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An erector spinae plane block (ESPB), in which a local anesthetic is injected into the plane anterior to the erector spinae muscles, is a relatively new technique for delivering regional anesthesia and is typically performed in the mid-thoracic region. ESPBs demonstrate great potential to control regional neuropathic pain, and, accordingly, may be particularly effective at the T1 level for controlling pain in patients undergoing first rib resections for thoracic outlet syndrome (TOS). Four patients undergoing first rib resections for TOS were administered an ultrasound-guided ESPB at the T1 level. Two patients received the injection sitting upright without general anesthesia; the other patients received the block in the lateral decubitus position while under general anesthesia. Each patient's postoperative pain was adequately controlled, and no complications were observed. T1 ESPBs offer the potential to mitigate postoperative pain. Better pain management may decrease the need for opioids and shorten recovery times. As such, further investigation to establish the safety and efficacy of T1 ESPBs in this patient population can greatly improve patient outcomes.
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Background: Loneliness and social isolation are associated with poor health outcomes such as an increased risk of cardiovascular diseases. Objectives: The authors aimed to explore the association between social isolation with biological aging which was determined by artificial intelligence-enabled electrocardiography (AI-ECG) as well as the risk of all-cause mortality. Methods: The study included adults aged ≥18 years seen at Mayo Clinic from 2019 to 2022 who respond to a survey for social isolation assessment and had a 12-lead ECG within 1 year of completing the questionnaire. Biological age was determined from ECGs using a previously developed and validated convolutional neural network (AI-ECG age). Age-Gap was defined as AI-ECG age minus chronological age, where positive values reflect an older-than-expected age. The status of social isolation was measured by the previously validated multiple-choice questions based on Social Network Index (SNI) with score ranges between 0 (most isolated) and 4 (least isolated). Results: A total of 280,324 subjects were included (chronological age 59.8 ± 16.4 years, 50.9% female). The mean Age-Gap was -0.2 ± 9.16 years. A higher SNI was associated with a lower Age-Gap (ß of SNI = 4 was -0.11; 95% CI: -0.22 to -0.01; P < 0.001, adjusted to covariates). Cox proportional hazard analysis revealed the association between social connection and all-cause mortality (HR for SNI = 4, 0.47; 95% CI: 0.43-0.5; P < 0.001). Conclusions: Social isolation is associated with accelerating biological aging and all-cause mortality independent of conventional cardiovascular risk factors. This observation underscores the need to address social connection as a health care determinant.
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The topic of vertical integration of the basic and clinical sciences is an area of great concern and active investigation in medical education. To explore the feasibility of integrating basic sciences into the clinical phase of medical education, gross anatomy was selected as an appropriate discipline. Anatomy faculty, clerkship directors, medical students, and graduate students developed case-based anatomy modules with a design consistent with the principles of self-directed learning. This pilot study aimed to explore medical student responses to the integration of anatomy sessions during clinical clerkships. One-hour anatomy sessions were conducted during rotations of the following clerkships: internal medicine, pediatrics, family medicine, neurology, obstetrics and gynecology, and general surgery during the academic year 2022-2023. Each session consisted of four case-based stations. Voluntary, anonymous surveys were distributed at the end of each session. Descriptive statistics of survey responses from the 490 participants revealed the overall ratings of the anatomy sessions to be above an 8.50 on a scale of 1.00 (low) to 9.00 (high). A small q thematic analysis of the open-ended survey questions revealed the following themes: relevance of clinical correlations presented, a timely review of anatomical content, appreciation for the collaborative setting and interactivity among the participants, and constructive feedback regarding areas needing improvement. Students reported a high overall rating of the anatomy sessions and shared positive comments about these vertically integrated anatomy experiences. With a reduction in the amount of anatomy instruction during the pre-clinical years and limited exposure during the clinical years, anatomy sessions like the ones proposed could allow for the fluid incorporation of gross anatomy across all 4 years of medical school.
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The p75 Neurotrophin Receptor (p75 NTR ) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75 NTR signaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75 NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson's disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75 NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75 NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75 NTR from the cell surface. This activation of p75 NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75 NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75 NTR , thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75 NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75 NTR in response to oxidative stress, underscore a key role for p75 NTR in dopaminergic neurodegeneration, and highlight p75 NTR as a potential therapeutic target for reducing neurodegeneration in PD.
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We introduce a model for sputter cone formation that includes only the angular dependence of the sputter yield and a fourth-order smoothing effect like surface diffusion. In one dimension, a sputter cone is a particular kind of shock wave that is known as an undercompressive shock. Simulations of our model show that a wide variety of initial conditions lead to the formation of sputter cones and that the opening angle of the cones does not depend on the detailed form of the initial condition. In two dimensions, a sputter cone is a higher-dimensional analog of an undercompressive shock. For two particularly simple choices of parameters, a sputter cone is a four-sided pyramid with rounded edges that is produced by the superposition of two orthogonal, one-dimensional undercompressive shocks.
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INTRODUCTION: Beta-lactam prophylaxis is the first-line preoperative antibiotic in open abdominal wall reconstruction. However, of the 11% patients reporting a penicillin allergy (PA), most receive second-line, non-ß-lactam prophylaxis. Previously, abdominal wall reconstruction research from our institution demonstrated increased wound complications, readmissions, and reoperations with non-ß-lactam prophylaxis. Therefore, a collaborative quality improvement initiative was developed with the infectious disease service, and a penicillin allergy protocol was instituted that stratified patients' risk of allergic reaction with a goal to increase ß-lactam prophylaxis use. The effect of the penicillin allergy protocol on open abdominal wall reconstruction outcomes was prospectively evaluated. METHODS: Patients with penicillin allergy undergoing open abdominal wall reconstruction were identified and grouped according to penicillin allergy protocol implementation. Pre-penicillin allergy protocol underwent open abdominal wall reconstruction before January 1, 2020, predominantly receiving non-ß-lactam prophylaxis; post-penicillin allergy protocol underwent open abdominal wall reconstruction between January 1, 2020-November 1, 2023, predominantly receiving ß-lactam prophylaxis. Incidence of surgical site infection was the primary outcome. Standard and inferential statistical analyses were performed. RESULTS: Of 315 patients with penicillin allergy, 250 underwent open abdominal wall reconstruction pre-penicillin allergy protocol and 65 post-penicillin allergy protocol. Pre- and post-penicillin allergy protocol were similar in allergic reaction severity history, sex, race, age, diabetes, American Society of Anesthesiologists score, hernia defect size, and mesh type (P > .05). Post-penicillin allergy protocol had lower body mass index (33.4 ± 7.9 vs 29.8 ± 5.3 kg/m2; P = .002) and fewer active smokers (12.4% vs 1.5%; P = .019). Expectedly, post-penicillin allergy protocol received more ß-lactam prophylaxis (22.8% vs 83.1%; P < .001) and no antibiotic-induced allergic reactions. Post-penicillin allergy protocol had significantly fewer surgical site infections (24.4% vs 3.1%; P < .001), wound breakdown (16.0% vs 3.1%; P = .004), reoperations (19.2% vs 0.0%; P < .001), and readmissions (25.3% vs 9.2%; P = .006) but no statistically significant reduction in recurrence (8.4% vs 1.5%; P = .057). CONCLUSIONS: The penicillin allergy protocol safely increased the number of patients with penicillin allergy undergoing open abdominal wall reconstruction receiving ß-lactam prophylaxis and decreased the rate of surgical site infections, wound complications, reoperations, and readmissions. These data supported the systemwide implementation of the penicillin allergy protocol for both general and orthopedic surgery, which has been incorporated into the electronic medical record of 13 hospitals within the system.
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Background: Internal fixation of hip fractures is associated with high reoperation rates. This study investigated the reoperation rates after internal fixation with the femoral neck system (FNS). Materials and Methods: A single-institution cohort study was conducted on patients aged 18 years or older who sustained intracapsular femoral neck fractures and underwent internal fixation with a fixed-angle implant. Surgeons, patients, and investigators were not blinded. The primary outcome was any hip reoperation at the final follow-up. Secondary outcomes were to characterize a cohort of patients regarding demographics, fracture classification, intraoperative findings, postoperative fracture complications and union rates, and postoperative pain. Results: This study found that internal fixation with FNS for intracapsular femoral neck fractures was associated with a 23% rate of revision surgery. Of the initial 94 patients who received FNS internal fixation, 44 patients were included for analysis; of those, 10 patients underwent revision surgery. Patients had a 22% rate of in-hospital medical adverse events with a 30-day readmission rate of 9%. Increasing body mass index was associated with increased revision rates (P = 0.037). Patients who sustained displaced femoral neck fractures had a significant decrease in SF-12 Mental Health Composite, SF-12 Physical Health Composite, and quality-of-life subscale scores. Conclusions: The FNS is a viable alternative for internal fixation of intracapsular femoral neck fractures. The observed rate of revision after internal fixation was comparable with previously published outcomes following fixation with cannulated screws and sliding hip screws. Level of Evidence: Level IV, Therapeutic Study.
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BACKGROUND: Clinical features and outcomes in severe aortic stenosis (AS) have been described according to the hemodynamic phenotypes. OBJECTIVES: The aim of this study was to investigate the clinical features and prognosis of patients with high-gradient (HG) AS with aortic valve area (AVA) >1.0 cm2. METHODS: A total of 3,209 patients were identified according to AVA (cm2), peak velocity (m/s), systolic mean pressure gradient (MG) (mm Hg): HG-AVA >1 = >1.0, ≥4, and ≥40, HG-AVA ≤1 = ≤1.0, ≥4, and ≥40; LG-AVA ≤1 (low-gradient) = ≤1.0, <4, and <40; moderate AS = 1.0
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Changes in specific behaviors across the lifespan are frequently reported as an inverted-U trajectory. That is, young adults exhibit optimal performance, children are conceptualized as developing systems progressing towards this ideal state, and older adulthood is characterized by performance decrements. However, not all behaviors follow this trajectory, as there are instances in which children outperform young adults. Here, we acquired data from 7-35 and >55 year-old participants and assessed potential developmental advantages in motor sequence learning and memory consolidation. Results revealed no credible evidence for differences in initial learning dynamics among age groups, but 7- to 12-year-old children exhibited smaller sequence-specific learning relative to adolescents, young adults and older adults. Interestingly, children demonstrated the greatest performance gains across the 5 h and 24 h offline periods, reflecting enhanced motor memory consolidation. These results suggest that children exhibit an advantage in the offline processing of recently learned motor sequences.
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Feral swine are invasive in the United States and a reservoir for infectious diseases. The increase in feral swine population and the geographic range are a concern for the spread of zoonotic diseases to humans and livestock. Feral swine could contribute to the spread of Coxiella burnetii, the causative agent of human Q fever. In this study, we characterized the seroprevalence of C. burnetii in feral swine populations of Hawai'i and Texas, which have low and high rates of human Q fever, respectively. Seropositivity rates were as high as 0.19% and 6.03% in Hawai'i and Texas, respectively, indicating that feral swine cannot be ruled out as a potential reservoir for disease transmission and spread. In Texas, we identified the overlap between seropositivity of feral swine and human Q fever incidence. These results indicate that there is a potentially low but detectable risk of C. burnetii exposure associated with feral swine populations in Hawai'i and Texas.
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Coxiella burnetii , Fiebre Q , Enfermedades de los Porcinos , Animales , Texas/epidemiología , Coxiella burnetii/inmunología , Coxiella burnetii/aislamiento & purificación , Coxiella burnetii/genética , Hawaii/epidemiología , Fiebre Q/epidemiología , Fiebre Q/veterinaria , Fiebre Q/microbiología , Estudios Seroepidemiológicos , Humanos , Porcinos , Enfermedades de los Porcinos/epidemiología , Enfermedades de los Porcinos/microbiología , Incidencia , Anticuerpos Antibacterianos/sangreRESUMEN
Purpose: To compare risk of problematic internet use (PIU) and importance of digital media interactions for transgender and cisgender adolescents. Methods: A nationally representative group of adolescents took an online survey that included a measure of PIU (Problematic and Risky Internet Use Screening Scale-3 [PRIUSS-3]) and technology interactions (Adolescent Digital Technology Interactions and Importance scale). We compared mean scores for these scales and their subscales and rates of positive screens for PIU for transgender and cisgender adolescents. Results: Of 4575 adolescents participating, 53 (1.2%) were transgender, nonbinary, and gender-diverse (TNG) adolescents. TNG adolescents had higher PRIUSS-3 scores and higher mean scores for importance of technology to explore identity/go outside their offline environment. Conclusions: TNG adolescents report higher PIU risk, which may relate to differences in technology importance for this group.
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For endovascular treatment of below-the-knee (BTK) peripheral artery disease (PAD), independently adjudicated real-world outcomes comparing non-stent-based balloon angioplasty (percutaneous transluminal angioplasty) and adjunctive treatments with or without a concomitant ipsilateral femoropopliteal (FP) artery intervention are scarce. A total of 1,060 patients from the multicenter XLPAD registry who underwent non-stent-based BTK PAD intervention between 2006 and 2021 were included. The primary outcome was the 1-year incidence of major adverse limb events (MALEs), a composite of all-cause death, any amputation, or clinically driven repeat revascularization. A total of 566 patients underwent BTK and 494 BTK + FP interventions; 72% were men, with a mean age of 68.4 ± 10.9 years. Diabetes mellitus was more prevalent in the BTK-only group (76.5% vs 69%, p = 0.006). Mean Rutherford class was 4.2 ± 1.18; chronic limb-threatening ischemia was more frequent in the BTK group (55.3% vs 49%, p = 0.040). Moderate to severe calcification was more frequent in the BTK + FP group (21.2% vs 27.1%, p = 0.024), as was lesion length (110.6 ± 77.3 vs 135.4 ± 86.3 mm, p <0.001). Nearly 81% of lesions were treated with percutaneous transluminal angioplasty. Drug-coated balloon (1.6% vs 14%, p <0.001) and atherectomy (38% vs 58.5%, p <0.001) use was more frequent in the BTK + FP group. The rate of procedural success was higher in the BTK + FP group (86% vs 91%, p = 0.009), with amputation being the most common complication at 3.3% within 30 days after the procedure. The rates of 1-year MALE (21.2% vs 22.3%, p = 0.675) and mortality (4.6% vs 3.4%, p = 0.3) were similar between the BTK and BTK + FP groups. Nonstent treatment for BTK PAD with concomitant FP intervention leads to high procedural success and similar rates of 1-year MALE compared with isolated BTK intervention. Condensed Abstract: The vast majority of below-the-knee (BTK) peripheral artery disease (PAD) interventions are performed with balloon angioplasty. Presence of inflow femoropopliteal PAD in patients who undergo BTK interventions can affect the outcome of the procedure. This report explores immediate procedural success and major adverse limb events at 1 year after balloon angioplasty treatment for isolated BTK PAD and in patients who underwent an additional femoropopliteal PAD intervention.
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Angioplastia de Balón , Enfermedad Arterial Periférica , Arteria Poplítea , Sistema de Registros , Humanos , Masculino , Femenino , Enfermedad Arterial Periférica/terapia , Anciano , Angioplastia de Balón/métodos , Persona de Mediana Edad , Resultado del Tratamiento , Amputación Quirúrgica , Arteria Femoral , Recuperación del MiembroRESUMEN
Our repertoire of motor skills is filled with sequential movements that need to be performed in a specific order. Here, we used functional magnetic resonance imaging to investigate whether the human hippocampus, a region known to support temporal order in non-motor memory, represents information about the order of sequential motor actions in human participants (both sexes). We also examined such representations in other regions of the motor network (i.e., the premotor cortex, supplementary motor area, anterior superior parietal lobule, and striatum) already known for their critical role in motor sequence learning. Results showed that the hippocampus represents information about movements in their learned temporal position in the sequence, but not about movements or temporal positions in random movement patterns. Other regions of the motor network coded for movements in their learned temporal position, as well as movements and positions in random movement patterns. Importantly, movement coding contributed to sequence learning patterns in primary, supplementary, and premotor cortices but not in striatal and parietal regions. Our findings deepen our understanding of how striatal and cortical regions contribute to motor sequence learning and point to the capacity of the hippocampus to represent movements in their temporal context, an ability possibly explaining its contribution to motor learning.
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Hipocampo , Aprendizaje , Imagen por Resonancia Magnética , Movimiento , Humanos , Masculino , Femenino , Hipocampo/fisiología , Hipocampo/diagnóstico por imagen , Adulto , Movimiento/fisiología , Adulto Joven , Aprendizaje/fisiología , Mapeo Encefálico , Desempeño Psicomotor/fisiología , Destreza Motora/fisiología , Procesamiento de Imagen Asistido por Computador , Aprendizaje Seriado/fisiologíaRESUMEN
Burkholderia pseudomallei (Bp) causes the tropical disease melioidosis that afflicts an estimated 165,000 people each year. Bp is a facultative intracellular pathogen that transits through distinct intracellular stages including attachment to host cells, invasion through the endocytic pathway, escape from the endosome, replication in the cytoplasm, generation of protrusions towards neighboring cells, and host cell fusion allowing Bp infection to spread without exiting the intracellular environment. We have identified a TetR-like transcriptional regulator, BP1026B_II1561, that is up-regulated during the late stages of infection as Bp protrudes toward neighboring cells. We have characterized BP1026B_II1561 and determined that it has a role in pathogenesis. A deletional mutant of BP1026B_II1561 is attenuated in RAW264.7 macrophage and BALB/c mouse models of infection. Using RNA-seq, we found that BP1026B_II1561 controls secondary metabolite biosynthesis, fatty acid degradation, and propanoate metabolism. In addition, we identified that BP1026B_II1561 directly controls expression of an outer membrane porin and genes in the shikimate biosynthetic pathway using ChIP-seq. Transposon mutants of genes within the BP1026B_II1561 regulon show defects during intracellular replication in RAW264.7 cells confirming the role of this transcriptional regulator and the pathways it controls in pathogenesis. BP1026B_II1561 also up-regulates the majority of the enzymes in shikimate and tryptophan biosynthetic pathways, suggesting their importance for Bp physiology. To investigate this, we tested fluorinated analogs of anthranilate and tryptophan, intermediates and products of the shikimate and tryptophan biosynthetic pathways, respectively, and showed inhibition of Bp growth at nanomolar concentrations. The expression of these pathways by BP1026b_II1561 and during intracellular infection combined with the inhibition of Bp growth by fluorotryptophan/anthranilate highlights these pathways as potential targets for therapeutic intervention against melioidosis. In the present study, we have identified BP1026B_II1561 as a critical transcriptional regulator for Bp pathogenesis and partially characterized its role during host cell infection.
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Hypermutated proviruses, which arise in a single HIV replication cycle when host antiviral APOBEC3 proteins introduce extensive G-to-A mutations throughout the viral genome, persist in all people living with HIV receiving antiretroviral therapy (ART). But, the within-host evolutionary origins of hypermutated sequences are incompletely understood because phylogenetic inference algorithms, which assume that mutations gradually accumulate over generations, incorrectly reconstruct their ancestor-descendant relationships. Using > 1400 longitudinal single-genome-amplified HIV env-gp120 sequences isolated from six women over a median 18 years of follow-up - including plasma HIV RNA sequences collected over a median 9 years between seroconversion and ART initiation, and > 500 proviruses isolated over a median 9 years on ART - we evaluated three approaches for removing hypermutation from nucleotide alignments. Our goals were to 1) reconstruct accurate phylogenies that can be used for molecular dating and 2) phylogenetically infer the integration dates of hypermutated proviruses persisting during ART. Two of the tested approaches (stripping all positions containing putative APOBEC3 mutations from the alignment, or replacing individual putative APOBEC3 mutations in hypermutated sequences with the ambiguous base R) consistently normalized tree topologies, eliminated erroneous clustering of hypermutated proviruses, and brought env-intact and hypermutated proviruses into comparable ranges with respect to multiple tree-based metrics. Importantly, these corrected trees produced integration date estimates for env-intact proviruses that were highly concordant with those from benchmark trees that excluded hypermutated sequences, indicating that the corrected trees can be used for molecular dating. Use of these trees to infer the integration dates of hypermutated proviruses persisting during ART revealed that these spanned a wide age range, with the oldest ones dating to shortly after infection. This indicates that hypermutated proviruses, like other provirus types, begin to be seeded into the proviral pool immediately following infection, and can persist for decades. In two of the six participants, hypermutated proviruses differed from env-intact ones in terms of their age distributions, suggesting that different provirus types decay at heterogeneous rates in some hosts. These simple approaches to reconstruct hypermutated provirus' evolutionary histories, allow insights into their in vivo origins and longevity, towards a more comprehensive understanding of HIV persistence during ART.
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PURPOSE: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC. METHODS: TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. RESULTS: At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. CONCLUSION: Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.
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Anticuerpos Monoclonales Humanizados , Camptotecina , Neoplasias Endometriales , Inmunoconjugados , Humanos , Femenino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Adulto , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/efectos adversos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Anciano de 80 o más Años , Supervivencia sin Progresión , Antígenos de Neoplasias/inmunología , Moléculas de Adhesión CelularRESUMEN
ObjectiveThis study aimed to investigate potential missed diagnoses of acute rheumatic fever and rheumatic heart disease during hospital-based care among persons subsequently identified with these conditions.MethodsThis retrospective cohort study used linked emergency department and inpatient administrative records from Queensland, Northern Territory, South Australia, and New South Wales during 2003-2018 (varying between jurisdictions by completeness of data) of all persons first identified with acute rheumatic fever or rheumatic heart disease while aged 8-24years. Using coded discharge diagnoses from the preceding 3years, we identified presentations (e.g. joint pains or heart murmur without specific identified cause) that potentially mimic and thereby represent a missed opportunity to detect acute rheumatic fever or rheumatic heart disease. Sociodemographic factors associated with experiencing ≥1 mimic diagnoses were investigated using multivariable logistic regression models.ResultsAmong 1855 persons, 65 (3.5%) (using narrow diagnostic inclusions) and 146 (7.9%) (with broad inclusions) experienced ≥1 mimic diagnosis. Joint disorders predominated. Mimics categorised as 'high-likelihood' (most specific) were more frequent among persons subsequently diagnosed as young adults (18-24years) than as children (8-12years) (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.34-4.47), and those from low-risk ethnic groups (including Australian-born non-Indigenous persons) compared with Aboriginal and Torres Strait Islander peoples (OR 2.44, 95% CI 1.02-5.85).ConclusionMissed opportunities to detect acute rheumatic fever and rheumatic heart disease continue to occur in Australian hospitals, and present disproportionately among persons from demographic groups considered to be at low risk, suggesting the need for enhanced clinical suspicion in these groups.
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Comprehensive molecular characterization and effective therapy in a rare case of metastatic renal oncocytoma.
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Adenoma Oxifílico , Neoplasias Renales , Humanos , Persona de Mediana Edad , Adenoma Oxifílico/secundario , Adenoma Oxifílico/patología , Adenoma Oxifílico/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Metástasis de la NeoplasiaRESUMEN
Alpha-synuclein seed amplification assays (αSyn-SAAs) have emerged as promising diagnostic tools for Parkinson's disease (PD) by detecting misfolded αSyn and amplifying the signal through cyclic shaking and resting in vitro. Recently, our group and others have shown that multiple biospecimens, including CSF, skin, and submandibular glands (SMGs), can be used to seed the aggregation reaction and robustly distinguish between patients with PD and non-disease controls. The ultrasensitivity of the assay affords the ability to detect minute quantities of αSyn in peripheral tissues, but it also produces various technical challenges of variability. To address the problem of variability, we present a high-yield αSyn protein purification protocol for the efficient production of monomers with a low propensity for self-aggregation. We expressed wild-type αSyn in BL21 Escherichia coli, lysed the cells using osmotic shock, and isolated αSyn using acid precipitation and fast protein liquid chromatography (FPLC). Following purification, we optimized the ionic strength of the reaction buffer to distinguish the fluorescence maximum (Fmax) separation between disease and healthy control tissues for enhanced assay performance. Our protein purification protocol yielded high quantities of αSyn (average: 68.7 mg/mL per 1 L of culture) and showed highly precise and robust αSyn-SAA results using brain, skin, and SMGs with inter-lab validation.