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1.
Int J Inj Contr Saf Promot ; : 1-3, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38982954

RESUMEN

The aim of this work is to analyze trends in youth transportation fatalities and injuries in North Carolina (NC), assess the implementation of ignition interlock devices (IIDs) in the United States and abroad, discuss policy implications for IIDs, and highlight health equity considerations related to motor vehicle collisions (MVCs). MVCs cause the highest number of unintentional injury-related deaths for children and teenagers in NC, and policymakers should pay special attention to MVCs related to alcohol consumption. IIDs are effective in reducing collision rates and recidivism for driving under the influence of alcohol (DUI). Ignition interlock device requirements have been increasingly implemented globally over the past three decades. However, the adoption of stricter IID policies after first-time DUI offenses in NC and across the U.S. is a prudent public health measure to enhance transportation safety for both adults and children. Evidence-based interventions such as IIDs must also strive to address inequities in transportation safety, and the framing of proposed policies should reflect the tenets of cultural humility.

2.
Pathog Dis ; 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39043447

RESUMEN

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection globally. Antibiotic treatment is highly effective, but infection is often asymptomatic resulting in most individuals going undetected and untreated. This untreated infection can ascend to the upper female genital tract to cause pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. Chlamydia screening and treatment programs have failed to control this epidemic and demonstrate the need for an efficacious vaccine to prevent transmission and disease. Animal models and human epidemiological data reveal that natural immunity can provide partial or short-lived sterilizing immunity. These data further demonstrate the importance of eliciting IFNγ-producing CD4 T cells (Th1 and Th1/17 cells) that can likely synergize with antibody-mediated opsonophagocytosis to provide optimal protection. These studies have guided preclinical rational vaccine design for decades and the first Phase 1 clinical trials have recently been completed. Recent advances have led to improvements in vaccine platforms and clinically safe adjuvants that help provide a path forward. This review describes vaccine models, correlates of immunity, antigen and adjuvant selection, and future clinical testing for Chlamydia vaccine development.

3.
Nat Commun ; 15(1): 6421, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39080316

RESUMEN

The rodent-borne Andes virus (ANDV) causes a severe disease in humans. We developed an ANDV mRNA vaccine based on the M segment of the viral genome, either with regular uridine (U-mRNA) or N1-methylpseudouridine (m1Ψ-mRNA). Female mice immunized by m1Ψ-mRNA developed slightly greater germinal center (GC) responses than U-mRNA-immunized mice. Single cell RNA and BCR sequencing of the GC B cells revealed similar levels of activation, except an additional cluster of cells exhibiting interferon response in animals vaccinated with U-mRNA but not m1Ψ-mRNA. Similar immunoglobulin class-switching and somatic hypermutations were observed in response to the vaccines. Female Syrian hamsters were immunized via a prime-boost regimen with two doses of each vaccine. The titers of glycoprotein-binding antibodies were greater for U-mRNA construct than for m1Ψ-mRNA construct; however, the titers of ANDV-neutralizing antibodies were similar. Vaccinated animals were challenged with a lethal dose of ANDV, along with a naïve control group. All control animals and two animals vaccinated with a lower dose of m1Ψ-mRNA succumbed to infection whereas other vaccinated animals survived without evidence of virus replication. The data demonstrate the development of a protective vaccine against ANDV and the lack of a substantial effect of m1Ψ modification on immunogenicity and protection in rodents.


Asunto(s)
Mesocricetus , Uridina , Vacunas Virales , Animales , Femenino , Ratones , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Mensajero/inmunología , Anticuerpos Antivirales/inmunología , Orthohantavirus/inmunología , Orthohantavirus/genética , Anticuerpos Neutralizantes/inmunología , Centro Germinal/inmunología , Seudouridina/inmunología , Cricetinae , Vacunas de ARNm , Fiebre Hemorrágica Americana/prevención & control , Fiebre Hemorrágica Americana/inmunología , Fiebre Hemorrágica Americana/virología , ARN Viral/genética , ARN Viral/inmunología , Linfocitos B/inmunología , Humanos , Desarrollo de Vacunas
4.
Trauma Case Rep ; 52: 101065, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38957175

RESUMEN

Unrecognized central venous catheter (CVC) infiltration is an uncommon but potentially life-threatening complication. For instance, a malpositioned subclavian line can infuse into the mediastinum, pleural cavity, or interstitial space of the neck. We present the case of a 30-year-old male with gunshot wounds to the right chest, resuscitated with an initially functional left subclavian CVC, which later infiltrated into the neck causing compression of the carotid sinus and consequent bradycardic arrest. Return of spontaneous circulation (ROSC) was achieved following intravenous epinephrine, cardiac massage, and emergency neck exploration and cervical fasciotomy. Our case highlights the importance of frequent reassessment of lines, especially those placed during fast-paced, high-intensity clinical situations. We recommend being mindful when using rapid transfusion devices as an interstitial catheter may not mount enough back pressure to trigger the system's alarm before significant tissue damage or compartment syndrome occurs.

5.
Mucosal Immunol ; 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38969067

RESUMEN

A vaccine is needed to combat the Chlamydia epidemic. Replication-deficient viral vectors are safe and induce antigen-specific T-cell memory. We tested the ability of intramuscular immunization with modified vaccinia Ankara (MVA) virus or chimpanzee adenovirus (ChAd) expressing chlamydial outer membrane protein (OmcB) or the secreted protein, chlamydial protease-like activating factor (CPAF), to enhance T-cell immunity and protection in mice previously infected with plasmid-deficient Chlamydia muridarum CM972 and elicit protection in naïve mice. MVA.OmcB or MVA.CPAF increased antigen-specific T cells in CM972-immune mice ∼150 and 50-fold, respectively, but failed to improve bacterial clearance. ChAd.OmcB/MVA.OmcB prime-boost immunization of naïve mice elicited a cluster of differentiation (CD) 8-dominant T-cell response dominated by cluster of differentiation (CD)8 T cells that failed to protect. ChAd.CPAF/ChAd.CPAF prime-boost also induced a CD8-dominant response with a marginal reduction in burden. Challenge of ChAd.CPAF-immunized mice genetically deficient in CD4 or CD8 T cells showed that protection was entirely CD4-dependent. CD4-deficient mice had prolonged infection, whereas CD8-deficient mice had higher frequencies of CPAF-specific CD4 T cells, earlier clearance, and reduced burden than wild-type controls. These data reinforce the essential nature of the CD4 T-cell response in protection from chlamydial genital infection in mice and the need for vaccine platforms that drive CD4-dominant responses.

6.
J Patient Exp ; 11: 23743735241259549, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38882945

RESUMEN

This article explores the deep impact of the COVID-19 pandemic on pediatric care volunteerism and specifically highlights the innovative responses and adaptations made by Project Sunshine, an international nonprofit organization headquartered in New York, NY. Prior to the pandemic, Project Sunshine's in-person volunteers played a critical role in providing comfort and support to hospitalized children and their families, bridging the gap between clinical treatment and patient satisfaction. However, COVID-19 brought unprecedented challenges to hospitals around the world, including widespread interruption of volunteer activities due to safety concerns and visitation restrictions. In response, Project Sunshine swiftly pivoted to virtual volunteering by launching TelePlay, an online playroom offering live interactive sessions between trained volunteers and pediatric patients. This approach addressed the immediate volunteering needs of patients during the pandemic and also extended support beyond traditional hospital settings, allowing Project Sunshine to reach children at home facing isolation and socialization challenges. Early pilot data is very encouraging: TelePlay participants were noted by their caregivers to be less anxious after a TelePlay session compared to before (p < 0.001). Additionally, the flexibility and accessibility of TelePlay have opened new avenues for volunteers to engage with their communities, transcending geographical barriers and accommodating varied schedules. As the healthcare landscape transitions back to in-person volunteerism, Project Sunshine embraces a hybrid model, offering both in-person and virtual volunteering opportunities. This flexible approach reflects the organization's commitment to helping shape the future of volunteerism to meet the evolving needs of pediatric patients and volunteers alike.

7.
Nat Rev Rheumatol ; 20(7): 432-451, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38858605

RESUMEN

Joint kinematic instability, arising from congenital or acquired musculoskeletal pathoanatomy or from imbalances in anabolism and catabolism induced by pathophysiological factors, leads to deterioration of the composition, structure and function of cartilage and, ultimately, progression to osteoarthritis (OA). Alongside articular cartilage degeneration, synovial fluid lubricity decreases in OA owing to a reduction in the concentration and molecular weight of hyaluronic acid and surface-active mucinous glycoproteins that form a lubricating film over the articulating joint surfaces. Minimizing friction between articulating joint surfaces by lubrication is fundamental for decreasing hyaline cartilage wear and for maintaining the function of synovial joints. Augmentation with highly viscous supplements (that is, viscosupplementation) offers one approach to re-establishing the rheological and tribological properties of synovial fluid in OA. However, this approach has varied clinical outcomes owing to limited intra-articular residence time and ineffective mechanisms of chondroprotection. This Review discusses normal hyaline cartilage function and lubrication and examines the advantages and disadvantages of various strategies for restoring normal joint lubrication. These strategies include contemporary viscosupplements that contain antioxidants, anti-inflammatory drugs or platelet-rich plasma and new synthetic synovial fluid additives and cartilage matrix enhancers. Advanced biomimetic tribosupplements offer promise for mitigating cartilage wear, restoring joint function and, ultimately, improving patient care.


Asunto(s)
Osteoartritis , Viscosuplementación , Humanos , Viscosuplementación/métodos , Osteoartritis/tratamiento farmacológico , Ácido Hialurónico/uso terapéutico , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Viscosuplementos/uso terapéutico , Viscosuplementos/administración & dosificación , Líquido Sinovial/metabolismo , Suplementos Dietéticos
8.
bioRxiv ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38903092

RESUMEN

Starvation triggers bacterial spore formation, a committed differentiation program that transforms a vegetative cell into a dormant spore. Cells in a population enter sporulation non-uniformly to secure against the possibility that favorable growth conditions, which puts sporulation-committed cells at a disadvantage, may resume. This heterogeneous behavior is initiated by a passive mechanism: stochastic activation of a master transcriptional regulator. Here, we identify a cell-cell communication pathway that actively promotes phenotypic heterogeneity, wherein Bacillus subtilis cells that start sporulating early utilize a calcineurin-like phosphoesterase to release glycerol, which simultaneously acts as a signaling molecule and a nutrient to delay non-sporulating cells from entering sporulation. This produced a more diverse population that was better poised to exploit a sudden influx of nutrients compared to those generating heterogeneity via stochastic gene expression alone. Although conflict systems are prevalent among microbes, genetically encoded cooperative behavior in unicellular organisms can evidently also boost inclusive fitness.

9.
JAMA Netw Open ; 7(6): e2414122, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38857050

RESUMEN

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.


Asunto(s)
COVID-19 , Hospitalización , Enfermedades del Sistema Nervioso , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , COVID-19/complicaciones , COVID-19/epidemiología , Niño , Femenino , Masculino , Preescolar , Hospitalización/estadística & datos numéricos , Adolescente , Estudios Prospectivos , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/epidemiología , Lactante , Índice de Severidad de la Enfermedad
10.
Immunity ; 57(6): 1413-1427.e9, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38823390

RESUMEN

Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Antivirales , Virus de la Influenza B , Gripe Humana , Neuraminidasa , Neuraminidasa/inmunología , Humanos , Virus de la Influenza B/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Vacunas contra la Influenza/inmunología , Ratones , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Proteínas Virales/inmunología , Replicación Viral/efectos de los fármacos
11.
J Patient Exp ; 11: 23743735241240881, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38699654

RESUMEN

Understanding differences in how demographic groups experience telehealth may be relevant in addressing potential disparities in telehealth usage. We seek to identify and examine themes most pertinent to patients' negative telehealth experiences by age and race in order to inform interventions to improve patients' future telehealth experiences. We performed a content analysis of Press Ganey patient experience surveys from adult patients at 17 primary care sites of a large, public healthcare system with visits from April 30, 2020 to August 27, 2021. We used sentiment analysis to identify negative comments. We coded for content themes and analyzed their frequency, stratifying by age and race. We analyzed 745 negative comments. Most frequent themes differed by demographic categories, but overall, the most commonly applied codes were "Contacting the Clinic" (n = 97), "Connectivity" (n = 84), and "Webside Manner" (n = 79). The top three codes accounted for >40% of the negative codes in each race category and >35% of the negative codes in each age category. While there were common negative experiences among groups, patients of different demographics highlighted different aspects of their telehealth experiences for potential improvement.

12.
Hosp Pediatr ; 14(6): e281-e291, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38726564

RESUMEN

BACKGROUND AND OBJECTIVES: Children with chronic neuromuscular conditions (CCNMC) have many coexisting conditions and often require musculoskeletal surgery for progressive neuromuscular scoliosis or hip dysplasia. Adequate perioperative optimization may decrease adverse perioperative outcomes. The purpose of this scoping review was to allow us to assess associations of perioperative health interventions (POHI) with perioperative outcomes in CCNMC. METHODS: Eligible articles included those published from January 1, 2000 through March 1, 2022 in which the authors evaluated the impact of POHI on perioperative outcomes in CCNMC undergoing major musculoskeletal surgery. Multiple databases, including PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature, Web of Science, the Cochrane Library, Google Scholar, and ClinicalTrials.gov, were searched by using controlled vocabulary terms and relevant natural language keywords. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines were used to perform the review. A risk of bias assessment for included studies was performed by using the Risk of Bias in Non-randomized Studies of Interventions tool. RESULTS: A total of 7013 unique articles were initially identified, of which 6286 (89.6%) were excluded after abstract review. The remaining 727 articles' full texts were then reviewed for eligibility, resulting in the exclusion of 709 (97.5%) articles. Ultimately, 18 articles were retained for final analysis. The authors of these studies reported various impacts of POHI on perioperative outcomes, including postoperative complications, hospital length of stay, and hospitalization costs. Because of the heterogeneity of interventions and outcome measures, meta-analyses with pooled data were not feasible. CONCLUSIONS: The findings reveal various impacts of POHI in CCNMC undergoing major musculoskeletal surgery. Multicenter prospective studies are needed to better address the overall impact of specific interventions on perioperative outcomes in CCNMC.


Asunto(s)
Enfermedades Neuromusculares , Humanos , Niño , Enfermedades Neuromusculares/complicaciones , Enfermedad Crónica , Atención Perioperativa/métodos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/epidemiología , Procedimientos Ortopédicos
13.
J Orthop Res ; 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38715519

RESUMEN

Cationic contrast-enhanced computed tomography (CECT) capitalizes on increased contrast agent affinity to the charged proteoglycans in articular cartilage matrix to provide quantitative assessment of proteoglycan content with enhanced images. While high resolution microCT has demonstrated success, we investigate cationic CECT use in longitudinal in vivo imaging at clinical resolution. We hypothesize that repeated administration of CA4+ will have no adverse side effects or complications, and that sequential in vivo imaging assessments will distinguish articular cartilage repair tissue from early degenerative and healthy cartilage in critically sized chondral defects. In an established equine translational preclinical model, lameness and synovial effusion scores are similar to controls after repeated injections of CA4+ (eight injections over 16 weeks) compared to controls. Synovial fluid total protein, leukocyte concentration, and sGAG and PGE2 concentrations and articular cartilage and synovial membrane scores are also equivalent to controls. Longitudinal in vivo cationic CECT attenuation in repair tissue is significantly lower than peripheral to (adjacent) and distantly from defects (remote sites) by 4 weeks (p < 0.001), and this difference persists until 16 weeks. At the 6- and 8-week time points, the adjacent locations exhibit significantly lower cationic CECT attenuation compared with the remote sites, reflecting peri-defect degeneration (p < 0.01). Cationic CECT attenuation at clinical resolution significantly correlates with cationic CECT (microCT) (r = 0.69, p < 0.0001), sGAG (r = 0.48, p < 0.0001), and ICRS II histology score (r = 0.63, p < 0.0001). In vivo cationic CECT imaging at clinical resolution distinguishes fibrous repair tissue from degenerative and healthy hyaline cartilage and correlates with molecular tissue properties of articular cartilage.

14.
J Intensive Care Med ; : 8850666241249169, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38689485

RESUMEN

OBJECTIVE: Delirium is an under-recognized problem in critically ill children. Although delirium is common in adults hospitalized with COVID-19, the relationship between pediatric COVID-19 and delirium has not been described. To address this gap, we characterized delirium in critically ill children with different manifestations of COVID-19 and investigated associations among demographic, disease, and treatment factors. We hypothesized that multisystem inflammatory syndrome in children (MIS-C) would be associated with a higher incidence of delirium given its underlying pathophysiology of hyperinflammation. DESIGN: Retrospective, single-center cohort study. SETTING: Quaternary-care pediatric intensive care unit (PICU). PATIENTS: Children less than 18 years of age hospitalized in the PICU between March 2020 and March 2023 with either active SARS-CoV-2 infection or serological evidence of prior infection. MEASUREMENTS AND MAIN RESULTS: The cohort included 149 PICU hospitalizations among children with evidence of COVID-19. Patients were categorized by reason for PICU admission: 75 (50%) for COVID-19 respiratory disease, 36 (24%) MIS-C, and 38 (26%) any other primary reason with positive COVID-19 testing. Delirium was diagnosed in 43 (29%) patients. Delirium incidence was highest in patients requiring invasive mechanical ventilation (IMV) (56% vs 7.5% in patients who did not require IMV, p < .001). Patients who were exposed to opioids, dexmedetomidine, paralytics or benzodiazepines more frequently experienced delirium compared to those unexposed (p < .001, p < .001, p < .001 and p = .001, respectively). After multivariable adjustment, delirium was associated with IMV (HR 3 [95% CI 1.5-5.7]), female sex (HR 2.4 [1.2-4.7]), and developmental disability (HR 3.4 [95% CI 1-11.1]). There was no association between delirium and reason for PICU hospitalization. CONCLUSIONS: Delirium was common among children hospitalized with COVID-19. The overall incidence was much less than has been reported in adults with COVID-19. Delirium reduction efforts should focus on children with developmental disability and minimizing ongoing risks during IMV.

15.
ScientificWorldJournal ; 2024: 2209301, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774420

RESUMEN

Ophthalmomyiasis is the result of fly larvae feeding on the tissues of the eye. Commonly associated with poor hygiene and open wounds, this condition is rare and often stigmatized. Treatment can be straightforward, and full recovery is common. Identifying the species responsible for ophthalmomyiasis is important for the medical, forensic, and entomological communities. Here, we present a case of ophthalmomyiasis where 30-40 blow fly (Diptera: Calliphoridae) larvae were removed from the eye of a human male. A representative subsample of five larvae was used for taxonomic identification via two approaches (a) DNA analysis, via sequencing of the complete mitochondrial genome (mtGenome) and comparison of the mtGenome and mitochondrial COI barcode region to GenBank, and (b) morphology, examination of the posterior spiracles using microscopy, and comparison to published larval descriptions of blow flies. Two species of blow flies were identified from the DNA analysis: Lucilia coeruleiviridis and Phormia regina. Morphological examination could only confirm L. coeruleiviridis as being present. To our knowledge, finding two blow fly species causing ophthalmomyiasis in a single individual has not been previously reported in the scientific literature. Neither P. regina nor L. coeruleiviridis prefers living tissue for larva development, but since they fill similar ecological niches, perhaps this was a show of competition rather than a normal feeding habit. Knowing these blow fly species can resort to this behavior, and that it can affect human populations, is valuable to the education of patients and providers.


Asunto(s)
Calliphoridae , Larva , Animales , Calliphoridae/genética , Masculino , Humanos , Miasis/parasitología , Miasis/diagnóstico , América del Norte , Filogenia , Dípteros/parasitología , Genoma Mitocondrial
16.
Nature ; 629(8013): 878-885, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38720086

RESUMEN

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Simulación por Computador , Diseño de Fármacos , SARS-CoV-2 , Animales , Femenino , Humanos , Ratones , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Mutación , Pruebas de Neutralización , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Análisis Mutacional de ADN , Deriva y Cambio Antigénico/genética , Deriva y Cambio Antigénico/inmunología , Diseño de Fármacos/métodos
17.
Nat Chem ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684816

RESUMEN

The importance of constructing Csp2-Csp3 bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)-C(sp3) coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.

18.
Otolaryngol Head Neck Surg ; 171(1): 146-154, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38643410

RESUMEN

OBJECTIVE: First bite syndrome (FBS) is a rare complication of transoral surgery (TOS) for oropharyngeal cancer (oropharyngeal squamous cell carcinoma [OPSCC]). Risk factors for developing this complication are not well described. In this study, we attempt to identify risks for developing FBS in TOS. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care medical center. METHODS: This study was exempted by the Mayo Clinic institutional review board. We performed a review from January 2017 to November 2022 of all patients who underwent TOS for OPSCC by a single provider. Exclusion criteria included less than 6 months follow up, prior treatment of head and neck cancer, or incomplete records. Demographic data, comorbidities, tumor characteristics, surgical details, adjuvant treatment details, functional outcomes, and oncologic outcomes were assessed. Fisher's Exact test and Kruskal-Wallis rank sum test were used to identify significant variables, and multivariable logistic regression was used to address confounding. RESULTS: One hundred and one patients were identified. Eighty-nine met the inclusion criteria. The mean follow-up was 34 months (median 33). Seven patients (7.9%) developed FBS. Palatine tumor primary (P = .041), resection of styloglossus/stylopharyngeus (P = .039), and parapharyngeal fat manipulation (P = .015) were associated with the presence of FBS. After adjusting for tumor location, manipulation of parapharyngeal fat maintained significance (P = .025). T and N staging, tumor volume, adjuvant radiation, and ligation of lingual/facial arteries were not associated with the development of FBS. Eighty-six percent (6/7) of patients had a resolution of FBS at an average of 11.3 months. CONCLUSION: Manipulation of the parapharyngeal space is independently associated with developing FBS in TOS in our cohort. Further confirmatory studies are warranted.


Asunto(s)
Neoplasias Orofaríngeas , Complicaciones Posoperatorias , Humanos , Masculino , Neoplasias Orofaríngeas/cirugía , Neoplasias Orofaríngeas/patología , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Anciano , Síndrome , Factores de Riesgo , Cirugía Endoscópica por Orificios Naturales/efectos adversos , Cirugía Endoscópica por Orificios Naturales/métodos , Adulto
19.
Artículo en Inglés | MEDLINE | ID: mdl-38451730

RESUMEN

Some individuals attempt to alleviate menstrual-related symptoms (MRS) by using cannabis and report having expectations that cannabis can improve MRS; however, no study has examined the effect of cannabinoids on MRS. The present study is a pre-post, randomized, open-label trial that aimed to examine the effects of oral cannabidiol (CBD) isolate for alleviating MRS. Participants were assigned randomly to one of two open-label dosing groups of CBD softgels (160 mg twice a day, BID, n = 17; 320 mg BID, n = 16) and completed a 1-month baseline period. Following baseline, participants were instructed to consume CBD starting the first day they believed they experienced symptoms each month and to take their assigned dose daily for 5 consecutive days for three CBD-consumption months. We examined differences in MRS and related outcomes between baseline and 3 months of CBD consumption. Results revealed reductions (in both dosing groups) in MRS, irritability, anxiety, global impression of change, stress, and subjective severity scores when comparing baseline to all 3 months of CBD consumption. Depression scores did not change in either dosing group. Findings suggest that CBD may have the potential for managing MRS. Importantly, changes in symptoms appeared in the first month of CBD consumption and persisted over the 3 consumption months. Further research is warranted comparing the effects of CBD to placebo (a limitation of the study) and examining the potential to optimize CBD consumption for reducing MRS (e.g., combining CBD with terpenes; varying routes and timing of administration). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

20.
Head Neck ; 46(5): 1178-1188, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38506149

RESUMEN

BACKGROUND: Velopharyngeal insufficiency (VPI) is a known complication of transoral surgery (TOS) for oropharyngeal HPV-mediated squamous cell carcinoma. Controversy exists regarding adequate resection margins for balancing functional and oncologic outcomes. METHODS: This retrospective study was exempted by the IRB. Patients who underwent TOS from January 2017 to October 2022 were included. Patient characteristics, treatment details, and oncologic and functional outcomes were evaluated. RESULTS: Fifty-five patients were included. Mean and median follow-up was 34 months. 98% of patients were AJCC stage I/II. Recurrence-free survival was 96% with no local recurrences. Univariate analysis demonstrated an association between VPI and pT stage (p = 0.035), medial pterygoid resection (p = 0.049), and palatal attachment sacrifice (p < 0.001). Multivariate analysis showed sacrifice of the palatal attachments remained a significant risk for VPI (p = 0.009). CONCLUSION: Loss of soft palate pharyngeal attachments is an independent risk factor for VPI. When oncologically appropriate, the palatal attachments to the pharynx may be preserved.


Asunto(s)
Neoplasias , Neoplasias Orofaríngeas , Procedimientos Quirúrgicos Robotizados , Insuficiencia Velofaríngea , Humanos , Insuficiencia Velofaríngea/etiología , Insuficiencia Velofaríngea/cirugía , Tonsila Palatina/patología , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias Orofaríngeas/patología , Procedimientos Quirúrgicos Robotizados/efectos adversos
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