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2.
Acad Psychiatry ; 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39158780

RESUMEN

OBJECTIVE: This article details a novel intervention for teaching psychiatric interviewing techniques implemented at McGovern Medical School at UTHealth Houston. METHODS: Forty medical students played the newly developed educational game Psychobabble to enhance their assessment of auditory hallucinations. Pre-session and post-session surveys assessed students' inquiry methods, competence, training relevance, and exercise efficacy. Paired t-tests compared pre-session and post-session data. Qualitative analysis identified emergent themes from participant comments. RESULTS: There was an average increase of 12.11 questions between the estimated number of questions (mean = 9.57; SD = 6.00) and the actual number of questions formulated during the game (mean = 21.68; SD = 5.40; p < 0.01). There was a significant increase from the pre-session (mean = 1.82; SD = 0.97) to the post-session (mean = 3.72; SD = 0.76) self-reported competence levels, which more than doubled on average (p < 0.01). CONCLUSION: The themes that emerged from the qualitative data demonstrate that Psychobabble encourages creativity, broadens assessment methods, has educational significance for learners, and may ultimately lead to improved patient care by enhancing the understanding and diagnosis of psychiatric symptomatology. Medical schools and residency training programs should consider incorporating educational games such as Psychobabble to enhance the interviewing techniques of trainees and their self-efficacy in these skills.

4.
Infection ; 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39117931

RESUMEN

PURPOSE: Sepsis causes significant worldwide morbidity and mortality. Inability to clear an infection and secondary infections are known complications in severe sepsis and likely result in worsened outcomes. We sought to characterize risk factors of these complications. METHODS: We performed a secondary analysis of clinical data from 401 subjects enrolled in the PHENOtyping sepsis-induced Multiple organ failure Study. We examined factors associated with prolonged infection, defined as infection that continued to be identified 7 days or more from initial identification, and secondary infection, defined as new infections identified ≥ 3 days from presentation. Multivariable adjustment was performed to examine laboratory markers of immune depression, with immunocompromised and immunocompetent subjects analyzed separately. RESULTS: Illness severity, immunocompromised status, invasive procedures, and site of infection were associated with secondary infection and/or prolonged infection. Persistent lymphopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL twice in the first five days, and persistent neutropenia, defined as absolute neutrophil count (ANC) < 1000 cells/µL twice in the first five days, were associated with secondary and prolonged infections. When adjusted in multivariable analysis, persistent lymphopenia remained associated with secondary infection in both immunocompromised (aOR = 14.19, 95% CI [2.69, 262.22] and immunocompetent subjects (aOR = 2.09, 95% CI [1.03, 4.17]). Persistent neutropenia was independently associated with secondary infection in immunocompromised subjects (aOR = 5.34, 95% CI [1.92, 15.84]). Secondary and prolonged infections were associated with worse outcomes, including death. CONCLUSIONS: Laboratory markers of immune suppression can be used to predict secondary infection. Lymphopenia is an independent risk factor in immunocompromised and immunocompetent patients for secondary infection.

5.
J Soc Cardiovasc Angiogr Interv ; 3(7): 102143, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39131994

RESUMEN

Background: We aimed to perform a meta-analysis of randomized trials comparing long-term outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) for severe aortic stenosis. The short-term efficacy and safety of TAVR are proven, but long-term outcomes are unclear. Methods: We included randomized controlled trials comparing TAVR vs SAVR at the longest available follow-up. The primary end point was death or disabling stroke. Secondary end points were all-cause mortality, cardiac mortality, stroke, pacemaker implantation, valve thrombosis, valve gradients, and moderate-to-severe paravalvular leaks. The study is registered with PROSPERO (CRD42023481856). Results: Seven trials (N = 7785 patients) were included. Weighted mean trial follow-up was 5.76 ± 0.073 years. Overall, no significant difference in death or disabling stroke was observed with TAVR vs SAVR (HR, 1.02; 95% CI, 0.93-1.11; P = .70). Mortality risks were similar. TAVR resulted in higher pacemaker implantation and moderate-to-severe paravalvular leaks compared to SAVR. Results were consistent across different surgical risk profiles. As compared to SAVR, self-expanding TAVR had lower death or stroke risk (P interaction = .06), valve thrombosis (P interaction = .06), and valve gradients (P interaction < .01) but higher pacemaker implantation rates than balloon-expandable TAVR (P interaction < .01). Conclusions: In severe aortic stenosis, the long-term mortality or disabling stroke risk of TAVR is similar to SAVR, but with higher risk of pacemaker implantation, especially with self-expanding valves. As compared with SAVR, the relative reduction in death or stroke risk and valve thrombosis was greater with self-expanding than with balloon-expandable valves.

6.
J Am Chem Soc ; 146(31): 21250-21256, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39052841

RESUMEN

Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski ß-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.


Asunto(s)
Diterpenos , Diterpenos/síntesis química , Diterpenos/química , Estereoisomerismo , Productos Biológicos/síntesis química , Productos Biológicos/química , Estructura Molecular , Reacción de Cicloadición , Alquilación
7.
iScience ; 27(7): 110265, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39027368

RESUMEN

Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.

8.
Ther Adv Rare Dis ; 5: 26330040241265411, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39070094

RESUMEN

Tuberous sclerosis complex (TSC) is a genetic disease leading to malformations, or tubers, in the cerebral cortex and growth of tumors, most frequently in the brain, heart, kidneys, skin, and lungs. Changes in the brain caused by TSC usually have the biggest negative impact on quality of life. Approximately 85% of individuals with TSC have epilepsy, and TSC-associated neuropsychiatric disorders (TAND) affect nearly all individuals with TSC in some way. TSC Alliance's research strategy is built upon both funding and catalyzing research. Through grants, the organization provides funding directly to researchers through a competitive application process. The organization has also built a set of resources available to researchers worldwide, including a Natural History Database, Biosample Repository, and Preclinical Consortium. These resources catalyze research because they are available to qualified academic or industry researchers around the world, enabling an almost unlimited number of scientists to access data and resources to enable and accelerate research on TSC. This research strategy continues to be shaped by the needs and priorities of the TSC community, working toward a future where everyone affected by TSC can live their fullest lives.


The role of the TSC Alliance in advancing therapy development: a patient organization perspective Finding a new treatment for any disease is a long and expensive process, and it can be even more challenging for a rare disease such as tuberous sclerosis complex (TSC). To encourage research on TSC and speed up the process developing new treatments, the TSC Alliance established a research strategy based upon the priorities of people living with TSC. TSC community members best know how the disease negatively affects their lives. Equally importantly, the TSC community is a necessary partner for any researcher or company who wants to bring forward a potential new treatment. The TSC Alliance awards research grants to individual researchers who are at early stages of their careers. We also collaborate with many researchers and healthcare providers, and with the TSC community, to build shared resources. These resources include data from medical records and biological samples, such as blood and tissue samples, which are shared with researchers around the world for a wide range of projects related to TSC. We also collaborate with researchers from academic laboratories and the pharmaceutical or biotech industry to test potential new drugs or other therapies in animals, which is required before new therapies can be tested in humans. Before and during human testing in clinical trials, we help researchers design a trial that is both meaningful to the TSC community and not overly burdensome to participants. As new therapies become available, the TSC Alliance educates the TSC community and advocates for patient access to new therapies. Over time, as more is learned about how best to monitor and treat people with TSC, the organization convenes a conference of TSC experts to update clinical consensus guidelines to guide improved treatment of this rare disease.

9.
J Psychoactive Drugs ; : 1-12, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38961638

RESUMEN

Sexualized drug use (SDU) describes drug-facilitated sexual enhancement, and chemsex is an SDU subculture involving the use of specific drugs by men who have sex with men (MSM). This study aimed to identify research trends, foci, and themes within the SDU and chemsex-specific literature. The Web of Science Core Collection was searched with a list of SDU synonyms. All SDU-related articles were analyzed using the R package, bibliometrix. Full text review identified chemsex-specific records, and text was extracted verbatim for content analysis in Leximancer. The search returned 1,866 unique records. A total of 521 addressed SDU, and 301 papers specifically addressed chemsex. The small but growing SDU literature primarily addressed consensual encounters between MSM, and drug-facilitated assault experienced by women, in Western settings. Little attention was given to transgender communities or consensual SDU in cisgender heterosexual individuals. The literature primarily viewed SDU through a public health lens, specifically focusing on the risk conferred to sexual health.The SDU and chemsex-specific literature are potentially limited in scope and may inadequately capture the geographical, demographic, and cultural diversity of these phenomena. Future research should address the myriad social and health implications of SDU and chemsex participation across all relevant communities and settings.

10.
Crit Care ; 28(1): 242, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39010134

RESUMEN

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.


Asunto(s)
Bradicardia , Reanimación Cardiopulmonar , Epinefrina , Humanos , Epinefrina/administración & dosificación , Epinefrina/uso terapéutico , Reanimación Cardiopulmonar/métodos , Reanimación Cardiopulmonar/estadística & datos numéricos , Masculino , Femenino , Bradicardia/tratamiento farmacológico , Bradicardia/terapia , Preescolar , Niño , Lactante , Adolescente , Unidades de Cuidados Intensivos/estadística & datos numéricos , Unidades de Cuidados Intensivos/organización & administración
11.
Acc Chem Res ; 57(14): 1931-1940, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-38920276

RESUMEN

ConspectusRh2L4 catalysts have risen in popularity in the world of organic synthesis, being used to accomplish a variety of reactions, including C-H insertion and cyclopropanation, and often doing so with high levels of stereocontrol. While the mechanisms and origins of selectivity for such reactions have been examined with computational quantum chemistry for decades, only recently have detailed pictures of the dynamic behavior of reacting Rh2L4-complexed molecules become accessible. Our computational studies on Rh2L4 catalyzed reactions are described here, with a focus on C-H insertion reactions of Rh2L4-carbenes. Several issues complicate the modeling of these reactions, each providing an opportunity for greater understanding and each revealing issues that should be incorporated into future rational design efforts. First, the fundamental mechanism of C-H insertion is discussed. While early quantum chemical studies pointed to transition structures with 3-center [C-H-C] substructures and asynchronous hydride transfer/C-C bond formation, recent examples of reactions with particularly flat potential energy surfaces and even discrete zwitterionic intermediates have been found. These reactions are associated with systems bearing π-donating groups at the site of hydride transfer, allowing for an intermediate with a carbocation substructure at that site to be selectively stabilized. Second, the possible importance of solvent coordination at the Rh atom distal to the carbene is discussed. While effects on reactivity and selectivity were found to be small, they turn out not to be negligible in some cases. Third, it is shown that, in contrast to many other transition metal promoted reactions, many Rh2L4 catalyzed reactions likely involve dissociation of the Rh2L4 catalyst before key chemical steps leading to products. When to expect dissociation is associated with specific features of substrates and the product-forming reactions in question. Often, dissociation precedes transition structures for pericyclic reactions that involve electrons that would otherwise bind to Rh2L4. Finally, the importance of nonstatistical dynamic effects, characterized through ab initio molecular dynamics studies, in some Rh2L4 catalyzed reactions is discussed. These are reactions where transition structures are shown to be followed by flat regions, very shallow minima, and/or pathways that bifurcate, all allowing for trajectories from a single transition state to form multiple different products. The likelihood of encountering such a situation is shown to be associated again with the likelihood of formation of zwitterionic structures along reaction paths, but ones for which pathways to multiple products are expected to be associated with very low or no barriers. The connection between these features and reduced yields of desired products are highlighted, as are the means by which some Rh2L4 catalysts modulate dynamic behavior to produce particular products in high yield.

12.
Ann Vasc Surg ; 106: 369-376, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38823478

RESUMEN

BACKGROUND: Fenestrated endovascular aortic aneurysm repair (FEVAR) has been widely applied for the treatment of pararenal (PAA) and thoracoabdominal aortic aneurysms (TAAA). If custom-made devices or off-the-shelf devices are not available, physician-modified endografts (PMEGs) are an alternative device option. Several different endograft platforms have been used for PMEG; however, minimal data exists on utilizing the Terumo TREO abdominal stent graft system in this setting. The purpose of this study was to evaluate our single-center experience treating PAA and TAAA, with a physician-modified FEVAR, using the Terumo TREO platform. METHODS: A prospective database of consecutive patients with PAA and TAAA treated at a single center, with a FEVAR, utilizing a PMEG device between March 2021 and September 2023 was queried for those having a Terumo TREO device implanted. The demographics, operative details, and postoperative complications were analyzed. The rates of technical success, type I or III endoleak, branch vessel status, reintervention, and 2-year survival were also assessed. RESULTS: Of the 153 patients who underwent FEVAR with a PMEG device during the study period, 100 had repair using a Terumo TREO stent graft. The mean age of the cohort was 73.7 ± 7.0 years with the majority suffering from hypertension (n = 94, 94%), coronary artery disease (n = 51, 51%), and chronic obstructive pulmonary disease (n = 40, 40%). Thirty-four patients (34%) had a prior failed EVAR device in place. The mean aneurysm size was 66.0 ± 13.7 mm, with 58 (50%) patients classified as PAA and 30 (30%) patients as an extent IV TAAA. Six (6%) patients presented with symptomatic/ruptured aneurysms. The average number of target arteries incorporated per patient was 3.8 ± 0.6. The overall technical success was 99%, procedure time was 218 ± 116 min, contrast volume was 82 ± 21 mL, and cumulative air kerma was 3,054 ± 1,560 mGy. Postoperative complications were present in 20 patients (20%), and 2 patients (2%) died within 30 days. Rates of type I or III endoleak, branch vessel stenosis or occlusion, and reintervention were 2%, 1%, and 7%, respectively. The two-year overall survival was 87%. CONCLUSIONS: Treatment of PAA and the extent IV TAAA using a physician-modified fenestrated Terumo TREO endograft is safe and effective. This large, early experience using the Terumo TREO platform supports preferential use of this device in this setting due to the device design and low likelihood of type I or III endoleak.


Asunto(s)
Aneurisma de la Aorta Toracoabdominal , Reparación Endovascular de Aneurismas , Complicaciones Posoperatorias , Diseño de Prótesis , Stents , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aneurisma de la Aorta Toracoabdominal/diagnóstico por imagen , Aneurisma de la Aorta Toracoabdominal/mortalidad , Aneurisma de la Aorta Toracoabdominal/cirugía , Prótesis Vascular , Bases de Datos Factuales , Reparación Endovascular de Aneurismas/efectos adversos , Reparación Endovascular de Aneurismas/instrumentación , Reparación Endovascular de Aneurismas/mortalidad , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
13.
Methods Enzymol ; 699: 231-263, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38942505

RESUMEN

Terpenes are a diverse class of natural products which have long been sought after for their chemical properties as medicine, perfumes, and for food flavoring. Computational docking studies of terpene mechanisms have been a challenge due to the lack of strong directing groups which many docking programs rely on. In this chapter, we dive into our computational method Terdockin (Terpene-Docking) as a successful methodology in modeling terpene synthase mechanisms. This method could also be used as inspiration for any multi-ligand docking project.


Asunto(s)
Transferasas Alquil y Aril , Dominio Catalítico , Simulación del Acoplamiento Molecular , Terpenos , Simulación del Acoplamiento Molecular/métodos , Transferasas Alquil y Aril/química , Transferasas Alquil y Aril/metabolismo , Terpenos/química , Terpenos/metabolismo , Ligandos
14.
Org Lett ; 26(26): 5441-5446, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38900922

RESUMEN

A new reaction mechanism for the construction of dioxabicyclo[4.2.1]nonanone skeletons via a cation cascade has been proposed and examined by DFT and ab initio computations. This mechanism features the following steps: (1) intramolecular Friedel-Crafts-type cyclization with a methyl oxocarbenium cation formed by carboxylate disconnection, (2) electron-rich aromatic ring assisted methoxide loss followed by lactone formation, and (3) stepwise dyotropic rearrangement resulting in skeletal isomerization from a dioxabicyclo[3.2.2]nonanone to the dioxabicyclo[4.2.1]nonanone product observed experimentally. The high regioselectivity and driving force for the overall rearrangement were rationalized, and Lewis and Brønsted acid mediated reactivities were compared.

15.
J Org Chem ; 89(13): 9187-9197, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38904985

RESUMEN

Selective functionalization of the indole-C3-C bond with aromatic/heteroaromatic 1,2-diketones has been uncovered for the first time. Cobalt catalyst was found to be an effective catalyst for this unusual transformation. This ipso-C-C bond functionalization occurred in the presence of easily available weakly coordinating groups such as ketone and ester. One of the salient features of this methodology is the in situ generation of water from hexafluoro-2-propanol which acts as a reactant for the removal of the pivaloyl/ester group in a deacylative manner. The plausible mechanism has been supported by DFT calculations. Moreover, photophysical studies show the potential utility of indole-C3-acyloin and indolo-fused carbazole, which could be used in photovoltaic and optoelectronic application.

16.
Beilstein J Org Chem ; 20: 1320-1326, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38887579

RESUMEN

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

17.
NPJ Vaccines ; 9(1): 99, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38839821

RESUMEN

Vaccination has proven to be a valuable tool to combat SARS-CoV-2. However, reports of rare adverse reactions such as thrombosis/thrombocytopenia syndrome after ChAdOx1 nCoV-19 vaccination have caused scientific, public and media concern. ChAdOx1 was vectorised from the Y25 chimpanzee adenovirus, which was selected due to low human seroprevalence to circumvent pre-existing immunity. In this study, we aimed to explore patterns of T-cell activation after SARS-CoV-2 COVID-19 vaccine exposure in vitro using PBMCs collected from pre-pandemic ChAdOx1 nCoV-19 naïve healthy donors (HDs), and ChAdOx1 nCoV-19 and Pfizer vaccinated controls. PBMCs were assessed for T-cell proliferation using the lymphocyte transformation test (LTT) following exposure to SARS-CoV-2 COVID-19 vaccines. Cytokine analysis was performed via intracellular cytokine staining, ELISpot assay and LEGENDplex immunoassays. T-cell assays performed in pre-pandemic vaccine naïve HDs, revealed widespread lymphocyte stimulation after exposure to ChAdOx1 nCoV-19 (95%), ChAdOx-spike (90%) and the Ad26.COV2. S vaccine, but not on exposure to the BNT162b2 vaccine. ICS analysis demonstrated that CD4+ CD45RO+ memory T-cells are activated by ChAdOx1 nCoV-19 in vaccine naïve HDs. Cytometric immunoassays showed ChAdOx1 nCoV-19 exposure was associated with the release of proinflammatory and cytotoxic molecules, such as IFN-γ, IL-6, perforin, granzyme B and FasL. These studies demonstrate a ubiquitous T-cell response to ChAdOx1 nCoV-19 and Ad26.COV2. S in HDs recruited prior to the SARS-CoV-2 pandemic, with T-cell stimulation also identified in vaccinated controls. This may be due to underlying T-cell cross-reactivity with prevalent human adenoviruses and further study will be needed to identify T-cell epitopes involved.

18.
Chem Res Toxicol ; 37(7): 1086-1103, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38912648

RESUMEN

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.


Asunto(s)
Interacciones Farmacológicas , Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología
19.
Hum Mov Sci ; 96: 103243, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38870744

RESUMEN

Mediolateral gait stability can be maintained by coordinating our foot placement with respect to the center-of-mass (CoM) kinematic state. Neurological impairments can reduce the degree of foot placement control. For individuals with such impairments, interventions that could improve foot placement control could thus contribute to improved gait stability. In this study we aimed to better understand two potential interventions, by investigating their effect in neurologically intact individuals. The degree of foot placement control can be quantified based on a foot placement model, in which the CoM position and velocity during swing predict subsequent foot placement. Previously, perturbing foot placement with a force-field resulted in an enhanced degree of foot placement control as an after-effect. Moreover, timed muscle vibration enhanced the degree of foot placement control whilst the vibration was applied. Here, we replicated these two findings and further investigated whether Q1) timed muscle vibration leads to an after-effect and Q2) whether combining timed muscle vibration with force-field perturbations leads to a larger after-effect, as compared to force-field perturbations only. In addition, we evaluated several potential contributors to the degree of foot placement control, by considering foot placement errors, CoM variability and the CoM position gain (ßpos) of the foot placement model, next to the R2 measure as the degree of foot placement control. Timed muscle vibration led to a higher degree of foot placement control as an after-effect (Q1). However, combining timed muscle vibration and force-field perturbations did not lead to a larger after-effect, as compared to following force-field perturbations only (Q2). Furthermore, we showed that the improved degree of foot placement control following force-field perturbations and during/following muscle vibration, did not reflect diminished foot placement errors. Rather, participants demonstrated a stronger active response (higher ßpos) as well as higher CoM variability.


Asunto(s)
Pie , Marcha , Músculo Esquelético , Equilibrio Postural , Vibración , Humanos , Marcha/fisiología , Masculino , Pie/fisiología , Fenómenos Biomecánicos/fisiología , Músculo Esquelético/fisiología , Adulto , Femenino , Equilibrio Postural/fisiología , Adulto Joven
20.
J Endovasc Ther ; : 15266028241249571, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38721860

RESUMEN

PURPOSE: This study aims to explore the feasibility and effectiveness of a unilateral transfemoral access endovascular salvage technique for complex abdominal aortic aneurysms with concurrent type Ia and Ib endoleaks following previous endovascular repair. CASE REPORT: A 69-year-old female with multiple comorbidities presented with an extent IV thoracoabdominal aortic aneurysm complicated by type Ia and Ib endoleaks and chronically occluded left iliac endoprosthesis after prior endovascular repair. Given the patient's medical complexities, open explant repair was deemed high risk. The case was successfully managed using a physician-modified fenestrated/branched endograft (PM-F/BEVAR) and an iliac branch device (IBD) deployed through a single percutaneous transfemoral access. CONCLUSION: The presented case demonstrates the safety and efficacy of PM-F/BEVAR with concomitant IBD deployment via unilateral transfemoral access. This innovative approach allows endovascular salvage in cases with restricted iliofemoral access and avoids the complexities associated with upper extremity or aortic arch manipulation. While acknowledging the technical challenges, this technique offers a viable alternative for salvaging failed endovascular repairs, emphasizing the importance of real-time modifications in achieving successful outcomes. Further studies and long-term follow-up are warranted to validate the broader applicability and durability of this approach in the management of complex abdominal aortic aneurysms with multiple endoleaks. CLINICAL IMPACT: Although not the conventional approach, unilateral transfemoral access can be utilized to implant either a physician-modified fenestrated aortic endograft or an iliac branch device. Such an approach avoids complicating issues related to upper extremity access. This innovative technique may be necessary when there is a failed prior EVAR in the setting of significant contralateral iliofemoral occlusive disease. Doing both procedures in the same setting to resolve a type Ia and Ib endoleak is feasible as demonstrated in this case report. Expanding the endovascular armamentarium to address EVAR failure will be increasingly useful in the future, especially given the morbidity profile of EVAR explantation.

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