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1.
Front Physiol ; 15: 1371096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694206

RESUMO

Introduction: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions. Method: Age-matched Gramd1c +/+ and Gramd1c -/- mice were fed either low (0.02%, wt/wt) or high (0.2%, wt/wt) dietarycholesterol and levels of sterol-derived metabolites were assessed in the feces, liver, and plasma. Results: Compared to wild type controls (Gramd1c +/+) mice, mice lackingGramd1c (Gramd1c -/-) have no significant alterations in fecal, liver, or plasma cholesterol. Given the potential role for Aster C in modulating cholesterol metabolism in diverse tissues, we quantified levels of cholesterol metabolites such as bile acids, oxysterols, and steroid hormones. Compared to Gramd1c +/+ controls, Gramd1c -/- mice had modestly reduced levels of select bile acid species and elevated cortisol levels, only under low dietary cholesterol conditions. However, the vast majority of bile acids, oxysterols, and steroid hormones were unaltered in Gramd1c -/- mice. Bulk RNA sequencing in the liver showed that Gramd1c -/- mice did not exhibit alterations in sterol-sensitive genes, but instead showed altered expression of genes in major urinary protein and cytochrome P450 (CYP) families only under low dietary cholesterol conditions. Discussion: Collectively, these data indicate nominal effects of Aster-C on whole body cholesterol transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38758390

RESUMO

PURPOSE: Little is known about the optimal analgesia regimen after HTO. Thus, this study systematically reviewed the literature on clinical and patient-reported outcomes of pain management strategies for patients after HTO. METHODS: A comprehensive search of the PubMed, Cochrane CENTRAL, and CINAHL databases was conducted from inception through September 2023. Studies were included if they evaluated pain reduction with analgesia strategies after HTO and were excluded if they did not report pain control outcomes. RESULTS: Five studies with 217 patients were included. Patients with a multimodal intraoperative injection cocktail to the knee, femoral nerve block (FNB), or adductor canal block (ACB) for HTO had significant improvement in visual analog scale (VAS) and numerical rating scale (NRS) scores in the first 12 h postoperatively compared to controls. Patients on duloxetine had significantly lower NRS scores at 1, 7, and 14 days postoperatively and significantly lower nonsteroidal anti-inflammatory drug (NSAID) usage throughout the two-week postoperative period than the control group. Patients receiving an ACB had significantly lower opioid consumption than controls at 12 h postoperative. In patients with an FNB or ACB, no significant difference in quadriceps strength or time to straight leg raise postoperatively was observed compared to controls. CONCLUSION: A multimodal periarticular injection cocktail, FNB, or an ACB effectively reduces pain on the first day after HTO, with an ACB able to reduce opioid consumption on the first postoperative day. Duloxetine combined with an ACB effectively decreases pain for two weeks postoperatively while reducing NSAID consumption in patients after HTO. LEVEL OF EVIDENCE: IV.

3.
Innovation (Camb) ; 5(4): 100612, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38756954

RESUMO

Environmental pollution is escalating due to rapid global development that often prioritizes human needs over planetary health. Despite global efforts to mitigate legacy pollutants, the continuous introduction of new substances remains a major threat to both people and the planet. In response, global initiatives are focusing on risk assessment and regulation of emerging contaminants, as demonstrated by the ongoing efforts to establish the UN's Intergovernmental Science-Policy Panel on Chemicals, Waste, and Pollution Prevention. This review identifies the sources and impacts of emerging contaminants on planetary health, emphasizing the importance of adopting a One Health approach. Strategies for monitoring and addressing these pollutants are discussed, underscoring the need for robust and socially equitable environmental policies at both regional and international levels. Urgent actions are needed to transition toward sustainable pollution management practices to safeguard our planet for future generations.

4.
Ambio ; 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38795283

RESUMO

Globally, climate warming is increasing air temperatures and changing river flows, but few studies have explicitly considered the consequences for lake temperatures of these dual effects, or the potential to manage lake inflows to mitigate climate warming impacts. Using a one-dimensional model, we tested the sensitivity of lake temperatures to the separate and interacting effects of changes in air temperature and inflow on a small, short-residence time (annual average ≈ 20 days), temperate lake. Reducing inflow by 70% increased summer lake surface temperatures 1.0-1.2 °C and water column stability by 11-19%, equivalent to the effect of 1.2 °C air temperature warming. Conversely, similar increases in inflow could result in lake summer cooling, sufficient to mitigate 0.75 °C air temperature rise, increasing to more than 1.1 °C if inflow temperature does not rise. We discuss how altering lake inflow volume and temperature could be added to the suite of adaptation measures for lakes.

5.
Surg Endosc ; 38(6): 3470-3477, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38769187

RESUMO

BACKGROUND: Soilage of the surgical endoscope occurs frequently during minimally invasive surgery. The resultant impairment of visualization of the surgical field compromises patient safety, prolongs operative times, and frustrates surgeons. The standard practice for cleaning the surgical camera involves a disruption in the conduct of surgery by completely removing the endoscope from the field, manually cleaning its lens, treating it with a surfactant, and reinserting it into the patient; after which the surgeon resumes the procedure. METHODS: We developed an automated solution for in vivo endoscope cleaning in minimally invasive surgery- a port that detects the position of the endoscope in its distal lumen, and precisely and automatically delivers a pressurized mist of cleaning solution to the lens of the camera. No additions to the scope and minimal user interaction with the port are required. We tested the efficacy of this troCarWash™ device in a porcine model of laparoscopy. Four board-certified general surgeons were instructed to soil and then clean the laparoscope using the device. Representative pre- and post-clean images were exported from the surgical video and clarity was graded (1) digitally by a canny edge detection algorithm, and (2) subjectively by 3 blinded, unbiased observers using a semi-quantitative scale. RESULTS: We observed statistically significant improvements in clarity by each method and for each surgeon, and we noted significant correlation between digital and subjective scores. CONCLUSION: Based on these data, we conclude that the troCarWash™ effectively restored impaired visualization in a large animal model of laparoscopy.


Assuntos
Laparoscopia , Laparoscopia/métodos , Laparoscopia/instrumentação , Animais , Suínos , Laparoscópios , Contaminação de Equipamentos/prevenção & controle , Desenho de Equipamento
6.
J Am Chem Soc ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38743719

RESUMO

Electrocatalytic water oxidation is a key transformation in many strategies designed to harness solar energy and store it as chemical fuels. Understanding the mechanism(s) of the best electrocatalysts for water oxidation has been a fundamental chemical challenge for decades. Here, we quantitate evolved dioxygen isotopologue composition via gas-phase EPR spectroscopy to elucidate the mechanisms of water oxidation on metal oxide electrocatalysts with high precision. Isotope fractionation is paired with computational and kinetic modeling, showing that this technique is sensitive enough to differentiate O-O bond-forming steps. Strong agreement between experiment and theory indicates that for the nickel-iron layered double hydroxide─one of the best earth-abundant electrocatalysts to be studied─water oxidation proceeds via a dioxo coupling mechanism to form a side-bound peroxide rather than a hydroxide attack to form an end-bound peroxide.

7.
J Clin Invest ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38743922

RESUMO

Recently developed anti-migraine therapeutics targeting calcitonin gene-related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin (NTG)-mediated chronic migraine exhibit reduced pain and light avoidance compared to NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared to cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1)-interacting CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial (VE)-cadherin rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-Cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice, but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLVs-immune interactions and reduces CSF efflux.

8.
Cureus ; 16(3): e57109, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38681455

RESUMO

While Ewing sarcoma is traditionally a malignant tumor of bone, it may uncommonly present extra-skeletally, leading to an array of puzzling presentations depending on the tissue involved. Here, we describe the case of a 66-year-old man who presented to the primary care office for evaluation of intermittent melena. He ultimately underwent capsule endoscopy and developed a secondary small bowel obstruction, unveiling his neoplasm. The tumor was then resected and managed with surveillance only, and the patient remains without evidence of disease after four years of follow-up.

9.
bioRxiv ; 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38659798

RESUMO

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation. We have determined a sequential binding mechanism for modulation of -1A bulged 5'SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged a -1A bulged 5'SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam is a ribonucleoprotein, not RNA duplex alone, targeting drug whose action depends on fundamental properties of 5'SS recognition.

10.
J Am Acad Orthop Surg ; 32(11): e558-e567, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38669669

RESUMO

INTRODUCTION: The purpose of this study was to determine how variations in lower limb alignment affect tibiofemoral joint contact biomechanics in the setting of medial meniscus posterior root tear (MMPRT) and associated root repair. METHODS: A finite-element model of an intact knee joint was developed. Limb alignments ranging from 4° valgus to 8° varus were simulated under a 1,000 N compression load applied to the femoral head. For the intact, MMPRT, and root repair conditions, the peak contact pressure (PCP), total contact area, mean and maximum local contact pressure (LCP) elevation, and total area of LCP elevation of the medial tibiofemoral compartment were quantified. RESULTS: The PCP and total contact area of the medial compartment in the intact knee increased from 2.43 MPa and 361 mm 2 at 4° valgus to 9.09 MPa and 508 mm 2 at 8° of varus. Compared with the intact state, in the MMPRT condition, medial compartment PCP was greater and the total contact area smaller for all alignment conditions. Root repair roughly restored PCPs in the medial compartment; however, this ability was compromised in knees with increasing varus alignment. Specifically, elevations in PCP relative to the intact state increased with increasing varus, as did the total contact area with LCP elevation. After root repair, medial compartment PCP remained elevated above the intact state at all degrees tested, ranging from 0.05 MPa at 4° valgus to 0.27 MPa at 8° of varus, with overall PCP values increasing from 2.48 to 9.09 MPa. For varus alignment greater than 4°, root repair failed to reduce the total contact area with LCP elevation relative to the MMPRT state. DISCUSSION: Greater PCPs and areas of LCP elevation in varus knees may reduce the clinical effectiveness of root repair in delaying or preventing the development of tibiofemoral osteoarthritis.


Assuntos
Análise de Elementos Finitos , Articulação do Joelho , Meniscos Tibiais , Lesões do Menisco Tibial , Humanos , Fenômenos Biomecânicos , Lesões do Menisco Tibial/cirurgia , Lesões do Menisco Tibial/fisiopatologia , Articulação do Joelho/fisiopatologia , Articulação do Joelho/cirurgia , Meniscos Tibiais/cirurgia , Meniscos Tibiais/fisiopatologia , Tíbia/cirurgia , Extremidade Inferior/fisiopatologia , Extremidade Inferior/cirurgia , Fêmur/cirurgia , Articulação Tibiofemoral
11.
Brain Res ; 1837: 148951, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38642789

RESUMO

Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, using 3-, 12- and 18- month-old APP/PS1 mice and age matched WT littermates, we conducted a series of memory tests, measured synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters in the hippocampus and prefrontal cortex (PFC). Our results showed impaired recognition and long-term spatial memory in 18-month-old WT mice and impaired recognition, short-term working, and long-term spatial reference memory in 12-and 18- month-old APP/PS1 mice. These memory impairments are associated with changes of synapse-related gene (nr2a, glur1, glur2, psd95) expression, HDAC abundance, and H3K9ac levels; more specifically, increased HDAC2 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, increased HDAC3 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest memory impairments in aging and AD may associated with a differential HDAC modulation of synapse-related gene expression in the brain.

12.
Orthop J Sports Med ; 12(4): 23259671241237289, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38617886

RESUMO

Background: Surfing is an increasingly popular sport with a high propensity for both traumatic and atraumatic injuries. Purpose: To analyze the trends, etiologies, and diagnoses of lower extremity orthopaedic-related surfing injuries presenting to United States (US) emergency departments (EDs) within a 21-year study period. Study Design: Descriptive epidemiology study. Methods: The National Electronic Injury Surveillance System database was queried for data on lower extremity surfing injuries presenting to US EDs from January 1 to December 31, 2022. Data collected included year, injury mechanism, injury location, diagnosis, and disposition. The raw data were used to calculate national estimates (NEs) based on each hospital's assigned statistical sample weight. Linear regressions were performed to analyze annual trends. Results: A total of 776 lower extremity surfing injuries were included (NE = 49,218 injuries). The mean age of the patients was 29.4 ± 13.6 years. The most common injured areas were the foot (NE = 17,411; 35.4%), lower leg (NE = 8673, 17.6%), and knee (NE = 8139; 16.5%). The most common mechanism of injury was impact with board (NE = 17,144; 34.8%), and the most common fracture locations were the lower leg (NE = 1195; 29.5%), ankle (NE = 1594; 24.5%), and foot (NE = 1495; 23.0%). There were statistically significant decreases in weighted estimates for lower extremity surfing injuries by 108 per year (P < .001), for lacerations by 76 per year (P < .001), and for sprains by 18 per year (P = .01). Impact-with-board injuries decreased by 59 injuries per year (P < .001) and constituted 63.5% of lacerations and 12.1% of fractures. Only 3.9% of patients were admitted for hospitalization. Conclusion: There was a decreasing trend in lower extremity surfing injuries presenting to US EDs during the 21-year study period.

13.
BMJ Open Qual ; 13(2)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589054

RESUMO

INTRODUCTION: Effective communication in the operating room (OR) is crucial. Addressing a colleague by their name is respectful, humanising, entrusting and associated with improved clinical outcomes. We aimed to enhance team communication in the perioperative environment by offering personalised surgical caps labelled with name and provider role to all OR team members at a large academic medical centre. MATERIALS AND METHODS: This was a quasi-experimental, uncontrolled, before-and-after quality improvement study. A survey regarding perceptions of team communication, knowledge of names and roles, communication barriers, and culture was administered before and after cap delivery. Survey results were measured on a 5-point Likert Scale; descriptive statistics and mean scores were compared. All cause National Surgical Quality Improvement Project (NSQIP) morbidity and mortality outcomes for surgical specialties were examined. RESULTS: 1420 caps were delivered across the institution. Mean survey scores increased for knowing the names and roles of providers around the OR, feeling that people know my name and feeling comfortable communicating without barriers across disciplines. The mean score for team communication around the OR is excellent was unchanged. The highest score both before and after was knowing the name of an interdisciplinary team member is important for patient care. A total of 383 and 212 providers participated in the study before and after cap delivery, respectively. Participants agreed or strongly agreed that labelled surgical caps made it easier to talk to colleagues (64.9%) while improving communication (66.0%), team culture (60.5%) and patient care (56.8%). No significant differences were noted in NSQIP outcomes. CONCLUSIONS: Personalised labelled surgical caps are a simple, inexpensive tool that demonstrates promise in improving perioperative team communication. Creating highly reliable surgical teams with optimal communication channels requires a multifaceted approach with engaged leadership, empowered front-line providers and an institutional commitment to continuous process improvement.


Assuntos
Beluga , Salas Cirúrgicas , Humanos , Animais , Comunicação , Centros Médicos Acadêmicos , Complicações Pós-Operatórias
14.
Materials (Basel) ; 17(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38591376

RESUMO

We investigate the transmittance spectrum of a multichannel filter composed of dielectric (A) and plasma (P) materials in the microwave region within the transfer matrix formalism. Two configurations of the proposed filter are studied under the influence of an applied magnetic field: (1) a periodic structure containing (A/P)N unit cells surrounded by air and (2) the introduction of a second dielectric material (D) acting as a defect layer to produce an (AP)N/2/D/(AP)N/2 structure. Our findings reveal that in the periodic case, the number of resonant states of the transmittance increases with number N; however, the observed blue and red shifts depend on the intensity and orientation of the applied magnetic field. We present contour plots of the transmission coefficients that show the effect of the incident angle on the shifts of the photonic band gaps. Furthermore, we find that the introduction of a defect layer generates additional resonant states and merges the central resonant peak into a miniband of resonances. Moreover, we show that the number of resonant peaks and their locations can be modulated by increasing the unit cell number, N, as well as increasing the width of the inserted defect layer. Our proposed structures enable the design of novel photonic filters using magnetized plasma materials operating in the microwave region.

15.
Am J Sports Med ; : 3635465241233161, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622858

RESUMO

BACKGROUND: Rehabilitation after anterior cruciate ligament ACL reconstruction (ACLR) is crucial for safe return to play (RTP) and reducing the chances of a reinjury. Yet, there is no consensus on the ideal functional tests to assess rehabilitation progress in soccer players after ACLR. PURPOSE: The primary objective was to highlight the existing gap in the literature concerning the most effective standardized rehabilitation protocols and testing for facilitating successful RTP among soccer players. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review using PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. Inclusion criteria encompassed original studies (level of evidence 1-4) that examined rehabilitation protocols, metrics of knee rehabilitation, and clinical outcomes after ACLR in soccer players. RESULTS: This review incorporated 23 studies, predominantly retrospective case series, with a total number of 874 soccer players who underwent ACLR and rehabiliation. 5 (21.7%) studies utilized an accelerated rehabilitation protocol, while 7 (30.4%) of studies utilized a criterion-based rehabilitation. A wide heterogeneity of data was extracted including functional tests of rehabilitation and RTP such as strength test batteries, hop test batteries, and movement quality assessments. Of the 23 selected studies, 2 (8.7%) used all 3 test batteries, 8 (34.8%) used 2 test batteries, 12 (52.2%) used 1 test battery, and 1 (4.3%) used 0 of the test batteries. The mean time between surgery and RTP ranged from 3 to 8 months with only 2 (8.7%) studies reporting complications after ACLR. Lastly, out of the total studies examined, 9 (39.1%) assessed patient-reported outcome measures (PROMs), all of which demonstrated significant improvement from the initial assessment to the final follow up. CONCLUSION: Soccer-specific rehabilitation after ACLR lacks standardization. Even though many studies have assessed protocols for optimal RTP and reduced secondary ACL injuries, there is a gap in the literature regarding the most effective protocols and RTP testing. The methodology reported by Kyritsis et al could serve as a foundation for future prospective randomized multicenter studies to establish a standard rehabilitation protocol and enable a successful return to soccer.

16.
Shoulder Elbow ; 16(2): 119-128, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38655412

RESUMO

Background: A total shoulder arthroplasty (TSA) system utilizing an inlay glenoid component has been proposed as a means of reducing glenoid component loosening while still providing patients with desirable functional and clinical outcomes. The purpose of this study was to systematically review current outcomes literature on TSA using an inlay glenoid component. Methods: A literature search was conducted using PubMed/MEDLINE, Cochrane Database of Systematic Reviews, and Web of Science databases. Studies comparing pre- and postoperative functional and clinical outcomes were included. Results: Five studies with 148 shoulders (133 patients) were included. Patient-reported outcomes improved, including the American Shoulder and Elbow Surgeons score (mean change 34.1 to 80.6), Penn Shoulder Score (mean change 43.3 to 85.5), Single Assessment Numeric Evaluation score (mean change 34.1 to 80.6), and visual analog scale-pain (mean change 6.9 to 1.6). Range of motion improved for forward elevation (mean change 109.6 to 156.2) and external rotation (mean change 21.5 to 50.8). Glenoid component loosening occurred in one shoulder (0.68%). Two revision surgeries (1.35%) were performed. Discussion: The use of an inlay glenoid component is associated with improvements in postoperative pain, function, and satisfaction while minimizing rates of glenoid component loosening and the need for revision surgery over short-term follow-up. Level of evidence: systematic review, level IV.

17.
Biomed Mater Eng ; 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38669519

RESUMO

BACKGROUND: Wearing protective helmets is an important prevention strategy to reduce work-related traumatic brain injuries. The existing standardized testing systems are used for quality control and do not provide a quantitative measure of the helmet performance. OBJECTIVE: To analyze the failure characterizations of Type I industrial helmets and develop a generalized approach to quantify the shock absorption performance of Type I industrial helmets based on the existing standardized setups. METHODS: A representative basic Type I construction helmet model was selected for the study. Top impact tests were performed on the helmets at different drop heights using two different impactor masses (3.6 and 5.0 kg). RESULTS: When the helmets were impacted with potential impact energies smaller than the critical potential impact energy values, there was a consistent relationship between the peak impact force and the potential impact energy. When the helmets were impacted under potential impact energies greater than the critical potential impact energy values, the peak impact forces increased steeply with increasing potential impact energy. CONCLUSION: A concept of safety margin for construction helmets based on potential impact energy was introduced to quantify the helmets' shock absorption performance. The proposed method will help helmet manufacturers improve their product quality.

18.
bioRxiv ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38562904

RESUMO

Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.

19.
Sci Adv ; 10(14): eadk5949, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578991

RESUMO

The transplantation of engineered cells that secrete therapeutic proteins presents a promising method for addressing a range of chronic diseases. However, hydrogels used to encase and protect non-autologous cells from immune rejection often suffer from poor mechanical properties, insufficient oxygenation, and fibrotic encapsulation. Here, we introduce a composite encapsulation system comprising an oxygen-permeable silicone cryogel skeleton, a hydrogel matrix, and a fibrosis-resistant polymer coating. Cryogel skeletons enhance the fracture toughness of conventional alginate hydrogels by 23-fold and oxygen diffusion by 2.8-fold, effectively mitigating both implant fracture and hypoxia of encapsulated cells. Composite implants containing xenogeneic cells engineered to secrete erythropoietin significantly outperform unsupported alginate implants in therapeutic delivery over 8 weeks in immunocompetent mice. By improving mechanical resiliency and sustaining denser cell populations, silicone cryogel skeletons enable more durable and miniaturized therapeutic implants.


Assuntos
Criogéis , Hidrogéis , Camundongos , Animais , Silicones , Alginatos , Oxigênio , Esqueleto , Sobrevivência Celular
20.
Shoulder Elbow ; 16(1): 76-84, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38435033

RESUMO

Background: The objective of this study was to retrospectively report on the outcomes of female patients undergoing the Latarjet procedure. Methods: Female patients undergoing the Latarjet procedure with minimum 1 year follow-up were identified and contacted to obtain Numeric Pain Rating Scale (NPRS), Subjective Shoulder Value (SSV), and return to sport (RTS) data. Eligible females were then matched 1:1 with a male counterpart based on laterality and age (± 3 years), and outcomes compared. Results: A total of 20 female patients with a mean follow-up of 73.8 months reported postoperative NPRS and SSV scores of 2.2 ± 2.3 and 69.3 ± 22.0, respectively. Of the nine athletes, 3 (33%) reported a successful RTS at a mean of 9 months. Four patients (20.0%) required reoperation at a mean of 27.1 months. The matched analysis demonstrated similar NPRS scores between male and female patients and a trend towards lower SSV scores and rates of RTS. Conclusion: At mid-term follow-up female patients reported pain levels similar to female-specific literature reports, but overall low subjective shoulder function and RTS. Compared to propensity-matched males, females reported similar levels of pain, lower shoulder function, and lower rates of RTS, however, differences did not reach statistical significance. Level of Evidence: IV, retrospective case series.

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