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Aminoglycoside antibiotics have played a critical role in the treatment of both Gram-negative and Gram-positive bacterial infections. However, antibiotic resistance has severely compromised the efficacy of aminoglycosides. A leading cause of aminoglycoside resistance is mediated by bacterial enzymes that inactivate these drugs via chemical modification. Aminoglycoside nucleotidyltransferase-6 (ANT(6)) enzymes inactivate streptomycin by transferring an adenyl group from ATP to position 6 on the antibiotic. Despite the clinical significance of this activity, ANT(6) enzymes remain relatively uncharacterized. Here, we report the first high resolution x-ray crystallographic structure of ANT(6)-Ib from Campylobacter fetus subsp. fetus bound with streptomycin. Structural modeling and gel filtration chromatography experiments suggest that the enzyme exists as a dimer in which both subunits contribute to the active site. Moreover, superposition of the ANT(6)-Ib structure with the structurally related enzyme lincosamide nucleotidyltransferase B (LinB) permitted the identification of a putative nucleotide binding site. These data also suggest that residues D44 and D46 coordinate essential divalent metal ions and D102 functions as the catalytic base.
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OBJECTIVE: To highlight the evolution of surgical morbidity and mortality conferences (MMCs) from the early 20th century as a means of identifying surgeon error into current practices as identifying hospital-based system factors that contribute to adverse patient events. Further, to elucidate differences in the perception of MMCs between trainees and attending surgeons as well as differences in the structure of MMCs geographically and by institution type. DESIGN: We developed a survey that was distributed to current American College of Surgeon members through Survey Monkey. SETTING: Survey-based study. PARTICIPANTS: Current members of the American College of Surgeons, including Board of Governors, surgeons, and trainees. RESULTS: There were a total of 1,396 responses to the survey, 814 (58%) from surgical trainees and 582 (42%) from attending surgeons. Both surgical trainees and attending surgeons noted that the most common day for MMCs was Wednesday and that the most common time for MMCs was before 7:30 AM. Further, most surgical trainees and attending surgeons noted that there was no structured format to their institution's MMCs and that increased attending surgeon engagement would make MMCs more educational. Significant variations in MMCs existed across both geographic region and by institution type. CONCLUSION: The results from this survey highlight key aspects of MMCs that contribute to their educational value. Staff engagement was noted to be the most educational aspect of MMCs. While geographic and institutional differences will likely persist, efforts should be made to increase staff engagement at MMCs in addition to a more structured approach.
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Weakfish (Cynoscion regalis) is not federally managed but feeds on species of management and ecological interest. We examined the trophic ecology of weakfish in Chesapeake Bay and the coastal and offshore waters of the eastern United States. For these areas, we determined the dominant prey of weakfish; identified how much diet variation was explained by the factors: season, size class, and year; and quantified prey biomass removed by weakfish from 2007 to 2019. In general, diet composition was mostly dominated by Engraulidae, Osteichthyes (bony fishes), and Mysidacea, and significantly varied by season and size class in Chesapeake Bay and coastal waters, although this was less dramatic in Chesapeake Bay. The total amount of variance explained by the three factors was 23.1% (Chesapeake Bay) and 14.7% (coastal waters), with year not being a significant factor in explaining weakfish diet variation for these areas. Weakfish total prey biomass removal occurred primarily in coastal waters in the fall and small size class (annual mean: approximately 41,038 t; maximum: approximately 63,793 t). Highly opportunistic feeders, weakfish cannibalism also played an essential part of their diet. These results have implications for fisheries and ecosystem management of weakfish when considering ecological interactions in regulatory approaches, such as recruitment and cannibalism, competition with federally managed fishes, and the natural mortality of their prey.
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BACKGROUND: In adults with anterior cruciate ligament (ACL) tears, bone bruises on magnetic resonance imaging (MRI) scans provide insight into the underlying mechanism of injury. There is a paucity of literature that has investigated these relationships in children with ACL tears. PURPOSE: To examine and compare the number and location of bone bruises between contact and noncontact ACL tears in pediatric patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Boys ≤14 years and girls ≤12 years of age who underwent primary ACL reconstruction surgery between 2018 and 2022 were identified at 3 separate institutions. Eligibility criteria required detailed documentation of the mechanism of injury and MRI performed within 30 days of the initial ACL tear. Patients with congenital lower extremity abnormalities, concomitant fractures, injuries to the posterolateral corner and/or posterior cruciate ligament, previous ipsilateral knee injuries or surgeries, or closed physes evident on MRI scans were excluded. Patients were stratified into 2 groups based on a contact or noncontact mechanism of injury. Preoperative MRI scans were retrospectively reviewed for the presence of bone bruises in the coronal and sagittal planes using fat-suppressed T2-weighted images and a grid-based mapping technique of the tibiofemoral joint. RESULTS: A total of 109 patients were included, with 76 (69.7%) patients sustaining noncontact injuries and 33 (30.3%) patients sustaining contact injuries. There were no significant differences between the contact and noncontact groups in terms of age (11.8 ± 2.0 vs 12.4 ± 1.3 years; P = .12), male sex (90.9% vs 88.2%; P > .99), time from initial injury to MRI (10.3 ± 8.1 vs 10.4 ± 8.9 days; P = .84), the presence of a concomitant medial meniscus tear (18.2% vs 14.5%; P = .62) or lateral meniscus tear (69.7% vs 52.6%; P = .097), and sport-related injuries (82.9% vs 81.8%; P = .89). No significant differences were observed in the frequency of combined lateral tibiofemoral (lateral femoral condyle + lateral tibial plateau) bone bruises (87.9% contact vs 78.9% noncontact; P = .41) or combined medial tibiofemoral (medial femoral condyle [MFC] + medial tibial plateau) bone bruises (54.5% contact vs 35.5% noncontact; P = .064). Patients with contact ACL tears were significantly more likely to have centrally located MFC bruising (odds ratio, 4.3; 95% CI, 1.6-11; P = .0038) and less likely to have bruising on the anterior aspect of the lateral tibial plateau (odds ratio, 0.27; 95% CI, 0.097-0.76; P = .013). CONCLUSION: Children with contact ACL tears were 4 times more likely to present with centrally located MFC bone bruises on preoperative MRI scans compared with children who sustained noncontact ACL tears. Future studies should investigate the relationship between these bone bruise patterns and the potential risk of articular cartilage damage in pediatric patients with contact ACL tears.
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Lesiones del Ligamento Cruzado Anterior , Contusiones , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Lesiones del Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/diagnóstico por imagen , Niño , Contusiones/diagnóstico por imagen , Adolescente , Estudios Retrospectivos , Reconstrucción del Ligamento Cruzado Anterior , Tibia/diagnóstico por imagenRESUMEN
Background: Previous reports identified an association between obese adolescents (OAs) and lower extremity (LE) fractures after blunt trauma. However, the type of LE fracture remains unclear. We hypothesized that OAs presenting after motor vehicle collision (MVC) have a higher risk of severe LE fracture and will require a longer length of stay (LOS) and more support services upon discharge, compared to non-OAs. Methods: The 2017-2019 Trauma Quality Improvement Program database was queried for adolescents (12-17-years-old) presenting after MVC. The primary outcome was LE fracture. A severe fracture was defined by abbreviated injury scale ≥3. OAs were defined by a body mass index (BMI) ≥30. Results: From 22,610 MVCs, 3325 (14.7 %) included OAs. The rate of any LE fracture was higher for OAs (21.6 % vs. 18.8 %, p < 0.001). On subset analysis the only LE fracture at higher risk in OAs was a femur fracture (13 % vs. 9.1 %, p < 0.001). After adjusting for sex and age, the risk for severe LE fracture (OR 1.34, CI 1.18-1.53, p < 0.001) was higher for OAs. OAs with a femur fracture had a longer median LOS (5 vs. 4 days, p = 0.003) and were more likely discharged with additional support services including home-health or inpatient rehabilitation (30.6 % vs. 21.4 %, p < 0.001). Conclusion: OAs sustaining MVCs have increased associated risk of femur fractures. OAs are more likely to have a higher-grade LE injury, experience a longer LOS, and require additional support services upon discharge. Future research is needed to determine if early disposition planning with social work assistance can help shorten LOS.
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Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention. SUMMARY: Macrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.
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Virtual reality (VR) simulation offers a proactive, cost effective, immersive, and low risk platform for studying pedestrian safety. Within immersive virtual environments (IVEs), existing and alternative design conditions and intelligent transportation systems (ITS) technologies can be directly compared, prior to real-world implementation, to assess the impacts alternatives may have on pedestrian safety, perception, and behavior. Environmental factors can be controlled within IVEs so that test trials are replicable and directly comparable. Coupled with stated preference feedback, participants' observed preferences and behavior provide a comprehensive understanding of the impacts of proposed design alternatives. This research presents a case study of pedestrian behavior with three different mid-block crossing safety treatments modeled within a one-to-one scale IVE replication of a real-world location in Charlottesville, Virginia. The three safety treatments consider both passive and active collision avoidance designs and technologies, including (1) the existing painted crosswalk, (2) the addition of rectangular rapid flashing beacons (RRFBs), and (3) a pedestrian to everything (P2X) ITS phone application. Additionally, this paper demonstrates a VR simulation experimental design and framework for testing pedestrian safety treatments within naturalistic and replicable IVEs to assess both stated and observed preferences and behaviors of pedestrians. Repeated measures ANOVA indicated changes in both accepted gap size (p = 0.001) and crossing speed (p < 0.001) with alternative safety treatments. Generalized mixed models showed that pedestrians waited for statistically larger gap sizes (p = 0.02) without the assistance of alternative safety technologies (RRFBs and P2X application) and pedestrians crossed the street significantly faster (p = 0.001) without the alternative safety technologies, leading to unsafe dashing behavior. Through post-experiment surveys, it was found that participants perceived the As Built environment to be the least safe of the three treatments and that their sense of risk within the IVE was realistic. Considering both the observed crossing behavior and stated feedback, pedestrians exhibited intentionally unsafe darting behavior without assistive safety technology. This study demonstrates how VR simulation may be leveraged to study both stated preferences and observed behavior for understanding the safety implications of alternative roadway designs, providing a proactive approach for assessing and designing for pedestrian safety.
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Accidentes de Tránsito , Planificación Ambiental , Peatones , Seguridad , Realidad Virtual , Humanos , Accidentes de Tránsito/prevención & control , Masculino , Femenino , Adulto , Adulto Joven , Caminata , Simulación por Computador , AdolescenteRESUMEN
The incorporation of artificial intelligence (AI) into the general surgery residency recruitment process holds great promise for overcoming limitations inherent to traditional application review methods. This study assesses the consistency of AI, particularly ChatGPT, in evaluating medical student performance evaluation (MSPE) letters in comparison to experienced human reviewers. While the results suggest that ChatGPT demonstrates greater consistency in grading than human reviewers, AI still has its limitations. This underscores the necessity for careful refinement and consideration in its implementation. While AI presents opportunities to enhance residency selection procedures, further research is imperative to fully grasp its capabilities and implications.
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A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the Emax of A3AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A3ARs. The chain length, functionality, and attachment position were varied to modulate A3AR PAM activity. For example, 26 (MRS8247, p-alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's Emax and potency ([35S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A3AR PAM activity through rational design based on an extrahelical, lipidic binding site.
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Agonistas del Receptor de Adenosina A3 , Receptor de Adenosina A3 , Humanos , Regulación Alostérica/efectos de los fármacos , Animales , Receptor de Adenosina A3/metabolismo , Receptor de Adenosina A3/química , Ratones , Agonistas del Receptor de Adenosina A3/farmacología , Agonistas del Receptor de Adenosina A3/química , Relación Estructura-Actividad , Lípidos/química , Cricetulus , Sitio Alostérico , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Células CHORESUMEN
INTRODUCTION: The Greulich & Pyle (G&P) Radiographic Atlas of Skeletal Development uses hand x-rays obtained between 1926 and 1942 on children of Caucasian ancestry. Our study uses modern Caucasian, Black, Hispanic, and Asian children to investigate patterns of development as a function of percent final height (PFH). METHODS: A retrospective review, at a single institution, was conducted using children who received a hand x-ray, a height measurement taken within 60 days of that x-ray, and a final height. BA and CA were compared between races. PFH was calculated by dividing height at the time of the x-ray by their final height. To further evaluate differences between races in CA or BA, PFH was then modeled as a function of CA or BA using a fifth-degree polynomial regression, and mean ages at the 85th PFH were compared. Patients were then divided into Sanders stages 1, 2-4, and 5-8 and the mean PFH, CA, and BA of the Asian, Black, and Hispanic children were compared with the White children using Student t test. P values less than 0.05 were considered significant. RESULTS: We studied 498 patients, including 53 Asian, 83 Black, 190 Hispanic, and 172 White patients. Mean BA was significantly greater than CA in Black males (1.27 y) and females (1.36 y), Hispanic males (1.12 y) and females (1.29 y), and White females (0.74 y). Hispanic and Black patients were significantly more advanced in BA than White patients (P<0.001). At the 85th PFH, White and Hispanic males were older than Black males by at least 7 months (P<0.001), and White females were significantly older than Hispanic females by 6.4 months (P<0.001). At 85th PFH for males, Hispanic and Black males had greater BA than White males by at least 5 months (P<0.001), and Asian females had a greater BA than Black females by at least 5 months (P<0.001). Compared with White children, Hispanic children were significantly younger at Sanders 2-4 than White children, and Black children were skeletally older at Sanders 5-8. CONCLUSIONS: BA was greater than CA by ≥1 year in Black and Hispanic children, and that these children had a significantly greater BA than their White counterparts. Black males and Hispanic females reached their 85th PFH at younger ages, and Hispanic males and Asian females were the most skeletally mature at their 85th PFH. Our results suggest that BA and CA may vary as a function of race, and further studies evaluating growth via the 85th PFH may be necessary. LEVEL OF EVIDENCE: Therapeutic Study - Level IV.
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Importance: Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated. Objective: To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone. Design, Setting, and Participants: A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023. Interventions: A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants. Main Outcomes and Measures: The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events. Results: A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group). Conclusions and Relevance: In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence. Trial Registration: anzctr.org.au Identifier: ACTRN12618001792213.
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Agentes para el Cese del Hábito de Fumar , Cese del Hábito de Fumar , Dispositivos para Dejar de Fumar Tabaco , Vareniclina , Humanos , Vareniclina/uso terapéutico , Masculino , Femenino , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/estadística & datos numéricos , Dispositivos para Dejar de Fumar Tabaco/estadística & datos numéricos , Persona de Mediana Edad , Método Doble Ciego , Adulto , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Australia , Hospitalización/estadística & datos numéricos , Fumadores/estadística & datos numéricos , Anciano , Resultado del Tratamiento , Terapia de Reemplazo de NicotinaRESUMEN
When animals learn the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), later presentation of the CS invokes a representation of the US. When the expected US fails to occur, theoretical accounts predict that conditioned inhibition can accrue to any other stimuli that are associated with this change in the US. Empirical work with mammals has confirmed the existence of conditioned inhibition. But the way it is manifested, the conditions that produce it, and determining whether it is the opposite of excitatory conditioning are important considerations. Invertebrates can make valuable contributions to this literature because of the well-established conditioning protocols and access to the central nervous system (CNS) for studying neural underpinnings of behavior. Nevertheless, although conditioned inhibition has been reported, it has yet to be thoroughly investigated in invertebrates. Here, we evaluate the role of the US in producing conditioned inhibition by using proboscis extension response conditioning of the honeybee (Apis mellifera). Specifically, using variations of a "feature-negative" experimental design, we use downshifts in US intensity relative to US intensity used during initial excitatory conditioning to show that an odorant in an odor-odor mixture can become a conditioned inhibitor. We argue that some alternative interpretations to conditioned inhibition are unlikely. However, we show variation across individuals in how strongly they show conditioned inhibition, with some individuals possibly revealing a different means of learning about changes in reinforcement. We discuss how the resolution of these differences is needed to fully understand whether and how conditioned inhibition is manifested in the honeybee, and whether it can be extended to investigate how it is encoded in the CNS. It is also important for extension to other insect models. In particular, work like this will be important as more is revealed of the complexity of the insect brain from connectome projects.
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Condicionamiento Clásico , Inhibición Psicológica , Refuerzo en Psicología , Animales , Abejas/fisiología , Condicionamiento Clásico/fisiología , Odorantes , Conducta Animal/fisiologíaRESUMEN
OBJECTIVE: Selective dorsal rhizotomy (SDR) is a neurosurgical procedure to reduce spasticity in children with cerebral palsy and spastic diplegia. The authors developed a procedure called focal SDR for children with spasticity predominantly in the L5 or S1 motor distribution, which can be combined with orthopedic correction of fixed soft-tissue or bony deformity. The authors describe in detail the technique of minimally invasive focal SDR and propose selection criteria. METHODS: The authors conducted a retrospective study of patients who underwent focal SDR at their institution and underwent baseline and 1-year postoperative 3D gait analysis. Modified Ashworth scale (MAS) and Gait Deviation Index (GDI) scores were the primary outcome measures. RESULTS: Ten patients met the study criteria, all with an underlying diagnosis of cerebral palsy. All underwent focal SDR at the unilateral or bilateral S1 level, and 4 additionally underwent focal SDR at the L5 level unilaterally or bilaterally. All but 1 patient underwent concurrent orthopedic surgery. The improvement in spasticity of the plantar flexors, as measured by the MAS score, was 2.2 (p < 0.001). In the patients who underwent L5 focal SDR, there was an improvement in the hamstring MAS score of 1.4 (p = 0.004). The mean improvement in the GDI score following focal SDR was 11 (range -6 to 29, p < 0.001). CONCLUSIONS: Focally impairing spasticity in the gastrocsoleus complex and/or hamstrings muscle group in the setting of less functionally impactful proximal tone is extremely common in cerebral palsy. The novel technique of focal SDR, combined with orthopedic intervention, improves spasticity scores and overall gait mechanics. Further investigation is warranted to define the ideal candidacy and outcomes.
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Parálisis Cerebral , Espasticidad Muscular , Rizotomía , Humanos , Rizotomía/métodos , Parálisis Cerebral/complicaciones , Parálisis Cerebral/cirugía , Masculino , Femenino , Niño , Estudios Retrospectivos , Espasticidad Muscular/cirugía , Espasticidad Muscular/fisiopatología , Preescolar , Resultado del Tratamiento , AdolescenteRESUMEN
Background: Posttraumatic stress disorder (PTSD) is associated with incident diabetes. However, past studies have often included predominantly male samples, despite important sex and gender differences in diabetes. To address this limitation, this study examined the association between PTSD and diabetes in older Veteran women, a population with a high burden of PTSD. Materials and Methods: Data were collected from 4,105 women (Mage = 67.4 years), participating in the Health of Vietnam-Era Veteran Women's Study (HealthViEWS; Department of Veterans Affairs Cooperative Studies Program #579). Participants completed self-report measures of demographics, health conditions, and health behaviors. Information on military service was obtained through service records. A structured clinical interview was conducted by telephone to assess current and lifetime PTSD and other mental health disorders. Weighted descriptive and logistic regression analyses were used to examine associations between PTSD and diabetes. Results: The prevalence of diabetes was 28.4% among women with current full PTSD compared to 23.4%, 17.6%, and 17.5% for current subthreshold, remitted, and no PTSD. In unadjusted analyses, women with current full and subthreshold PTSD were 1.87 [1.49; 2.33] and 1.44 [1.11; 1.85] times more likely to have diabetes compared to women with no PTSD. Remitted PTSD was not associated with increased odds of diabetes. Effects were attenuated but remained significant after adjustment for relevant covariates. Conclusions: Vietnam-era women with current PTSD, including subthreshold symptoms, had a greater likelihood of diabetes compared to women without PTSD. These findings suggest that women with PTSD may benefit from increased diabetes prevention efforts.
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Diabetes Mellitus , Trastornos por Estrés Postraumático , Veteranos , Guerra de Vietnam , Humanos , Femenino , Trastornos por Estrés Postraumático/epidemiología , Veteranos/estadística & datos numéricos , Veteranos/psicología , Anciano , Persona de Mediana Edad , Estados Unidos/epidemiología , Prevalencia , Diabetes Mellitus/epidemiología , Modelos LogísticosRESUMEN
BACKGROUND: The modified Gartland classification is the most widely accepted grading method of supracondylar humeral fractures among orthopedic surgeons and is relevant to identifying fractures that may require surgery. OBJECTIVE: To assess the interobserver reliability of the modified Gartland classification among pediatric radiologists, pediatric orthopedic surgeons, and pediatric emergency medicine physicians. MATERIALS AND METHODS: Elbow radiographs for 100 children with supracondylar humeral fractures were retrospectively independently graded by two pediatric radiologists, two pediatric orthopedic surgeons, and two pediatric emergency medicine physicians using the modified Gartland classification. A third grader of the same subspecialty served as a tie-breaker as needed to reach consensus. Readers were blinded to one another and to the medical record. The modified Gartland grade documented in the medical record by the treating orthopedic provider was used as the reference standard. Interobserver agreement was assessed using kappa statistics. RESULTS: There was substantial interobserver agreement (kappa = 0.77 [95% CI, 0.69-0.85]) on consensus fracture grade between the three subspecialties. Similarly, when discriminating between Gartland type I and higher fracture grades, there was substantial interobserver agreement between specialties (kappa = 0.77 [95% CI, 0.66-0.89]). The grade assigned by pediatric radiologists differed from the reference standard on 15 occasions, pediatric emergency medicine differed on 19 occasions, and pediatric orthopedics differed on 9 occasions. CONCLUSION: The modified Gartland classification for supracondylar humeral fractures is reproducible among pediatric emergency medicine physicians, radiologists, and orthopedic surgeons.
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Fracturas del Húmero , Variaciones Dependientes del Observador , Cirujanos Ortopédicos , Radiólogos , Humanos , Fracturas del Húmero/diagnóstico por imagen , Niño , Femenino , Masculino , Estudios Retrospectivos , Reproducibilidad de los Resultados , Preescolar , Lactante , Adolescente , Medicina de Urgencia Pediátrica/métodos , Radiografía/métodosRESUMEN
Our careers as surgeons are some of the busiest and perhaps most sought after in existence. We have all put in countless years of tenacious effort, at times blood, frequent sweat, and occasional tears, to have the privilege to care for others and correct their ailments. Many of us are like freight trains rolling down the tracks indefinitely. But all too often we finish our training and head down those tracks without considering what stops we should make along the way, which forks in the tracks we should consider taking, and perhaps most often, we do not consider how we are going to eventually stop the train. Most of us have been witness to colleagues who keep working beyond their prime, be it for lack of alternative opportunities, lack of hobbies to retire to, or for lack of insight into their own decline. From these observations was born this presidential panel. As you can see, it is a collection of past presidents of So Cal ACS, with the exception for Dr Freischlag (who we all know would have served as president at some point had she never relocated away from Southern California). Each of these speakers has unique experience from their own careers that they will share with us so we can take pause and consider their insights and wisdom for how to navigate a successful and satisfying career.
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Cirujanos , Humanos , Selección de Profesión , Satisfacción en el Trabajo , Envejecimiento/fisiología , Jubilación , Estados UnidosRESUMEN
Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR 4 ), which is expressed in sensory neurons of the peripheral nervous system, has emerged as a promising target for pain relief. However, the presence of several closely related receptors with similar ligand-binding surfaces complicates the design of receptor-specific agonists. In this study, we report the discovery of a potent and selective SSTR 4 peptide, consomatin Fj1, derived from extensive venom gene datasets from marine cone snails. Consomatin Fj1 is a mimetic of the endogenous hormone somatostatin and contains a minimized binding motif that provides stability and drives peptide selectivity. Peripheral administration of synthetic consomatin Fj1 provided analgesia in mouse models of postoperative and neuropathic pain. Using structure-activity studies, we designed and functionally evaluated several Fj1 analogs, resulting in compounds with improved potency and selectivity. Our findings present a novel avenue for addressing persistent pain through the design of venom-inspired SSTR 4 -selective pain therapeutics. One Sentence Summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.
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BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.
Asunto(s)
Apoptosis , Canal Aniónico 2 Dependiente del Voltaje , Proteína Destructora del Antagonista Homólogo bcl-2 , Canal Aniónico 2 Dependiente del Voltaje/metabolismo , Canal Aniónico 2 Dependiente del Voltaje/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Humanos , Unión Proteica , Mitocondrias/metabolismo , Animales , Células HEK293RESUMEN
OBJECTIVE: Chat generative pre-trained transformer (ChatGPT) has garnered attention in health care for its potential to reshape patient interactions. As patients increasingly rely on artificial intelligence platforms, concerns about information accuracy arise. In-toeing, a common lower extremity variation, often leads to pediatric orthopaedic referrals despite observation being the primary treatment. Our study aims to assess ChatGPT's responses to pediatric in-toeing questions, contributing to discussions on health care innovation and technology in patient education. METHODS: We compiled a list of 34 common in-toeing questions from the "Frequently Asked Questions" sections of 9 health care-affiliated websites, identifying 25 as the most encountered. On January 17, 2024, we queried ChatGPT 3.5 in separate sessions and recorded the responses. These 25 questions were posed again on January 21, 2024, to assess its reproducibility. Two pediatric orthopaedic surgeons evaluated responses using a scale of "excellent (no clarification)" to "unsatisfactory (substantial clarification)." Average ratings were used when evaluators' grades were within one level of each other. In discordant cases, the senior author provided a decisive rating. RESULTS: We found 46% of ChatGPT responses were "excellent" and 44% "satisfactory (minimal clarification)." In addition, 8% of cases were "satisfactory (moderate clarification)" and 2% were "unsatisfactory." Questions had appropriate readability, with an average Flesch-Kincaid Grade Level of 4.9 (±2.1). However, ChatGPT's responses were at a collegiate level, averaging 12.7 (±1.4). No significant differences in ratings were observed between question topics. Furthermore, ChatGPT exhibited moderate consistency after repeated queries, evidenced by a Spearman rho coefficient of 0.55 ( P = 0.005). The chatbot appropriately described in-toeing as normal or spontaneously resolving in 62% of responses and consistently recommended evaluation by a health care provider in 100%. CONCLUSION: The chatbot presented a serviceable, though not perfect, representation of the diagnosis and management of pediatric in-toeing while demonstrating a moderate level of reproducibility in its responses. ChatGPT's utility could be enhanced by improving readability and consistency and incorporating evidence-based guidelines. LEVEL OF EVIDENCE: Level IV-diagnostic.