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1.
J Biol Chem ; : 107702, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39173948

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B*39:06, B*39:01, and B*38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B*39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B*39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B*39:06 by only two amino acids. HLA-B*38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B*39:06 and B*39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B*39:06 and B*39:01 provided an explanation for the distinct peptide C-terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B*38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B*39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding.

2.
Sci Rep ; 14(1): 18688, 2024 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-39134635

RESUMO

While the simultaneous degradation of muscle composition and postural stability in aging are independently highly investigated due to their association with fall risk, the interplay between the two has received little attention. Thus, the purpose of this study is to explore how age-related changes in muscle composition relate to postural stability. To that aim, we collected posturography measures and ultrasound images of the dominant Vastus Lateralis and Biceps Brachii from 32 young (18-35 year old) and 34 older (65-85 year old) participants. Muscle properties were quantified with echo-intensity and texture-based metrics derived from gray-level co-occurrence matrix analysis, and postural stability with the variability of the center of pressure during bipedal stance tasks. Ultrasound parameters revealed that young muscle possessed lower echo-intensity and higher homogeneity compared to the elderly. Echo-intensity and muscle thickness, and several texture-based parameters possessed outstanding young versus older classification performance. A canonical correlation analysis demonstrated a significant relationship between ultrasound and postural measures only within the young group (r = 0.53, p < 0.002), where those with 'better' muscle composition displayed larger postural sways. Our results indicate that, in older individuals, postural stability and muscle composition, two common fall risk factors, are unrelated. In view of this decoupling, both may contribute independently to fall risk. Furthermore, our data support the view that texture-based parameters provide a robust alternative to echo-intensity in providing markers of muscle composition.


Assuntos
Envelhecimento , Músculo Esquelético , Equilíbrio Postural , Ultrassonografia , Humanos , Idoso , Equilíbrio Postural/fisiologia , Ultrassonografia/métodos , Adulto , Masculino , Idoso de 80 Anos ou mais , Feminino , Envelhecimento/fisiologia , Adulto Jovem , Músculo Esquelético/fisiologia , Músculo Esquelético/diagnóstico por imagem , Adolescente , Acidentes por Quedas
3.
J Imaging Inform Med ; 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164451

RESUMO

In this study, we present a method based on Monte Carlo Dropout (MCD) as Bayesian neural network (BNN) approximation for confidence-aware severity classification of lung diseases in COVID-19 patients using chest X-rays (CXRs). Trained and tested on 1208 CXRs from Hospital 1 in the USA, the model categorizes severity into four levels (i.e., normal, mild, moderate, and severe) based on lung consolidation and opacity. Severity labels, determined by the median consensus of five radiologists, serve as the reference standard. The model's performance is internally validated against evaluations from an additional radiologist and two residents that were excluded from the median. The performance of the model is further evaluated on additional internal and external datasets comprising 2200 CXRs from the same hospital and 1300 CXRs from Hospital 2 in South Korea. The model achieves an average area under the curve (AUC) of 0.94 ± 0.01 across all classes in the primary dataset, surpassing human readers in each severity class and achieves a higher Kendall correlation coefficient (KCC) of 0.80 ± 0.03. The performance of the model is consistent across varied datasets, highlighting its generalization. A key aspect of the model is its predictive uncertainty (PU), which is inversely related to the level of agreement among radiologists, particularly in mild and moderate cases. The study concludes that the model outperforms human readers in severity assessment and maintains consistent accuracy across diverse datasets. Its ability to provide confidence measures in predictions is pivotal for potential clinical use, underscoring the BNN's role in enhancing diagnostic precision in lung disease analysis through CXR.

4.
Neurosci Bull ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39120643

RESUMO

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

6.
Sci Data ; 11(1): 881, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39143100

RESUMO

Large-extent maps of three-dimensional vegetation structure are important for understanding the hydrologic cycle, climate, carbon fluxes, and habitat. We aggregated over 7 billion lidar shots from the Global Ecosystem Dynamics Investigation (GEDI) to produce analysis-ready, gridded rasters of 36 vegetation structure metrics at three spatial resolutions (1, 6, and 12 km). We used 8 statistics to grid shots in every pixel, specifically the mean, bootstrapped standard error of the mean, median, standard deviation, interquartile range, Shannon's Diversity Index, and shot count. We quantified uncertainty of the mean by randomly selecting 100 subsets of shots (i.e. bootstrapping) within each pixel. We also assessed the accuracy of several gridded metrics using fine spatial resolution airborne laser scanning data. The gridded metrics are generally more accurate at mid latitudes due to higher shot density and lower density of vegetation. Statistics associated with the central or maximum tendency of a metric are more accurate than statistics related to variability of metric values within the pixel.

7.
Geriatr Orthop Surg Rehabil ; 15: 21514593241273312, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144450

RESUMO

Introduction: A minority of geriatric hip fracture patients pursue non-operative treatment. Compared with surgical patients, non-operative patients have higher mortality rates. However, patient satisfaction following non-operative vs operative treatment has not been investigated extensively. The purpose of this study was to compare satisfaction among non-operatively vs operatively treated hip fracture patients. Methods: We identified patients aged 60+ years with proximal femur fractures treated over a 10-year period. Excluded were patients with isolated greater/lesser trochanteric fractures. Patients or relatives were asked to complete a 6-question survey about their treatment satisfaction. Results: Survey responses from 56 operative and 28 non-operative patients were recorded. Overall, 91.1% of operative and 82.1% of non-operative patients were satisfied with their treatment course (P = 0.260). However, only 71.4% of non-operative patients were satisfied with treatment option explanations vs 83.9% of operative patients (P = 0.014). While only 64.3% of non-operative respondents were satisfied with the ultimate treatment outcome (vs 85.7% of operative patients, P = 0.025), 89.3% of patients in each cohort would choose the same treatment plan again. Discussion: Our findings highlight the complexity of defining patient satisfaction, particularly in a geriatric hip fracture population. Unlike previous studies, we chose a direct approach to quantifying patient satisfaction by asking participants specifically about satisfaction with treatment outcome and the overall treatment course. Additional survey questions were then included to assess factors considered important in treatment satisfaction, such as health care provider treatment explanations, post-treatment mobility, and palliative care service involvement. Conclusions: We identified significant differences between non-operatively and operatively treated geriatric hip fracture patients regarding satisfaction with the explanation of treatment options, and ultimate treatment outcomes. There was no significant difference in overall satisfaction with the treatment course or likelihood of choosing the same treatment again. Further research investigating patient satisfaction following geriatric hip fracture treatment is warranted.

8.
Lancet Glob Health ; 12(9): e1485-e1497, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39151983

RESUMO

BACKGROUND: Streptococcus pneumoniae has been estimated to cause 9·18 million cases of pneumococcal pneumonia, meningitis, and invasive non-pneumonia non-meningitis disease and 318 000 deaths among children younger than 5 years in 2015. We estimated the potential impact and cost-effectiveness of pneumococcal conjugate vaccine (PCV) introduction. METHODS: We updated our existing pseudodynamic model to estimate the impact of 13-valent PCV (PCV13) in 112 low-income and middle-income countries by adapting our previously published pseudodynamic model with new country-specific evidence on vaccine coverage, burden, and post-introduction vaccine impact from WHO-UNICEF estimates of national immunisation coverage and a global burden study. Deaths, disability-adjusted life-years (DALYs), and cases averted were estimated for children younger than 5 years born between 2000 and 2030. We used specific PCV coverage in each country and a hypothetical scenario in which coverage increased to diphtheria-tetanus-pertussis (DTP) levels. We conducted probabilistic uncertainty analyses. FINDINGS: Using specific vaccine coverage in countries, we estimated that PCV13 could prevent 697 000 (95% credibility interval 359 000-1 040 000) deaths, 46·0 (24·0-68·9) million DALYs, and 131 (89·0-172) million cases in 112 countries between 2000 and 2030. PCV was estimated to prevent 5·3% of pneumococcal deaths in children younger than 5 years during 2000-30. The incremental cost of vaccination would be I$851 (510-1530) per DALY averted. If PCV coverage were increased to DTP coverage in 2020, PCV13 could prevent an additional 146 000 (75 500-219 000) deaths. INTERPRETATION: The inclusion of real-world evidence from lower-income settings revealed that delays in PCV roll-out globally and low PCV coverage have cost many lives. Countries with delays in vaccine introduction or low vaccine coverage have experienced many PCV-preventable deaths. These findings underscore the importance of rapidly scaling up PCV to achieve high coverage and maximise vaccine impact. FUNDING: Bill & Melinda Gates Foundation and Gavi, the Vaccine Alliance.


Assuntos
Análise Custo-Benefício , Países em Desenvolvimento , Infecções Pneumocócicas , Vacinas Pneumocócicas , Vacinas Conjugadas , Humanos , Vacinas Pneumocócicas/economia , Vacinas Pneumocócicas/administração & dosagem , Lactente , Pré-Escolar , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/economia , Infecções Pneumocócicas/epidemiologia , Vacinas Conjugadas/economia , Vacinas Conjugadas/administração & dosagem
9.
J Environ Radioact ; 278: 107503, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39088872

RESUMO

Americium-241 whole body and internal biokinetics were experimentally investigated in the euryhaline diamond sturgeon Acipenser gueldenstaedtii during its uptake from water and food, in fresh (FW) and brackish water (BW; 9 psu). Whole-body uptake rates of 241Am from water and subsequent depuration rates were quantified over 14 and 28 days, respectively, and assimilation efficiency (AE) of 241Am from diet (chironomid) was determined over 28 days. FW reduced the biological half-life of 241Am following aqueous uptake by an order of magnitude. In contrast BW greatly reduced 241Am assimilation efficiency (AE) from diet (chironomid) by several orders of magnitude (from an AE of 8.5% (FW) down to 0.003% (BW)). Hence, salinity per se is indicated as a major environmental variable in determining the radiological exposure of A. gueldenstaedtii to 241Am. During aqueous exposure BW appreciably increased 241Am activity concentrations in most body components, but aqueous or dietary exposure pathway at either salinity did not determine marked differences in how 241Am was distributed among six body components. The highly mineralized skin of A. gueldenstaedtii recurred as a major repository of 241Am in all experimental treatments, as high as 50% among body components, due to its internal transfer from diet, surface adsorption and/or active absorption from water. The indicated prominence of the aqueous, compared to the dietary, exposure pathway for 241Am accumulation by A. gueldenstaedtii suggests its radiological exposure would be enhanced by BW as it leads to its greater long-term retention, due to a much longer biological half-life.


Assuntos
Amerício , Peixes , Poluentes Radioativos da Água , Animais , Peixes/metabolismo , Poluentes Radioativos da Água/metabolismo , Amerício/farmacocinética , Monitoramento de Radiação
10.
Org Lett ; 26(32): 6872-6877, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39102356

RESUMO

A peptide-catalyzed enantioselective oxidation of sulfides to yield pharmaceutically relevant chiral sulfoxides is reported. Experimental evidence suggesting that a hydrogen bond-donating moiety must be present in the substrate to achieve high levels of enantioinduction is supported by computational modeling of transition states. These models also indicate that dual points of contact between the peptidic catalyst and substrate are likely responsible for the formation of one desired sulfoxide in 94:6 er.


Assuntos
Ácido Aspártico , Oxirredução , Peptídeos , Sulfetos , Sulfóxidos , Catálise , Estereoisomerismo , Peptídeos/química , Peptídeos/síntese química , Sulfetos/química , Ácido Aspártico/química , Sulfóxidos/química , Estrutura Molecular , Ligação de Hidrogênio
11.
NPJ Microgravity ; 10(1): 86, 2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39152140

RESUMO

Test subjects were assessed in a partial gravity environment during parabolic flight while they performed mission-critical activities that challenged their balance and locomotion. These functional activities included rising from a seated position and walking, jumping down, recovering from falls, and maintaining an upright stance. Twelve volunteers were tested during 10 parabolas that produced 0.25×g, 0.5×g, or 0.75×g, and at 1×g during level flight intervals between parabolas. Additionally, 14 other subjects were tested using identical procedures in a 1×g laboratory setting. Partial gravity altered the performance of settling after standing and navigating around obstacles. As gravity levels decreased, the time required to stand up, settle, walk, and negotiate obstacles, and the number of falls increased. Information obtained from these tests will allow space agencies to assess the vestibular, sensorimotor, and cardiovascular risks associated with different levels of partial gravity.

12.
Artigo em Inglês | MEDLINE | ID: mdl-39161931

RESUMO

Background: The current literature shows similar clinical outcomes between first metatarsophalangeal (MTP) joint arthrodesis and synthetic cartilage implant (SCI) hemiarthroplasty in the treatment of hallux rigidus; however, prior studies have not reported validated patient-reported outcome measures (PROMs). To our knowledge, this is the first study to compare PROMs using 6 domains of the validated Patient-Reported Outcomes Measurement Information System (PROMIS) in patients treated for hallux rigidus with MTP joint arthrodesis and with SCI hemiarthroplasty. In addition, this novel study provides comparative data on the complication and revision rates for each procedure. Methods: A single-center, retrospective registry search identified all patients with preoperative PROMIS scores who underwent MTP joint arthrodesis or SCI hemiarthroplasty for hallux rigidus between February 2016 and June 2021. The study aimed to determine if the 2 procedures showed statistically or clinically equivalent PROMIS scores in 6 domains: physical function, pain interference, pain intensity, global physical health, global mental health, and depression. A multivariable linear regression analysis was performed to compare adjusted 1-year postoperative PROMIS scores between the 2 cohorts. Complication and revision rates were also compared. Results: The study included 82 patients who underwent SCI hemiarthroplasty and 101 who underwent MTP joint arthrodesis. Demographic data and preoperative hallux rigidus severity showed no significant differences between the cohorts. PROMIS scores were mostly comparable between the 2 groups, except for the pain intensity domain. The patients who underwent MTP joint arthrodesis exhibited significantly better pain relief at 1 and 2 years postoperatively, which was supported by adjusted postoperative PROMIS scores. At 2 years, the SCI group had worse pain intensity scores and lower global physical health scores. There were no differences between the cohorts in additional PROMIS scores or complication data. Conclusions: While outcomes in most of the domains were similar, MTP joint arthrodesis was more effective at mitigating pain intensity compared with SCI hemiarthroplasty. This information can guide patient counseling and decision-making when considering surgical intervention for hallux rigidus. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

14.
Eur Spine J ; 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39103615

RESUMO

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: CCS is the most common type of incomplete spinal cord injury and can occur without or with bony injury. Surgical intervention and its timing for patients diagnosed with CCS has been controversial. The current study assessed utilization of and factors associated with operative intervention and its timing in patients diagnosed with central cord syndrome (CCS) in the absence of bony injury. METHODS: Adult patients diagnosed with CCS in the absence of vertebral fracture were queried from the national, multi-insurance, administrative 2015-2020 M151 PearlDiver database. The incidence, trends, and timing of operative intervention following CCS were assessed. Patient characteristics associated with surgical intervention and its timing were determined. RESULTS: From 2015 to 2020, 11,653 patients meeting inclusion criteria were identified, of which surgical intervention was identified for 2,003 (17.2%) and thus nonsurgical intervention for 9,650 (82.8%). The proportion of patients undergoing operative intervention evolved from 11.5% in 2015 to 19.7% in 2020 (p < 0.0001). Of those undergoing surgical intervention, the greatest increase was seen for those undergoing surgery within two days of diagnosis (5.5% in 2015 to 12.3% in 2020, p < 0.0001). On multivariable analysis, more recent year of service, region of service, younger age, and higher comorbidity burden were independent predictors of operative management (p < 0.05 for all). CONCLUSION: The majority of a large cohort of patients with first diagnosis CCS in the absence of bony injury were managed non-operatively. Operative management increased over the years of study, were performed earlier after diagnosis, and varied based on patient characteristic and geographic region.

15.
J Vasc Interv Radiol ; 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39142515

RESUMO

PURPOSE: To assess the technical feasibility and safety of image-guided percutaneous biphasic monopolar pulsed electric field (PEF) ablation of primary and metastatic tumors. METHODS AND METHODS: With IRB approval and HIPAA compliance, this retrospective, single-institution study cohort of 17 patients (mean age: 53.5 years, range: 20 - 94 years) with overall progressive disease underwent 26 PEF ablation procedures for 30 metastatic (90%) and primary (10%) target lesions in the thorax (n=20), abdomen (n=7), and head and neck (n=3). Concurrent systemic therapy was used in 14/17 patients (82%). Follow-up imaging was scheduled for 1, 3, and 6 months after PEF ablation, and target and off-target lesion sizes were recorded. The overall response was assessed by the RECIST 1.1 criteria with imaging immediately before PEF serving as baseline. Adverse events (AEs) were determined by the Society of Interventional Radiology classification. RESULTS: PEF ablation procedures were well tolerated and technically feasible for all 17 of 17 patients. The mean initial size of the target and off-target tumors were 2.6±1.5 cm (range: 0.4 - 6.9cm) and 2.2±1.1 cm (range: 1.0 - 5.2cm), respectively. Overall, 15/30 (50%) target lesions and 12/24 (50%) off-target lesions were unchanged or decreased in size at the patient's last follow-up. Eight patients had overall stable disease (47%) at the last follow-up. There were nine mild (9/26, 35%) and one moderate (1/26, 4%) AE. CONCLUSION: All PEF procedures were technically feasible with one moderate AE and stable disease for 47% of patients with a median follow-up period of three months.

16.
Ann Am Thorac Soc ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39137349

RESUMO

RATIONALE: The factors that lead to poor pulmonary exacerbation (PEx) outcomes in individuals with cystic fibrosis (CF) are still being investigated; however, delayed diagnosis and treatment are likely contributory. Identifying individuals at imminent risk of PEx could enable closer monitoring and/or earlier initiation of therapies to improve outcomes. OBJECTIVE: The goal of this study was to develop blood-based biomarkers that associate with imminent PEx risk in CF individuals. METHODS: We examined the whole blood transcriptome and 55 inflammatory proteins from plasma and serum on 72 blood samples from 53 CF individuals. Biomarker candidate genes and proteins were selected from 14 CF individuals with paired stable and PEx visits (Cohort 1). The biomarker candidates were then estimated and tested to classify CF individuals who would experience a PEx within 4-months of a stable clinic visit or not (Cohort 2). RESULTS: A 16-gene panel and 9-protein panel were identified that could distinguish paired stable and PEx visits (AUC = 0.83 ± SE 0.28 and AUC = 0.92 ± SE 0.18, respectively). These two panels also demonstrated strong performance in classifying CF individuals who would experience a PEx within 4 months of a clinically stable visit or not (16-gene panel: AUC = 0.88; 9-protein panel: AUC = 0.83). In comparison, serum calprotectin and clinical variables (i.e. sex, ppFEV1, and the number of IV antibiotics in the preceding year) had AUCs of 0.75 and 0.71, respectively. CONCLUSION: Blood-based mRNA and protein biomarkers demonstrated strong performance in classifying CF individuals at risk of imminent PEx. If the findings from this study can be validated, there is the potential to use blood biomarkers to enable more personalized disease activity monitoring in CF.

17.
Acta Biomater ; 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39111679

RESUMO

Bioresorbable shape memory polymers (SMP) are an emerging class of polymers that can help address several challenges associated with minimally invasive surgery by providing a solution for structural tissue repair. Like most synthetic polymer networks, SMPs require additional biorelevance and modification for biomedical applications. Methodologies used to incorporate bioactive ligands must preserve SMP thermomechanics and ensure biofunctionality following in vivo delivery. We have previously described the development of a novel thermoresponsive bioresorbable SMP, poly (glycerol dodecanedioate) (PGD). In this study, cell-adhesive peptide sequences RGD and YIGSR were conjugated with PGD. We investigated 1) the impact of conjugated peptides on the fixity (Rf), recovery (Rr), and recovery rate (dRr/dT), 2) the impact of conjugated peptides on cell binding, and 3) the impact of the shape memory cycle (Tprog) on conjugated peptide functionality towards binding human bone marrow stromal cells (BMSC). Peptide conjugation conditions impact fixity but not the recovery or recovery rate (p < 0.01). Peptide-conjugated substrates increased cell attachment and proliferation compared with controls (p < 0.001). Using complementary integrin binding cell-adhesive peptides increased proliferation compared with using single peptides (p < 0.05). Peptides bound to PGD substrates exhibited specificity to their respective integrin targets. Following the shape memory cycle, peptides maintained functionality and specificity depending on the shape memory cycle conditions (p < 0.001). The dissipation of strain energy during recovery can drive differential arrangement of conjugated sequences impacting functionality, an important design consideration for functionalized SMPs. STATEMENT OF SIGNIFICANCE: Shape memory elastomers are an emerging class of polymers that are well-suited for minimally invasive repair of soft tissues. Tissue engineering approaches commonly utilize biodegradable scaffolds to deliver instructive cues, including cells and bioactive signals. Delivering these instructive cues on biodegradable shape memory elastomers requires modification with bioactive ligands. Furthermore, it is necessary to ensure the specificity of the ligands to their biological targets when conjugated to the polymer. Moreover, the bioactive ligand functionality must be conserved after completing the shape memory cycle, for applications in tissue engineering.

18.
Artigo em Inglês | MEDLINE | ID: mdl-39131815

RESUMO

In the field of tissue engineering, 3D printed shape memory polymers (SMPs) are drawing increased interest. Understanding how these 3D printed SMPs degrade is critical for their use in the clinic, as small changes in material properties can significantly change how they behave after in vivo implantation. Degradation of 3D printed acrylated poly(glycerol-dodecanedioate) (APGD) was examined via in vitro hydrolytic, enzymatic, and in vivo subcutaneous implantation assays. Three APGD manufacturing modalities were assessed to determine differences in degradation. Material extrusion samples showed significantly larger mass and volume loss at 2 months, compared to lasercut and vat photopolymerization samples, under both enzymatic and in vivo degradation. Critically, melt transition temperatures of degraded PGD increased over time in vitro, but not in vivo. Histology of tissue surrounding APGD implants showed no significant signs of inflammation compared to controls, providing a promising outlook for use of 3D printed APGD devices in the clinic.

19.
Sci Adv ; 10(31): eadn7979, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093975

RESUMO

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.


Assuntos
Biofilmes , Testes de Sensibilidade Microbiana , Piridonas , Infecções dos Tecidos Moles , Infecções Estreptocócicas , Streptococcus pyogenes , Streptococcus pyogenes/efeitos dos fármacos , Animais , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Biofilmes/efeitos dos fármacos , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/microbiologia , Camundongos , Piridonas/farmacologia , Piridonas/química , Antibacterianos/farmacologia , Antibacterianos/química , Modelos Animais de Doenças , Tiazóis/farmacologia , Tiazóis/química , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia , Feminino , Cicatrização/efeitos dos fármacos , Humanos
20.
Foot Ankle Orthop ; 9(3): 24730114241266843, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39091403

RESUMO

Background: Hallux valgus deformity affects more than 35% of people aged ≥65 years. Surgical correction in this population can be more complicated because of poor bone quality, worse deformity, and postoperative recovery challenges. The purpose of this study was to compare the radiographic and clinical outcomes of patients aged ≥65 years who underwent either open Lapidus or minimally invasive chevron Akin osteotomy for bunion correction. Methods: A retrospective review identified 62 patients aged ≥65 years who were treated surgically for hallux valgus with at least 1-year postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores (physical function and pain interference). Preoperative and at least 6-month postoperative radiographs were measured for the hallux valgus angle and intermetatarsal angle. PROMIS scores were obtained preoperatively and at 1 and/or 2 years postoperatively. Differences in demographic, clinical, and radiographic outcomes were assessed using the Mann Whitney U test and P values were adjusted for a false discovery rate of 5%. Results: There was no difference between the MIS and open cohorts in pre- or postoperative radiographic measurements or clinical outcomes at any time point. At 1 year postoperatively, both groups had statistically significant improvements in the PROMIS pain interference domain but only the MIS group had a statistically significant improvement in the PROMIS physical function domain. Clinical significance was equivocal. At 2 years postoperatively, there were clinically and statistically significant improvements in the PROMIS pain interference and physical function domains for the open and MIS groups. Conclusion: Patients in both surgical groups had improvement in radiographic measurements and 2-year PROMIS scores, although there was no clinical or statistical difference found between groups. MIS and open surgical techniques appear to be safe and effective in correcting hallux valgus in older patients; however, patients may need to be counseled that maximum improvement after surgery may take more than 1 year. Level of Evidence: Level III, retrospective cohort study.

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