and lateral profiles were measured for uncollimated and GRID-collimated beamlets. A library of collimated GRID dose distributions were simulated by placing beamlets within a specified uniform grid and weighting the beamlets to achieve a volume-averaged tumor cell survival equivalent to an open field delivery. The healthy tissue sparing afforded by the GRID distribution was then estimated across a range of spot spacings and collimation widths, which were later optimized based on the radiosensitivity of the tumor cell line and the nominal spot size of the PBS system. This was accomplished by using validated models of the IBA universal and dedicated nozzles., Results: Excellent agreement was observed between the measured and simulated profiles. The IDDs matched above 98.7% when analyzed using a 1%/1-mm gamma criterion with some minor deviation observed near the Bragg peak for higher beamlet energies. Lateral profile distributions predicted using Monte Carlo methods agreed well with the measured profiles; a gamma passing rate of 95% or higher was observed for all in-depth profiles examined using a 3%/2-mm criteria. Additional collimation was shown to improve PBS GRID treatments by sharpening the lateral penumbra of the beamlets but creates a trade-off between enhancing the valley-to-peak ratio of the GRID delivery and the dose-volume effect. The optimal collimation width and spot spacing changed as a function of the tumor cell radiosensitivity, dose, and spot size. In general, a spot spacing below 2.0 cm with a collimation less than 1.0 cm provided a superior dose distribution among the specific cases studied., Conclusions: The ability to customize a GRID dose distribution using different collimation sizes and spot spacings is a useful advantage, especially to maximize the overall therapeutic benefit. In this regard, the capabilities of the DCS, and perhaps alternative dynamic collimators, can be used to enhance GRID treatments. Physical dose models calculated using Monte Carlo methods were experimentally benchmarked in water and were found to accurately predict the respective dose distributions of uncollimated and DCS-collimated GRID profiles., (© 2022 American Association of Physicists in Medicine.)

Competing Interests: AN received grant funding from the US National Institutes of Health (NIH; grant number NS003130) and is a board member for the American Neurology Society and the International Society of Neurovirology. KTT received research funding from NIH Center for Disease Control and Prevention and Biomerieux/Filmarray. BRS declares no competing interests.

Background: In March 2020, the Surgeon General recommended limiting elective procedures to prepare for the COVID-19 surge. We hypothesize a consequence of COVID-19 is reduced operative volume across the country. We aim to examine changes in volume of common gastrointestinal operations during COVID-19, including elective, urgent/emergent, and cancer operations. We also evaluate if hospitals with more COVID-19 admissions were most impacted., Methods: The Vizient database was used to determine monthly operative volume from November 2019 to June 2020 for elective operations (hiatal hernia repairs, bariatric surgery), urgent operations (cholecystectomies, appendectomies, inguinal hernia repairs), and cancer operations (colectomies, gastrectomies, esophagectomies). COVID-19 admissions per hospital were also determined. November 2019-January 2020 was defined as "pre-COVID." The monthly reduction in volume from pre-COVID was calculated for each operation. The top quartile (25%) of hospitals with the most COVID admissions were also evaluated separately from hospitals with fewer COVID cases. Data were analyzed using analysis of variance., Results: Data from 559 hospitals were analyzed. The volumes of all operations evaluated were significantly reduced during the pandemic except gastrectomies and esophagectomies for cancer. The greatest reduction in all operations was in April. In April, the volume of bariatric surgery reduced by 98% (P < 0.001), hiatal hernia repairs by 96% (P < 0.001), urgent cholecystectomies by 42% (P < 0.001), urgent inguinal hernia repairs by 40% (P < 0.001), urgent appendectomies by 24% (P < 0.001), and colectomies for cancer by 39% (P < 0.001). Hospitals with the most COVID-19 admissions had greater reductions in all operations than hospitals with fewer COVID cases., Conclusions: The coronavirus pandemic led to a significant reduction in volume of all gastrointestinal operations evaluated except gastrectomies and esophagectomies. While elective, non-cancer operations were most affected, urgent and some cancer operations also declined significantly. As COVID-19 continues to surge, Americans may suffer continued limited access to surgical care and a significant operative backlog may be forthcoming., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPα inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFκB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect., Competing Interests: Competing Interests I.L.W. and N.J.L. are co-founders and directors of Bitterroot Bio Incorporated, a cardiovascular company studying macrophage checkpoint inhibition. K.-U.J., Y.K., I.L.W., and N.J.L. have filed a provisional patent (U.S. Application Serial No. 63/106,794): ‘CD47 Blockade and Combination Therapies Thereof For Reduction Of Vascular Inflammation’. The remaining authors declare no competing interests.

Background: Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most., Methods: Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease., Results: Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%)., Conclusions: This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose . The Dynamic Collimation System (DCS) is an energy layer-specific collimation device designed to reduce the lateral penumbra in pencil beam scanning proton therapy. The DCS consists of two pairs of nickel trimmers that rapidly and independently move and rotate to intercept the scanning proton beam and an integrated range shifter to treat targets less than 4 cm deep. This work examines the validity of a single aperture approximation to model the DCS, a commonly used approximation in commercial treatment planning systems, as well as higher-order aperture-based approximations for modeling DCS-collimated dose distributions. Methods . An experimentally validated TOPAS/Geant4-based Monte Carlo model of the DCS integrated with a beam model of the IBA pencil beam scanning dedicated nozzle was used to simulate DCS- and aperture-collimated 100 MeV beamlets and composite treatment plans. The DCS was represented by three different aperture approximations: a single aperture placed halfway between the upper and lower trimmer planes, two apertures located at the upper and lower trimmer planes, and four apertures, located at both the upstream and downstream faces of each pair of trimmers. Line profiles and three-dimensional regions of interest were used to evaluate the validity and limitations of the aperture approximations investigated. Results . For pencil beams without a range shifter, minimal differences were observed between the DCS and single aperture approximation. For range shifted beamlets, the single aperture approximation yielded wider penumbra widths (up to 18%) in the X-direction and sharper widths (up to 9.4%) in the Y-direction. For the example treatment plan, the root-mean-square errors (RMSEs) in an overall three-dimensional region of interest were 1.7%, 1.3%, and 1.7% for the single aperture, two aperture, and four aperture models, respectively. If the region of interest only encompasses the lateral edges outside of the target, the resulting RMSEs were 1.7%, 1.1%, and 0.5% single aperture, two aperture, and four aperture models, respectively. Conclusions . Monte Carlo simulations of the DCS demonstrated that a single aperture approximation is sufficient for modeling pristine fields at the Bragg depth while range shifted fields require a higher-order aperture approximation. For the treatment plan considered, the double aperture model performed the best overall, however, the four-aperture model most accurately modeled the lateral field edges at the expense of increased dose differences proximal to and within the target., (© 2022 IOP Publishing Ltd.)

Novel targeted therapies are rapidly emerging for the treatment of cancer. With the advent of new immune targeting agents, understanding the changes in the tumor microenvironment (TME) is critical. Given the complexity and several cellular mechanisms and factors that play a role in the TME, novel imaging methods to assess and evaluate the dynamic changes in the TME during treatment are needed. Several techniques are being developed for imaging TME including optical, fluorescence and photoacoustic methods. Positron emission tomography (PET) imaging can be used to track the dynamics of different molecular targets in the TME in live animals and in humans. Several novel PET imaging probes including radiolabeled antibodies, antibody fragments, and small molecules have been developed with many more that are under development preclinically and in early human studies. This review is a brief overview of some of the PET agents that are either in the preclinical developmental phase or undergoing early clinical studies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Recent studies have revealed a high rate of burnout among general surgery (GS) residents. Efforts to design and implement interventions to mitigate fatigue in surgical trainees are critical. Our aim was to assess the educational and wellness impact of outpatient scribe utilization at an academic GS residency program., Methods: Electronic surveys were sent to 38 GS residents and 15 faculties who used outpatient scribes for at least 12 months. Questions were scored on a 5-point Likert scale with answers of "Strongly agree" or "Agree" representing affirmative responses., Results: Thirty residents and 14 faculty completed the survey, resulting in an 83% overall response rate. Twenty-eight (93%) residents and 12 (86%) faculty believed that scribes decrease the daily workload of trainees. Twenty-seven (90%) residents felt that scribes allow them more time to focus on patient care and improve the quality of their surgical education. Ninety-three percent of residents (n = 28) and faculty (n = 13) believed that scribes enhance resident well-being. Twenty-four (80%) residents reported that scribes help improve adherence to duty hour restrictions. Twenty-five (83%) residents believed that utilizing scribes is an effective fatigue mitigation strategy for surgical training programs., Conclusion: Our findings demonstrate that the implementation of an outpatient scribe program at an academic GS residency program may enhance resident education and wellness.

Background: Anosmia and ageusia are symptoms commonly associated with COVID-19, but the relationship with disease severity, onset and recovery are unclear., Objective: To examine factors associated with anosmia and ageusia and the recovery from these symptoms in an ethnically diverse cohort., Methods: Individuals tested for SARS-CoV-2 between March and April 2020 were eligible for the study. Randomly selected participants answered a telephone questionnaire on COVID-19 symptoms with a focus on anosmia and ageusia. Additionally, relevant past medical history and data on the COVID-19 clinical course were obtained from electronic medical records. 486 patients were in the COVID-19 group and 103 were COVID-19-negative., Results: Patients who were younger were more likely to report anosmia and/or ageusia (odds ratio (OR) for anosmia per 1-year increase in age: 0·98, 95%CI:0-97-0·99, p  = 0·003; for ageusia: 0·98, 95%CI:0·97-0·99, p  = 0·005) as were patients with lower eosinophil counts (OR for anosmia per 0.1-K/μL increase in eosinophils: 0·02, 95%CI:0·001-0·46, p  = 0·01, for ageusia 0·10, 95%CI:0·01-0·97, p  = 0·047). Male gender was independently associated with a lower probability of ageusia (OR:0·56, 95%CI:0·38-0·82, p  = 0·003) and earlier sense of taste recovery (HR:1·44, 95%CI:1·05-1·98, p  = 0·02). Latinos showed earlier sense of taste recovery than white patients (HR:1·82, 95%CI:1·05-3·18, p  = 0·03)., Conclusion: Anosmia and ageusia were more common among younger patients and those with lower blood eosinophil counts. Ageusia was less commonly reported among men, and time to taste recovery was earlier among both men and Latinos.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects around 20-50% of people living with HIV (PLWH). Although batteries of tests are used to identify neurocognitive impairment (NCI), they are long and difficult to perform during a routine clinic visit, thus impairing the ability to diagnose HAND. Therefore, a brief yet sensitive screening tool to identify NCI is necessary. This study prospectively evaluated an abbreviated screening battery with reported 86.5%/87.1% sensitivity/specificity, identified from a planned post-hoc analysis in a prior neurocognitive study among military PLWH. Adult HIV-positive military beneficiaries in the U.S. Military HIV Natural History Study, who agreed to undergo a comprehensive seven-domain neuropsychological battery (16 tests), and who completed an additional 20-min abbreviated battery (AB), comprised of four tests, prior to the full battery (FB) were included in this analysis. A group of 169 individuals completed both tests, of which 25.4% had a positive AB and 17.8% had NCI on FB (global deficit score ≥ 0.5). With the FB as the reference standard, the specificity for the AB was 79.9% (73.2-86.5), however the sensitivity was 50.0% (32.1-67.9). In those with NCI by FB but not AB, the most common impaired domains were executive function (73.3%) and memory (73.3%), both being domains not fully tested by the AB. An abbreviated HAND screening battery of four tests requiring approximately 20 min provided a relatively high level of specificity but lacked sensitivity for detection of NCI. Inclusion of additional domains or alternative scoring approaches may improve sensitivity but require further study. Continued efforts are needed to develop an effective brief screening test for HAND., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Disruption of vulnerable atherosclerotic plaques often leads to myocardial infarction and stroke, the leading causes of morbidity and mortality in the United States. A diagnostic method that detects high-risk atherosclerotic plaques at early stages could prevent these sequelae. The abundance of immune cells in the arterial wall, especially inflammatory Ly-6C hi monocytes and foamy macrophages, is indicative of plaque‎ inflammation, and may be associated with plaque vulnerability. Hence, we sought to develop a new method that specifically targets these immune cells to offer clinically-relevant diagnostic information about cardiovascular disease. We combine ultra-selective nanoparticle targeting of Ly-6C hi monocytes and foamy macrophages with clinically-viable photoacoustic imaging (PAI) in order to precisely and specifically image inflamed plaques ex vivo in a mouse model that mimics human vulnerable plaques histopathologically. Within the plaques, high-dimensional single-cell flow cytometry (13-parameter) showed that our nanoparticles were almost-exclusively taken up by the Ly-6C hi monocytes and foamy macrophages that heavily infiltrate plaques. PAI identified inflamed atherosclerotic plaques that display ~6-fold greater signal compared to controls ( P <0.001) six hours after intravenous injection of ultra-selective carbon nanotubes, with in vivo corroboration via optical imaging. Our highly selective strategy may provide a targeted, non-invasive imaging strategy to accurately identify and diagnose inflamed atherosclerotic lesions.

This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability. Mechanical tests were first used to benchmark the electronic encoders within the stepper and were later expanded to evaluate the needle free length calculation accuracy. Needle reconstruction accuracy was rigorously evaluated at the treatment planning level. The calibration length of each probe was redundantly checked between the calculated and measured needle free length, which was found to be within 1 mm for a variety of scenarios. Needle placement relative to a reference fiducial and coincidence of imaging coordinate origins were verified to within 1 mm in both sagittal and transverse imaging planes. The source strength was also calibrated within the interstitial needle and was found to be 1.14% lower than when measured in a plastic needle. Dose calculations in the TPS and secondary dose calculation software were benchmarked against manual TG-43 calculations. Calculations among the three calculation methods agreed within 1% for all calculated points. Source positioning and dummy coincidence was tested following the recommendations of the TG-40 report. Finally, the development of the clinical workflow, checklists, and planning objectives are discussed and included within this report. The commissioning of real-time, US-guided HDR prostate systems requires careful consideration among several facets including the image quality, dosimetric, and mechanical accuracy. The TPS relies on each of these components to develop and administer a treatment plan, and as such, should be carefully examined., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe., Methods: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 10 6 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 10 6 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783., Findings: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months., Interpretation: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients., Funding: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH., Competing Interests: Declaration of interests IC reports providing free consultative advice to Cellevolve and is a shareholder in Nouscom AG and Keires AG, outside the submitted work. DSR reports non-financial support from Biogen, outside the submitted work. In addition, DSR has two patents issued (System and Method of Automatically Detecting Tissue Abnormalities [US patent 9607392]; and Method of Analyzing Multi-Sequence MRI Data for Analyzing Brain Abnormalities in a Subject [US patent 9888876]). PM reports having received consultation fees from ATARA Biological and AstraZeneca, outside the submitted work. JB is a member of the data safety monitoring board for the AMADEUS trial (azacitidine after a stem cell transplant). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: The suspension of elective operations in March 2020 to prepare for the COVID-19 surge posed significant challenges to resident education. To mitigate the potential negative effects of COVID-19 on surgical education, it is important to quantify how the pandemic influenced resident operative volume., Objective: To examine the association of the pandemic with general surgical residents' operative experience by postgraduate year (PGY) and case type and to evaluate if certain institutional characteristics were associated with a greater decline in surgical volume., Design, Setting, and Participants: This retrospective review included residents' operative logs from 3 consecutive academic years (2017-2018, 2018-2019, and 2019-2020) from 16 general surgery programs. Data collected included total major cases, case type, and PGY. Faculty completed a survey about program demographics and COVID-19 response. Data on race were not collected. Operative volumes from March to June 2020 were compared with the same period during 2018 and 2019. Data were analyzed using Kruskal-Wallis test adjusted for within-program correlations., Main Outcome and Measures: Total major cases performed by each resident during the first 4 months of the pandemic., Results: A total of 1368 case logs were analyzed. There was a 33.5% reduction in total major cases performed in March to June 2020 compared with 2018 and 2019 (45.0 [95% CI, 36.1-53.9] vs 67.7 [95% CI, 62.0-72.2]; P < .001), which significantly affected every PGY. All case types were significantly reduced in 2020 except liver, pancreas, small intestine, and trauma cases. There was a 10.2% reduction in operative volume during the 2019-2020 academic year compared with the 2 previous years (192.3 [95% CI, 178.5-206.1] vs 213.8 [95% CI, 203.6-223.9]; P < .001). Level 1 trauma centers (49.5 vs 68.5; 27.7%) had a significantly lower reduction in case volume than non-level 1 trauma centers (33.9 vs 63.0; 46%) (P = .03)., Conclusions and Relevance: In this study of operative logs of general surgery residents in 16 US programs from 2017 to 2020, the first 4 months of the COVID-19 pandemic was associated with a significant reduction in operative experience, which affected every PGY and most case types. Level 1 trauma centers were less affected than non-level 1 centers. If this trend continues, the effect on surgical training may be even more detrimental.

Background: Resident evaluation of faculty teaching is an important metric in general surgery training, however considerable variability in faculty teaching evaluation (FE) instruments exists., Study Design: Twenty-two general surgery programs provided their FE and program demographics. Three clinical education experts performed blinded assessment of FEs, assessing adherence 2018 ACGME common program standards and if the FE was meaningful., Results: Number of questions per FE ranged from 1 to 29. The expert assessments demonstrated that no evaluation addressed all 5 ACGME standards. There were significant differences in the FEs effectiveness of assessing the 5 ACGME standards (p < 0.001), with teaching abilities and professionalism rated the highest and scholarly activities the lowest., Conclusion: There was wide variation between programs regarding FEs development and adhered to ACGME standards. Faculty evaluation tools consistently built around all suggested ACGME standards may allow for a more accurate and useful assessment of faculty teaching abilities to target professional development., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: To support the early detection and diagnosis of brain tumours we have developed a rapid, cost-effective and easy to use spectroscopic liquid biopsy based on the absorbance of infrared radiation. We have previously reported highly sensitive results of our approach which can discriminate patients with a recent brain tumour diagnosis and asymptomatic controls. Other liquid biopsy approaches (e.g., based on tumour genetic material) report a lower classification accuracy for early-stage tumours. In this manuscript we present an investigation into the link between brain tumour volume and liquid biopsy test performance., Methods: In a cohort of 177 patients (90 patients with high-grade glioma (glioblastoma (GBM) or anaplastic astrocytoma), or low-grade glioma (astrocytoma, oligoastrocytoma and oligodendroglioma)) tumour volumes were calculated from magnetic resonance imaging (MRI) investigations and patients were split into two groups depending on MRI parameters (T1 with contrast enhancement or T2/FLAIR (fluid-attenuated inversion recovery)). Using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with supervised learning methods and machine learning algorithms, 90 tumour patients were stratified against 87 control patients who displayed no symptomatic indications of cancer, and were classified as either glioma or non-glioma., Results: Sensitivities, specificities and balanced accuracies were all greater than 88%, the area under the curve (AUC) was 0.98, and cancer patients with tumour volumes as small as 0.2 cm 3 were correctly identified., Conclusions: Our spectroscopic liquid biopsy approach can identify gliomas that are both small and low-grade showing great promise for deployment of this technique for early detection and diagnosis.

Background: The US News & World Report (USNWR) annual ranking of the best hospitals for gastroenterology and gastrointestinal surgery offers direction to patients and healthcare providers, especially for recommendations on complex medical and surgical gastrointestinal (GI) conditions. The objective of this study was to examine the outcomes of complex GI cancer resections performed at USNWR top-ranked, compared to non-ranked, hospitals., Study Design: Using the Vizient database, data for patients who underwent esophagectomy, gastrectomy, and pancreatectomy for malignancy between January and December 2018 were reviewed. Perioperative outcomes were analyzed according to USNWR rank status. Primary outcome was in-hospital mortality. Secondary outcomes include length of stay, mortality index (observed-to-expected mortality ratio), rate of serious complication, and cost. Secondary analysis was performed for outcomes of patients who developed serious complications., Results: There were 3,054 complex GI cancer resections performed at 42 top-ranked hospitals vs 3,608 resections performed at 198 non-ranked hospitals. The mean annual case volume was 73 cases at top-ranked hospitals compared to 18 cases at non-ranked hospitals. Compared with non-ranked hospitals, top-ranked hospitals had lower in-hospital mortality (0.96% vs 2.26%, respectively, p < 0.001) and lower mortality index (0.71 vs 1.53, respectively). There were no significant differences in length of stay, rate of serious complications, or direct cost between groups. In patients who developed serious morbidity, top-ranked hospitals had a lower mortality compared with non-ranked hospitals (8.2% vs 16.8%, respectively, p < 0.01)., Conclusions: Within the context of complex GI cancer resection, USNWR top-ranked hospitals performed a 4-fold higher case volume and were associated with improved outcomes. Patients with complex GI-related malignancies may benefit from seeking surgical care at high-volume regional USNWR top-ranked hospitals., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The family Rhabdoviridae contains diverse viruses, including vector-borne and nonvector-borne viruses, some that are human pathogens, including rabies virus and also nonpathogenic viruses. Bats, which are a known reservoir of viruses with zoonotic potential including coronaviruses, also carry multiple rhabdoviruses such as but not limited to lyssaviruses. We collected samples from 193 insectivorous and frugivorous bats in the Republic of the Congo and tested them for rhabdovirus RNA. Four samples were found positive for viral RNA representing sequences of four different, not previously described rhabdoviruses. Although phylogenetic and taxonomic placement of the novel sequences is uncertain, similarities with previously detected rhabdovirus sequences in bats suggest that these could represent vertebrate viruses. Considering the pathogenic risks some rhabdoviruses pose for humans, these results highlight the need for more research and surveillance regarding rhabdoviruses and bats.

Objective: We evaluated brain glucose metabolism in people living with HIV (PWH) with [18F]-Fluoro-Deoxyglucose (FDG) PET/computed tomography (CT) before and after antiretroviral therapy (ART) initiation., Design: We conducted a longitudinal study wherein ART-naive late-presenting untreated PWH with CD4+ cell counts less than 100 cells/μl were prospectively assessed for FDG uptake at baseline and at 4-8 weeks (n = 22) and 19-26 months (n = 11) following ART initiation., Methods: Relative uptake in the subcortical regions (caudate, putamen and thalamus) and cortical regions (frontal, parietal, temporal and occipital cortices) were compared across time and correlated with biomarkers of disease activity and inflammation, in addition to being compared with a group of uninfected individuals (n = 10)., Results: Before treatment initiation, putaminal and caudate relative FDG uptake values in PWH were significantly higher than in uninfected controls. Relative putaminal and thalamic uptake significantly decreased shortly following ART initiation, while frontal cortex values significantly increased. FDG uptake changes correlated with changes in CD4+ cell counts and viral load, and, in the thalamus, with IL-6R and sCD14. Approximately 2 years following ART initiation, there was further decrease in subcortical relative uptake values, reaching levels below those of uninfected controls., Conclusion: Our findings support pretreatment basal ganglia and thalamic neuroinflammatory changes in PWH, which decrease after treatment with eventual unmasking of long-term irreversible neuronal damage. Meanwhile, increased frontal cortex metabolism following ART initiation suggests reversible cortical dysfunction which improves with virologic control and increased CD4+ cell counts. Early initiation of treatment after HIV diagnosis and secondary control of inflammation are thus necessary to halt neurological damage in PWH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The development of collimating technologies has become a recent focus in pencil beam scanning (PBS) proton therapy to improve the target conformity and healthy tissue sparing through field-specific or energy-layer-specific collimation. Given the growing popularity of collimators for low-energy treatments, the purpose of this work was to summarize the recent literature that has focused on the efficacy of collimators for PBS and highlight the development of clinical and preclinical collimators., Materials and Methods: The collimators presented in this work were organized into 3 categories: per-field apertures, multileaf collimators (MLCs), and sliding-bar collimators. For each case, the system design and planning methodologies are summarized and intercompared from their existing literature. Energy-specific collimation is still a new paradigm in PBS and the 2 specific collimators tailored toward PBS are presented including the dynamic collimation system (DCS) and the Mevion Adaptive Aperture., Results: Collimation during PBS can improve the target conformity and associated healthy tissue and critical structure avoidance. Between energy-specific collimators and static apertures, static apertures have the poorest dose conformity owing to collimating only the largest projection of a target in the beam's eye view but still provide an improvement over uncollimated treatments. While an external collimator increases secondary neutron production, the benefit of collimating the primary beam appears to outweigh the risk. The greatest benefit has been observed for low- energy treatment sites., Conclusion: The consensus from current literature supports the use of external collimators in PBS under certain conditions, namely low-energy treatments or where the nominal spot size is large. While many recent studies paint a supportive picture, it is also important to understand the limitations of collimation in PBS that are specific to each collimator type. The emergence and paradigm of energy-specific collimation holds many promises for PBS proton therapy., Competing Interests: Conflicts of Interest: Daniel E. Hyer, PhD, holds a patent for the dynamic collimation system that is currently licensed to IBA., (©Copyright 2021 The Author(s).)

Coronaviruses play an important role as pathogens of humans and animals, and the emergence of epidemics like SARS, MERS and COVID-19 is closely linked to zoonotic transmission events primarily from wild animals. Bats have been found to be an important source of coronaviruses with some of them having the potential to infect humans, with other animals serving as intermediate or alternate hosts or reservoirs. Host diversity may be an important contributor to viral diversity and thus the potential for zoonotic events. To date, limited research has been done in Africa on this topic, in particular in the Congo Basin despite frequent contact between humans and wildlife in this region. We sampled and, using consensus coronavirus PCR-primers, tested 3,561 wild animals for coronavirus RNA. The focus was on bats (38%), rodents (38%), and primates (23%) that posed an elevated risk for contact with people, and we found coronavirus RNA in 121 animals, of which all but two were bats. Depending on the taxonomic family, bats were significantly more likely to be coronavirus RNA-positive when sampled either in the wet (Pteropodidae and Rhinolophidae) or dry season (Hipposideridae, Miniopteridae, Molossidae, and Vespertilionidae). The detected RNA sequences correspond to 15 alpha- and 6 betacoronaviruses, with some of them being very similar (>95% nucleotide identities) to known coronaviruses and others being more unique and potentially representing novel viruses. In seven of the bats, we detected RNA most closely related to sequences of the human common cold coronaviruses 229E or NL63 (>80% nucleotide identities). The findings highlight the potential for coronavirus spillover, especially in regions with a high diversity of bats and close human contact, and reinforces the need for ongoing surveillance., Competing Interests: Metabiota (https://metabiota.com), Labyrinth Global Health (https://www.labyrinthgh.com), and Mosaic (https://mosaic.cm) are private contractors who receive funds from international donor organizations to conduct technical assistance and research. Metabiota employs or employed CK, FM, PMK, INL, FNK, JAL, PM, MM, UT, AG, BSS, DJM, JAA, CM, DOJ, KS, NDW, EMR, and CEL, Mosaic employs ML, and Labyrinth Global Health employs KS, MM and CEL. There are no patents, products in development or marketed products associated with this research to declare. The association with commercial entities that some of the authors have does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The impact of preoperative chemotherapy/radiation on esophageal anastomotic leaks (ALs) and the correlation between AL severity and mortality risk have not been fully elucidated. We hypothesized that lower severity ALs have a similar risk of mortality compared to those without ALs, and preoperative chemotherapy/radiation increases AL risk., Methods: The 2016-2017 American College of Surgeons National Surgical Quality Improvement Program's procedure-targeted esophagectomy database was queried for patients undergoing any esophagectomy for cancer. A multivariable logistic regression analysis was performed for risk of ALs., Results: From 2042 patients, 280 (13.7%) had ALs. AL patients requiring intervention had increased mortality risk including those requiring reoperation, interventional procedure, and medical therapy ( P < .05). AL patients requiring no intervention had similar mortality risk compared to patients without ALs ( P > .05). Preoperative chemotherapy/radiation was not predictive of ALs ( P > .05)., Conclusion: Preoperative chemotherapy/radiation does not contribute to risk for ALs after esophagectomy. There is a stepwise increased risk of 30-day mortality for ALs requiring increased invasiveness of treatment.

Self-assembled peptides and proteins possess tremendous potential as targeted drug delivery systems and key applications of these well-defined nanostructures reside in anti-cancer therapy. Peptides and proteins can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions such as pH, temperature, ionic strength, as well as host and guest molecular interactions; their countless benefits include good biocompatibility and high loading capacity for hydrophobic and hydrophilic drugs. These self-assembled nanomaterials can be adorned with functional moieties to specifically target tumor cells. Stimuli-responsive features can also be incorporated with respect to the tumor microenvironment. This review sheds light on the growing interest in self-assembled peptides and proteins and their burgeoning applications in cancer treatment and immunotherapy.

Purpose: The aim of this work was to develop and experimentally validate a Dynamic Collimation Monte Carlo (DCMC) simulation package specifically designed for the simulation of collimators in pencil beam scanning proton therapy (PBS-PT). The DCMC package was developed using the TOPAS Monte Carlo platform and consists of a generalized PBS source model and collimator component extensions., Methods: A divergent point-source model of the IBA dedicated nozzle (DN) at the Miami Cancer Institute (MCI) was created and validated against on-axis commissioning measurements taken at MCI. The beamline optics were mathematically incorporated into the source to model beamlet deflections in the X and Y directions at the respective magnet planes. Off-axis measurements taken at multiple planes in air were used to validate both the off-axis spot size and divergence of the source model. The DCS trimmers were modeled and incorporated as TOPAS geometry extensions that linearly translate and rotate about the bending magnets. To validate the collimator model, a series of integral depth dose (IDD) and lateral profile measurements were acquired at MCI and used to benchmark the DCMC performance for modeling both pristine and range shifted beamlets. The water equivalent thickness (WET) of the range shifter was determined by quantifying the shift in the depth of the 80% dose point distal to the Bragg peak between the range shifted and pristine uncollimated beams., Results: A source model of the IBA DN system was successfully commissioned against on- and off-axis IDD and lateral profile measurements performed at MCI. The divergence of the source model was matched through an optimization of the source-to-axis distance and comparison against in-air spot profiles. The DCS model was then benchmarked against collimated IDD and in-air and in-phantom lateral profile measurements. Gamma analysis was used to evaluate the agreement between measured and simulated lateral profiles and IDDs with 1%/1 mm criteria and a 1% dose threshold. For the pristine collimated beams, the average 1%/1 mm gamma pass rates across all collimator configurations investigated were 99.8% for IDDs and 97.6% and 95.2% for in-air and in-phantom lateral profiles. All range shifted collimated IDDs passed at 100% while in-air and in-phantom lateral profiles had average pass rates of 99.1% and 99.8%, respectively. The measured and simulated WET of the polyethylene range shifter was determined to be 40.9 and 41.0 mm, respectively., Conclusions: We have developed a TOPAS-based Monte Carlo package for modeling collimators in PBS-PT. This package was then commissioned to model the IBA DN system and DCS located at MCI using both uncollimated and collimated measurements. Validation results demonstrate that the DCMC package can be used to accurately model other aspects of a DCS implementation via simulation., (© 2021 American Association of Physicists in Medicine.)

Biopolymers are of prime importance among which gum polysaccharides hold an eminent standing owing to their high availability and non-toxic nature. Gum biopolymers offer a greener alternative to synthetic polymers and toxic chemicals in the synthesis of metal nanostructures. Metal nanostructures accessible via eco-friendly means endow astounding characteristics to gum-based biocomposites in the field of diagnosis and therapy towards cancer diseases. In this review, assorted approaches for the assembly of nanomaterials mediated by gum biopolymers are presented and their utility in cancer diagnosis and therapy, e.g., bioimaging, radiotherapy, and phototherapy, are deliberated to provide a groundwork for future stimulative research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease., (Published by Elsevier B.V.)

Objective: To test the hypothesis that brain white matter hyperintensities (WMH) are more common in people living with HIV (PLWH), even in the setting of well-controlled infection, and to identify clinical measures that correlate with these abnormalities., Methods: Research brain MRI scans, acquired within longitudinal studies evaluating neurocognitive outcomes, were reviewed to determine WMH load using the Fazekas visual rating scale in PLWH with well-controlled infection (antiretroviral therapy for at least 1 year and plasma viral load <200 copies/mL) and in sociodemographically matched controls without HIV (CWOH). The primary outcome measure of this cross-sectional analysis was increased WMH load, determined by total Fazekas score ≥2. Multiple logistic regression analysis was performed to evaluate the effect of HIV serostatus on WMH load and to identify MRI, CSF, and clinical variables that associate with WMH in the PLWH group., Results: The study included 203 PLWH and 58 CWOH who completed a brain MRI scan between April 2014 and March 2019. The multiple logistic regression analysis, with age and history of tobacco use as covariates, showed that the adjusted odds ratio of the PLWH group for increased WMH load is 3.7 (95% confidence interval 1.8-7.5; p = 0.0004). For the PLWH group, increased WMH load was associated with older age, male sex, tobacco use, hypertension, and hepatitis C virus coinfection, and also with the presence of measurable tumor necrosis factor α in CSF., Conclusion: Our results suggest that HIV serostatus affects the extent of brain WMH. This effect is mainly associated with aging and modifiable comorbidities., (© 2021 American Academy of Neurology.)

Early diagnosis of brain tumours is challenging and a major unmet need. Patients with brain tumours most often present with non-specific symptoms more commonly associated with less serious diagnoses, making it difficult to determine which patients to prioritize for brain imaging. Delays in diagnosis affect timely access to treatment, with potential impacts on quality of life and survival. A test to help identify which patients with non-specific symptoms are most likely to have a brain tumour at an earlier stage would dramatically impact on patients by prioritizing demand on diagnostic imaging facilities. This clinical feasibility study of brain tumour early diagnosis was aimed at determining the accuracy of our novel spectroscopic liquid biopsy test for the triage of patients with non-specific symptoms that might be indicative of a brain tumour, for brain imaging. Patients with a suspected brain tumour based on assessment of their symptoms in primary care can be referred for open access CT scanning. Blood samples were prospectively obtained from 385 of such patients, or patients with a new brain tumour diagnosis. Samples were analysed using our spectroscopic liquid biopsy test to predict presence of disease, blinded to the brain imaging findings. The results were compared to the patient's index brain imaging delivered as per standard care. Our test predicted the presence of glioblastoma, the most common and aggressive brain tumour, with 91% sensitivity, and all brain tumours with 81% sensitivity, and 80% specificity. Negative predictive value was 95% and positive predictive value 45%. The reported levels of diagnostic accuracy presented here have the potential to improve current symptom-based referral guidelines, and streamline assessment and diagnosis of symptomatic patients with a suspected brain tumour., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Transoral incisionless fundoplication (TIF) is an endoscopic alternative for the treatment of GERD. However, TIF does not address the hiatal hernia (HH). We present a novel approach with a laparoscopic HH repair followed by same-session TIF, coined concomitant transoral incisionless fundoplication (cTIF). The aim of this study was to assess the efficacy, safety, and feasibility of cTIF in a collaborative approach between Gastroenterology and surgery., Study Design: Patients with confirmed GERD and >2 cm HH who underwent cTIF between 2018 and 2020 were included. Symptoms were assessed using the Reflux Disease Questionnaire, GERD Health-Related Quality of Life Index, and the Reflux Symptom Index pre and post cTIF. One-way ANOVA and paired samples t-test were used for statistical analysis., Results: Sixty patients underwent cTIF (53% were men, mean age was 59.3 years) with 100% technical success. Mean ± SD HH measurement on endoscopy was 2.9 ± 1.5 cm. Scores on Reflux Disease Questionnaire for symptom frequency and symptom severity improved significantly from before to 6 months after cTIF (17.4 to 4.72; p < 0.01 and 16.7 to 4.56; p < 0.05, respectively). According to the GERD Health-Related Quality of Life Index, significant decreases were seen post cTIF in heartburn (23.26 to 7.37; p < 0.01) and regurgitation (14.26 to 0; p = 0.05). Reflux Symptom Index similarly decreased after cTIF (17.7 to 8.1 post cTIF; p < 0.01). Mean DeMeester score decreased from 43.7 to 4.9 and acid exposure time decreased from 12.7% to 1.28% post cTIF (p = 0.06)., Conclusions: We present a novel multidisciplinary approach to GERD using a combined endoscopic and surgical approach with close collaboration between Gastroenterology and surgery. Our results suggest that cTIF is safe and effective in reducing reflux symptoms in a large spectrum of GERD patients., (Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Conjugation, that is, covalent linkage, to immunological proteins is a common strategy to address the low immunogenicity issue of carbohydrate antigens in vaccine development. This chapter describes an easy and efficient method for oligosaccharide-protein conjugation employing dicarboxylic acid linkers. In this regard, a free amino group is introduced to an oligosaccharide antigen to facilitate coupling with the bifunctional linker upon reaction with its corresponding disuccinimidyl ester. The resultant monosuccinimidyl ester of the oligosaccharide antigen then reacts with the free amino groups of a carrier protein to provide the desired oligosaccharide-protein conjugate.

Critical advances have recently been made in the field of immunotherapy, contributing to an improved understanding of how to harness and balance the power of immune responses in the treatment of diseases such as cancer, cardiovascular disease, infectious diseases, and autoimmune diseases. Combining nanomedicine with immunotherapy provides the opportunity for customization, rational design, and targeting to minimize side effects and maximize efficacy. This review highlights current developments in the design and utilization of nano-based immunotherapy systems, including how rationally-designed nanosystems can target and modify immune cells to modulate immune responses in a therapeutic manner. We discuss the following topics: targeted immuno-engineered nanoformulations, commercial formulations, clinical applicability, challenges associated with current approaches, and future directions., Competing Interests: Conflict of interest Authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Possible human immunodeficiency virus (HIV)-1 clearance has rarely been reported. In this study, we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART., Methods: Leukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls., Results: No HIV-specific antibodies were detected in serum. Plasma HIV ribonucleic acid (RNA) levels were <0.2 copies/mL, and, except for low-frequency HIV deoxyribonucleic acid (DNA) + cells in lymph node tissue (1 copy/3 × 10 6 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/10 6 CD4 + T cells) or by most measurements of HIV RNA or DNA in blood, lymph node, or gut-associated mononuclear cells. Human immunodeficiency virus-specific T-cell responses were detectable but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. Human immunodeficiency virus DNA + cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis., Conclusions: This represents the first report of complete seroreversion, prolonged posttreatment virus suppression, a profoundly small HIV reservoir, and persistent HIV-specific T cells in an adult with prior AIDS., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2020.)

Objective: This study sought to determine whether 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography could be applied to a murine model of advanced atherosclerotic plaque vulnerability to detect response to therapeutic intervention and changes in lesion stability. Approach and Results: To analyze plaques susceptible to rupture, we fed ApoE -/- mice a high-fat diet and induced vulnerable lesions by cast placement over the carotid artery. After 9 weeks of treatment with orthogonal therapeutic agents (including lipid-lowering and proefferocytic therapies), we assessed vascular inflammation and several features of plaque vulnerability by 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography and histopathology, respectively. We observed that 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography had the capacity to resolve histopathologically proven changes in plaque stability after treatment. Moreover, mean target-to-background ratios correlated with multiple characteristics of lesion instability, including the corrected vulnerability index., Conclusions: These results suggest that the application of noninvasive 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography to a murine model can allow for the identification of vulnerable atherosclerotic plaques and their response to therapeutic intervention. This approach may prove useful as a drug discovery and prioritization method.