Methotrexate and Rituximab Use in Highly Recurrent Idiopathic Subglottic Stenosis.

OBJECTIVE: To evaluate the impact of methotrexate and rituximab therapy on highly recurrent idiopathic subglottic stenosis (iSGS) patients with a negative antineutrophil cytoplasmic antibody titer cANCA(-). METHODS: This was a retrospective cohort study of highly recurrent iSGS patients who recurred within 1 year or less and were treated with methotrexate (MTX), and rituximab (RTX), or a combination of both at different time points (MTX/RTX). Average surgical durations before and after drug treatment were summarized, and the differences were calculated. RESULTS: A total of 21 female patients with median age of 62 years were included. Fifteen patients were treated with MTX, three were treated with RTX, and five treated with both. Patients treated with immunosuppressants showed a trend toward longer intervals between operations (mean pre-drug interval: 338; mean post-drug interval: 697 days) (p-value = 0.25). Three patients did not recur following drug initiation with median follow-up of 1265 days. All three treatment groups demonstrated a trend toward increased post-drug recurrence intervals (MTX: 444 days, RTX: 374 days, MTX/RTX: 55 days), that was not statistically significant. Patients with prior dilations demonstrated longer post-drug recurrence intervals (mean pre-drug interval: 341 days, mean post-drug interval 978 days) (p-value = 0.17). Four patients in the cohort with the highest recurring disease improved from mean 129 days between operations to 509 days with drug therapy. The most common drug side effect was nausea (16%). CONCLUSION: MTX and RTX may be treatment options for some highly recurrent iSGS patients. Initial results are variable and demonstrate a need for further research on drug candidacy. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

"I feel like it should be but I know it's really not": exploring physical fitness priorities at the correctional training program in Canadian federal corrections.

The correctional training program (CTP), composed of three stages, includes a 14 week in-person component that Correctional Officer Recruits (CORs) must complete prior to their employment as a federal Correctional Officer (CO) for Correctional Service Canada (CSC). The CTP prepares recruits for a plethora of CO responsibilities, some dependent on physical fitness, such as responding to codes being called, physical altercations, or violent situations. Unlike other public safety positions (e.g. policing, border services, or coast guard) CSC does not require occupational fitness testing. In the current article, we use data from a multiyear longitudinal study of federal COs from across Canada to unpack how CORs manage physical fitness expectations at CTP; CSCs' expectations of COR physical fitness; and outline what types of physical fitness (e.g. weightlifting, cardiovascular, self-defence) are taught, thus valued most, during CTP. We situate the voices of CORs regarding physical fitness within the broader "body" literature and discuss policy recommendations tied to physical fitness, specifically COs' interest in reinstating pre-employment physical fitness screening.

Symptom-Free Intervals Following Laser Wedge Excision for Recurrent Idiopathic Subglottic Stenosis.

OBJECTIVE: Analyze the duration of symptom-free intervals following laser wedge excision (LWE) for recurrent idiopathic subglottic stenosis (iSGS). Secondary aim includes evaluating the influence of patient-related or disease factors. STUDY DESIGN: Retrospective review. SETTING: Tertiary center. METHODS: Review of iSGS patients who underwent LWE between 2002 and 2021. LWE patients without prior airway surgery were labeled LWE primary (LWEP) and those with prior history of dilation were labeled LWE secondary (LWES). A conditional frailty repeated events model was used to analyze the median time to recurrence (MTR) for each nth recurrence. Secondary analysis included stratification by use of medical therapy and initial preoperative characteristics of scar (Myer-Cotton grade, distance between the glottis and superior-most aspect of scar, DGS; length of scar, DL). RESULTS: Two hundred and ten iSGS patients underwent LWE (131 LWEP, 79 LWES). The proportion of patients experiencing at least 1, 3, 6, and 12 recurrences, respectively, was 68.0% (n = 143), 40.7% (n = 85), 20.0% (n = 42), and 5.2% (n = 11). There was exponential time-shortening from the 1st to 12th recurrence (P < .0001). While MTR was 4.1 years after the first LWE, this fell to 2.8, 1.7, 1.0, and 0.7 years for the 2nd, 3rd, 6th, and 12th recurrences. Furthermore, LWEP patients experienced longer MTR than LWES counterparts within the first 6 recurrences (P < .01). There was no significant relationship between intersurgical interval and medication adherence, DL, DGS, or grade for recurrences beyond the first (P = .207, P = .20, P = .43, P = .16). CONCLUSION: Symptom-free intervals in iSGS shorten with each subsequent recurrence and LWE. The difference in MTR between LWEP and LWES groups was significant within the first 6 recurrences with LWEP having longer MTR.

Remote assessment and management of patients with dizziness: development, validation, and feasibility of a gamified vestibular rehabilitation therapy platform.

Introduction: Dizziness is a growing public health concern with as many as 95 million adults in Europe and the United States experiencing vestibular hypofunction, which is associated with reduced quality of life, poorer health, and falls. Vestibular rehabilitation therapy (VRT) is effective in reducing symptoms and improving balance; however, limited access to qualified clinicians and poor patient adherence impedes optimal delivery. The goal of this study was to develop and evaluate the feasibility of a remote therapeutic monitoring VRT Platform application (APP) for the assessment and treatment of vestibular dysfunction. Methods: User-centered iterative design process was used to gather and integrate the needs of users (clinicians and patients) into the design at each stage of development. Commonly used vestibular patient-reported outcome measures (PROs) were integrated into the APP and adults with chronic dizziness were enrolled to evaluate validity and reliability of the APP compared to standard clinical measures (CLIN). Gaze stabilization exercises were gamified to provide an engaging experience and an off-the-shelf sensor captured eye and head movement to provide feedback on accuracy of performance. A prospective, pilot study design with pre-and post-treatment assessment assessed feasibility of the APP compared to standard VRT (CLIN). Results: Participants with dizziness wanted a summary rehabilitation report shared with their clinicians, felt that an app could help with accountability, and believed that a gaming format might help with exercise adherence. Clinicians felt that the app should include features to record and track eye and head movement, monitor symptoms, score accuracy of task performance, and measure adherence. Validity and reliability of the digital PROs (APP) were compared to scores from CLIN across two sessions and found to have good validity, good to excellent test-retest reliability, and excellent usability (≥88%ile). The pilot study demonstrated feasibility for use of the APP compared to CLIN for treatment of vestibular hypofunction. The mean standard system usability score of the APP was 82.5 indicating excellent usability. Discussion: Both adult patients with chronic dizziness and VRT clinicians were receptive to the use of technology for VRT. The HiM-V APP is a feasible alternative to clinical management of adults with chronic peripheral vestibular hypofunction.

18F-FDG PET/CT in Pediatric ALK-Positive Histiocytosis With Isolated CNS Involvement.

ABSTRACT: An 11-year-old girl presented with focal impaired awareness seizures. MRI brain demonstrated a T2 hyperintense cortical lesion in the left temporal lobe with surrounding vasogenic edema. 18F-FDG PET/CT was arranged to assess metabolic activity of the cerebral lesion, to screen the whole body for other metabolically active lesions, and to assist biopsy planning. The study demonstrated intensely increased FDG uptake within the left temporal lobe lesion without evidence of hypermetabolic lesions elsewhere on the whole-body acquisition. The brain lesion was excised, and histopathology and molecular testing were consistent with ALK-positive histiocytosis.

Comparing the Performance of ChatGPT-4 and Medical Students on MCQs at Varied Levels of Bloom's Taxonomy.

Introduction: This research investigated the capabilities of ChatGPT-4 compared to medical students in answering MCQs using the revised Bloom's Taxonomy as a benchmark. Methods: A cross-sectional study was conducted at The University of the West Indies, Barbados. ChatGPT-4 and medical students were assessed on MCQs from various medical courses using computer-based testing. Results: The study included 304 MCQs. Students demonstrated good knowledge, with 78% correctly answering at least 90% of the questions. However, ChatGPT-4 achieved a higher overall score (73.7%) compared to students (66.7%). Course type significantly affected ChatGPT-4's performance, but revised Bloom's Taxonomy levels did not. A detailed association check between program levels and Bloom's taxonomy levels for correct answers by ChatGPT-4 showed a highly significant correlation (p<0.001), reflecting a concentration of "remember-level" questions in preclinical and "evaluate-level" questions in clinical courses. Discussion: The study highlights ChatGPT-4's proficiency in standardized tests but indicates limitations in clinical reasoning and practical skills. This performance discrepancy suggests that the effectiveness of artificial intelligence (AI) varies based on course content. Conclusion: While ChatGPT-4 shows promise as an educational tool, its role should be supplementary, with strategic integration into medical education to leverage its strengths and address limitations. Further research is needed to explore AI's impact on medical education and student performance across educational levels and courses.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Effect of tobacco use on Zenker's diverticulotomy outcomes.

OBJECTIVE: To compare clinical outcomes in patients with and without history of tobacco use who underwent Zenker's diverticulotomy (ZD). STUDY DESIGN: Single institution retrospective review. SETTING: Tertiary care academic hospital. METHODS: A retrospective review of patients who underwent ZD via an open stapler, rigid endoscopic CO2 laser, stapler or harmonic scalpel, and flexible endoscopic technique from January 2006 to December 2020 was performed. Data were abstracted for patient demographics, diverticular features, and rates of adverse events and symptomatic recurrence. RESULTS: Out of 424 patients, 146 (34.4 %) had a history of tobacco use: 126 (29.7 %) were former smokers, and 20 (4.7 %) were active smokers. In univariable cross-sectional analyses, the likelihood of postoperative bleeding, perforation, emergency department visits, unplanned readmission, or recurrence did not demonstrate an association with tobacco use history even after adjustment for age, sex, and surgical approach. Similarly, in Cox Proportional Hazards regression, tobacco use was not associated with an increased risk of recurrence, even after correcting for age, sex, and type of surgery. The median time to recurrence observed in our cohort was 11.5 years amongst non-smokers, 8.7 years amongst former smokers, and 1.2 years amongst active smokers (p = 0.94). CONCLUSIONS: There were no significant differences in post-operative adverse events or frequency of recurrence of ZD between active, former, and non-smokers. Although underpowered and not statistically significant, median time to recurrence appears to be shorter in smokers when compared with former and non-smokers following surgery.

Chokeberry reduces inflammation in human preadipocytes.

Chokeberry, Aronia melanocarpa, is an indigenous fruit from North America used as food and to prevent chronic disease by Indigenous Peoples. The objective of this study was to test anti-inflammatory effects of anthocyanin on palmitic acid (PA)-induced IL-6 gene expression, IL-6 DNA methylation, and histone (H3) acetylation. Additionally, we examined effects of anthocyanins Cyanidin-3-O-galactoside (C3Gal) and Cyanidin-3-glucoside (C3G) on IL-6 gene expression. Human primary pre-adipocytes were treated with chokeberry juice extract (CBE), C3Gal or C3G in the presence or absence of PA or lipopolysaccharide (LPS). CBE inhibited LPS- and PA-induced IL-6 mRNA expression (p < 0.0001), while C3G and C3Gal had smaller effects. Human IL-6 promoter DNA methylation was increased (p = 0.0256) in CBE treated cells compared to control. Histone H3 acetylations were not affected by CBE or PA treatment. These data indicate that CBE epigenetically reduced PA-induced inflammation by regulating IL-6 DNA methylation without affecting histone modifications in human preadipocyte cells.

Medical Maintenance Therapy Following Laser Excision in Patients With Granulomatosis With Polyangiitis (GPA)-Associated Subglottic Stenosis.

OBJECTIVE: To report on a series of patients with cANCA/PR3-positive, granulomatosis with polyangiitis (GPA)-associated subglottic stenosis (SGS) and evaluate response to medical maintenance therapy with rituximab versus other immunosuppressants following initial endoscopic laser excision. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic center. METHODS: A retrospective chart review of patients with SGS and cANCA/PR3-positive GPA who received immunosuppressive maintenance therapy following endoscopic laser excision at our institution from June 1989 to March 2020 was performed. Data pertaining to patient demographics, clinical features, medications, and endoscopic laser procedures were collected. RESULTS: A total of 27 patients (15 women) with mean age (range) of 40 (19-59) years and mean (range) follow-up of 12.6 years (1.5-28.6) were identified. Sixteen patients (60%) had limited GPA. Six patients (24%) had previously received local intervention with open surgery (n = 1, 4%) or endoscopic techniques (n = 5, 20%). All patients experienced symptom improvement following initial CO2 laser excision at our institution without any procedural complications or adverse events. Following initial laser excision, 15 patients (60%) were treated with rituximab and 10 patients (40%) were treated with nonrituximab immunosuppressive agents. Patients treated with rituximab were less likely to recur (P = 0.040). Limited GPA was associated with an increased incidence of recurrence (P = 0.031). Median time (years) to recurrence (range) was 3.2 (0.3-19.3) and was not significantly associated with treatment or GPA subtype. CONCLUSION: Endoscopic CO2 laser excision is a safe and effective local intervention for GPA-associated SGS. Medical maintenance therapy with rituximab reduces risk of recurrence following initial laser excision relative to treatment with non-rituximab agents.

Single-use versus reusable rhinolaryngoscopes for inpatient otorhinolaryngology consults: Resident and patient experience.

Objectives: Single-use rhinolaryngoscopes were brought to market in 2019 as an alternative to traditional reusable scopes and have garnered interest across settings given portability and potential cost advantages. While single-use was previously evaluated compared to traditional devices, the overall impact to the consult experience for both users and patients has not been captured. Methods: Eighteen residents performed consults with both single-use and reusable rhinolaryngoscope systems on alternating weeks. A five-question cumulative survey administered across three assessment points over a 12-week period using a five-point rating system to rate favorability. Residents and patients also completed four-point scale surveys following procedure(s) to capture the consult experience. Statistical analyses were performed to measure significance differences between survey responses between the two systems. Results: Single-use rhinolaryngoscopes received higher overall ratings compared with reusables across each metric captured including overall consult time (4.3 vs. 2.2, p < .001), multiscope consults (4.4 vs. 3.1, p < .001), patient communication (4.6 vs. 2.1, p < .001), teaching opportunities (4.6 vs. 2.1, p < .001), and overall ease of use (4.7 vs. 2.6, p < .001). Residents rated single-use higher than reusable after each procedure in terms of ease of use (1.07 vs. 2.68, p < .001) and visual clarity (1.27 vs. 1.89, p = .003), while patients rated single-use higher for understanding of illness (3.9 vs. 3.1, p < .001) and understanding of treatment rationale (3.9 vs. 3.1, p < .001). Conclusion: Resident and patient experience feedback favored single-use rhinolaryngoscopes compared to reusable scope technology across multiple surveyed measurables. Single-use rhinolaryngoscopes provide a viable tool for otorhinolaryngologist and other clinicians to perform rhinolaryngoscopy consults. Level of Evidence: 4.

In Search of Nodular Gastric Antral Vascular Ectasia: A Distinct Entity or Simply Hyperplastic Polyps Arising in Gastric Antral Vascular Ectasia?

CONTEXT.­: Nodular gastric antral vascular ectasia (GAVE) is a reported phenotype of GAVE that has histologic features overlapping with gastric hyperplastic polyps (GHPs), with additional features often seen in flat mucosa of GAVE. OBJECTIVE.­: To determine if nodular GAVE and GHPs are distinct lesions by evaluating the prevalence of features reported in nodular GAVE in GHPs with or without associated GAVE. DESIGN.­: A review of all lesions diagnosed as GHPs between 2014 and 2017 was performed. Slides were analyzed for a number of features including established histologic features of GAVE without knowledge of clinical or endoscopic features. RESULTS.­: A total of 90 polyps were analyzed including 18 from patients with GAVE (20%). GAVE polyps were larger than non-GAVE polyps (average size, 1.3 cm versus 0.68 cm; P < .001), with more common extensive ulceration and associated granulation tissue (61.11% [n = 11] versus 4.17% [n = 3]; P = .004), fibrin thrombi (50% [n = 9] versus 15% [n = 11]; P = .003), moderate to marked vascular ectasia (83% [n = 15] versus 35% [n = 11]; P = .001), and fibrohyalinosis (72% [n = 13] versus 28% [n = 20]; P = .001). All polyps showed foveolar hyperplasia and smooth muscle proliferation. There were no features that were exclusively found in GAVE or non-GAVE cases. CONCLUSIONS.­: Nodular GAVE appears to represent GHPs arising in a background of GAVE, with superimposed features found in flat mucosa of GAVE stomachs. The presence of fibrin thrombi, marked vascular ectasia, fibrohyalinosis, and/or ulceration in a GHP is suggestive but not diagnostic of GAVE, and the absence of these features does not rule out GAVE.

Life-Threatening Subglottic Thrombus Formation after Administration of Nebulized Tranexamic Acid.

We present a case of subglottic thrombus formation after administration of nebulized tranexamic acid (TXA) for postoperative hemoptysis following CO2 laser wedge excision of subglottic stenosis. Although other factors certainly could have resulted in postoperative bleeding and subsequent thrombus formation, the patient's rapid decompensation following administration of nebulized TXA suggests a direct effect. We recommend implementing an airway action plan regarding TXA use for patients presenting to the emergency department with postoperative hemorrhage following otolaryngology procedures. Laryngoscope, 134:1356-1358, 2024.

The Antietam Staff Walk at the Uniformed Services University: A Program Evaluation.

INTRODUCTION: The battle along Antietam Creek in September 1862 was pivotal in shaping future combat medical readiness practices. With the full confidence of his commander, Major (Dr) Jonathan Letterman implemented an innovative ambulance corps system, which contributed immensely to modern-day battlefield medicine. Each year, the Uniformed Services University (USU) holds the Antietam Staff Walk, during which military medical students are engaged by faculty at various "stops" along the 6-mile walk. The four learning objectives for the Antietam Staff Walk are to (1) introduce the role of the "staff ride," (2) orient learners to reading terrain, (3) reinforce the six principles of health service support, and (4) recall the heritage of the military medical officer. The Department of Military and Emergency Medicine at USU commissioned a program evaluation to determine if these course objectives were being met, evaluate the effectiveness of the Antietam Staff Walk as a teaching tool, and make recommendations for improving its educational impact. MATERIALS AND METHODS: We engaged in qualitative program evaluation to evaluate the Antietam Staff Walk course objectives. Our research team analyzed 156 reflection papers written by second-year military medical students attending Antietam in August 2021. We coded each of the papers, noting important words and phrases that were salient to the students' learning experiences at Antietam. Our research team then compiled each of these codes into a master list and then determined how to divide this list into major categories. We collectively defined each of these categories, which served as the resulting themes of this program evaluation. RESULTS: Three themes emerged: (1) creation of an ambulance corps allows for proximal battlefield medicine, (2) a lack of buddy aid inspires Tactical Casualty Combat Care, and (3) disease/nonbattle injury necessitates preventative medicine. The students foremost gained an appreciation for the impact of the ambulance corps and recognized that the ambulance corps not only impacted medical care, but also the mission as a whole. However, may not have completely understood the long, slow evolution of battlefield care and may have overestimated the knowledge of physicians practicing mid-19th century medicine. We provided recommendations for addressing these learning opportunities during future Antietam Staff Walks at USU. CONCLUSIONS: Our review of the Antietam Staff Ride resulted in several curricular recommendations for enhancing its learning impact. Our program evaluation serves as a model for line units and other military organizations to optimize the impact of the historical staff ride as a teaching tool.

Longer duration entry mitigates nystagmus and vertigo in 7-Tesla MRI.

Introduction: Patients and technologists commonly describe vertigo, dizziness, and imbalance near high-field magnets, e.g., 7-Tesla (T) magnetic resonance imaging (MRI) scanners. We sought a simple way to alleviate vertigo and dizziness in high-field MRI scanners by applying the understanding of the mechanisms behind magnetic vestibular stimulation and the innate characteristics of vestibular adaptation. Methods: We first created a three-dimensional (3D) control systems model of the direct and indirect vestibulo-ocular reflex (VOR) pathways, including adaptation mechanisms. The goal was to develop a paradigm for human participants undergoing a 7T MRI scan to optimize the speed and acceleration of entry into and exit from the MRI bore to minimize unwanted vertigo. We then applied this paradigm from the model by recording 3D binocular eye movements (horizontal, vertical, and torsion) and the subjective experience of eight normal individuals within a 7T MRI. The independent variables were the duration of entry into and exit from the MRI bore, the time inside the MRI bore, and the magnetic field strength; the dependent variables were nystagmus slow-phase eye velocity (SPV) and the sensation of vertigo. Results: In the model, when the participant was exposed to a linearly increasing magnetic field strength, the per-peak (after entry into the MRI bore) and post-peak (after exiting the MRI bore) responses of nystagmus SPV were reduced with increasing duration of entry and exit, respectively. There was a greater effect on the per-peak response. The entry/exit duration and peak response were inversely related, and the nystagmus was decreased the most with the 5-min duration paradigm (the longest duration modeled). The experimental nystagmus pattern of the eight normal participants matched the model, with increasing entry duration having the strongest effect on the per-peak response of nystagmus SPV. Similarly, all participants described less vertigo with the longer duration entries. Conclusion: Increasing the duration of entry into and exit out of a 7T MRI scanner reduced or eliminated vertigo symptoms and reduced nystagmus peak SPV. Model simulations suggest that central processes of vestibular adaptation account for these effects. Therefore, 2-min entry and 20-s exit durations are a practical solution to mitigate vertigo and other discomforting symptoms associated with undergoing 7T MRI scans. In principle, these findings also apply to different magnet strengths.

On the estimation of the effect of weight change on a health outcome using observational data, by utilising the target trial emulation framework.

BACKGROUND/OBJECTIVES: When studying the effect of weight change between two time points on a health outcome using observational data, two main problems arise initially (i) 'when is time zero?' and (ii) 'which confounders should we account for?' From the baseline date or the 1st follow-up (when the weight change can be measured)? Different methods have been previously used in the literature that carry different sources of bias and hence produce different results. METHODS: We utilised the target trial emulation framework and considered weight change as a hypothetical intervention. First, we used a simplified example from a hypothetical randomised trial where no modelling is required. Then we simulated data from an observational study where modelling is needed. We demonstrate the problems of each of these methods and suggest a strategy. INTERVENTIONS: weight loss/gain vs maintenance. RESULTS: The recommended method defines time-zero at enrolment, but adjustment for confounders (or exclusion of individuals based on levels of confounders) should be performed both at enrolment and the 1st follow-up. CONCLUSIONS: The implementation of our suggested method [adjusting for (or excluding based on) confounders measured both at baseline and the 1st follow-up] can help researchers attenuate bias by avoiding some common pitfalls. Other methods that have been widely used in the past to estimate the effect of weight change on a health outcome are more biased. However, two issues remain (i) the exposure is not well-defined as there are different ways of changing weight (however we tried to reduce this problem by excluding individuals who develop a chronic disease); and (ii) immortal time bias, which may be small if the time to first follow up is short.

'Through and Through' History: The Management of Gunshot Wounds From the 14th Century to the Present.

Gun violence killed over 46,000 Americans in 2021; almost 120,000 suffered gunshot wounds. This epidemic has attracted national attention and increasing concern from medical and surgical organizations, as evident in this special issue. 'Through and Through History' explores the surgical management of gunshot wounds from their earliest appearance in 14th-century Europe to the present. Interweaving the civilian and military experience, it details not only the evolution of care directly applied to patients but also the social, political, and scientific milieu that shaped decisions made and actions performed both in and out of the operating room. The article describes how surgeons have pushed the boundaries of medicine and science in each era, developing new therapies for their patients, a historical trend that persists today when such care has the potential to save tens of thousands of lives each year.

Breast Cancer After Reduction Mammoplasty: A Population-Based Analysis of Incidence, Treatment and Screening Patterns.

Background: The risk of breast cancer may be decreased in women who undergo reduction mammoplasty. The purpose of this study was to describe the incidence and treatment of breast cancer after reduction mammoplasty and to better understand the use of breast cancer screening modalities in these patients. Methods: This population-based retrospective analysis utilized the Discharge Abstract Database held by the Canadian Institute for Health Information and the National Ambulatory Care Reporting System to identify all women aged 20 years or older who underwent reduction mammoplasty in Alberta, Canada. The incidence and treatment of breast cancer were compared among patients who underwent reduction mammoplasty and age-sex-matched controls. Imaging utilization, including the use of mammography, ultrasound, and breast biopsy, was also compared. Results: Between 2003 and 2007, 8021 patients over 20 years old underwent reduction mammoplasty in Alberta. Patients were followed for an average of 12.6 years. Eighty-nine (1.1%) patients who underwent reduction mammoplasty developed breast cancer after surgery, compared to 453 (1.9%) controls (P < 0.0001). Among patients diagnosed with breast cancer, there was no difference in patient and tumor characteristics. Women who underwent reduction mammoplasty were more likely to undergo mastectomy for cancer (41.6% vs 1.5%; P < 0.0001) and were more likely to undergo mammography (66.7% vs 58.7%; P < 0.0001), ultrasound (29.2% vs 26.2%; P < 0.0001) and biopsy for benign disease (7.2% vs 6%, P < 0.0001) compared to controls. Conclusions: Despite an increased frequency of breast cancer screening, the incidence of breast cancer is lower after reduction mammoplasty compared with women who did not undergo breast reduction. After a diagnosis of breast cancer, surgical treatment patterns differ between groups, whereby mastectomy is more common after reduction mammoplasty.

Acoustic Noise Levels in High-field Magnetic Resonance Imaging Scanners.

7-Tesla (T) magnetic resonance imaging may allow for higher resolution images but may produce greater acoustic noise than 1.5- and 3-T scanners. We sought to characterize the intensity of acoustic noise from 7- versus 3-T scanners. A-weighted sound pressure levels from 5 types of pulse sequences used for brain and inner ear imaging in 3- and 7-T scanners were measured. Time-averaged sound level and maximum sound levels generated for each sequence were compared. Time-averaged sound levels exceeded 95 dB and reached maximums above 105 dB on the majority of 3- and 7-T scans. The mean time-averaged sound level and maximum sound level across pulse sequences were greater in 7- than 3-T (105.6 vs 91.4, P = .01; 114.0 vs. 96.5 dB, P < .01). 7- and 3-T magnetic resonance imaging scanners produce high levels of acoustic noise that exceed acceptable safety limits, emphasizing the need for active and passive noise protection.

Shorter Is Better: The α-(l)-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs.

Chemical modifications are necessary to ensure the metabolic stability and efficacy of oligonucleotide-based therapeutics. Here, we describe analyses of the α-(l)-threofuranosyl nucleic acid (TNA) modification, which has a shorter 3'-2' internucleotide linkage than the natural DNA and RNA, in the context of small interfering RNAs (siRNAs). The TNA modification enhanced nuclease resistance more than 2'-O-methyl or 2'-fluoro ribose modifications. TNA-containing siRNAs were prepared as triantennary N-acetylgalactosamine conjugates and were tested in cultured cells and mice. With the exceptions of position 2 of the antisense strand and position 11 of the sense strand, the TNA modification did not inhibit the activity of the RNA interference machinery. In a rat toxicology study, TNA placed at position 7 of the antisense strand of the siRNA mitigated off-target effects, likely due to the decrease in the thermodynamic binding affinity relative to the 2'-O-methyl residue. Analysis of the crystal structure of an RNA octamer with a single TNA on each strand showed that the tetrose sugar adopts a C4'-exo pucker. Computational models of siRNA antisense strands containing TNA bound to Argonaute 2 suggest that TNA is well accommodated in the region kinked by the enzyme. The combined data indicate that the TNA nucleotides are promising modifications expected to increase the potency, duration of action, and safety of siRNAs.