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1.
Nucleic Acids Res ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38994563

RESUMO

SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression.

2.
Genet Med ; 26(6): 101124, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38522067

RESUMO

PURPOSE: Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases. METHODS: We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients: 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States. The effects of using a population-mismatched control cohort are simulated by swapping the control cohorts used for each patient cohort, with or without the popmax computational strategy. RESULTS: Population-matched classifications revealed a combined 62 pathogenic or likely pathogenic (P/LP) variants in 34 genes across both cohorts. Using a population-mismatched control cohort resulted in misclassification of non-P/LP variants as P/LP, driven by the absence of ancestry-specific rare variants in the control cohort. Popmax was more effective in alleviating misclassifications for the Singapore cohort than the US cohort. CONCLUSION: Underrepresented population groups can suffer from higher rates of false-positive P/LP results. Popmax can partially alleviate these misclassifications, but its efficacy still depends on the degree with which the population groups are represented in the control cohort.


Assuntos
Neoplasias Colorretais , Mutação em Linhagem Germinativa , Humanos , Mutação em Linhagem Germinativa/genética , Singapura , Neoplasias Colorretais/genética , Estados Unidos , Estudos de Coortes , Masculino , Feminino , Predisposição Genética para Doença , Genética Populacional/métodos , Estudos de Casos e Controles , Grupos Minoritários , Bases de Dados Genéticas
3.
Opt Express ; 32(12): 20483-20490, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38859429

RESUMO

A novel deep-ridge laser structure with atomic-layer deposition (ALD) sidewall passivation was proposed that enhances the optical characteristics of 8-µm ridge width III-nitride violet lasers on freestanding m-plane GaN substrates. The internal loss was determined using the variable stripe length method, where the laser structure with ALD sidewall passivation showed lower internal loss compared to the conventional shallow-ridge laser design. ALD sidewall passivation plays a critical role in device improvements; compared to the lasers without ALD sidewall passivation, the lasers with ALD sidewall passivation yield improved optoelectrical performance and longer lifetime under continuous-wave operation at high current density. This work demonstrates the importance of ALD sidewall passivation to laser performance, which enables high energy efficiency.

4.
J Neurooncol ; 168(1): 69-76, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38551747

RESUMO

PURPOSE: There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). METHODS AND MATERIALS: A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60 Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. RESULTS: 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. CONCLUSION: Patients with recurrent glioblastoma who have been previously treated with 60 Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.


Assuntos
Antineoplásicos Imunológicos , Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Recidiva Local de Neoplasia , Hipofracionamento da Dose de Radiação , Reirradiação , Humanos , Glioblastoma/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Glioblastoma/patologia , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/tratamento farmacológico , Reirradiação/métodos , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Adulto , Estudos Prospectivos , Terapia de Salvação , Estudos Retrospectivos , Prognóstico , Quimiorradioterapia/métodos , Seguimentos , Taxa de Sobrevida
5.
Ann Emerg Med ; 83(6): 585-597, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38639673

RESUMO

The emergency department clinical environment is unique, and guidelines for promoting supportive and equitable workplace cultures ensure success and longevity for pregnant persons and parents in emergency medicine. There is paucity, variability, and dissatisfaction with current parental (historically referred to as maternity and paternity) leave policies. This paper describes the development of consensus-derived recommendations to serve as a framework for emergency departments across the country for incorporating family-friendly policies. Policies that foster a family-inclusive workplace by allowing for professional advancement without sacrificing personal values regardless of sex, gender, and gender identity are critical for emergency medicine recruitment and retention.


Assuntos
Medicina de Emergência , Licença Parental , Humanos , Feminino , Gravidez , Adoção/legislação & jurisprudência , Lactação , Consenso , Mães Substitutas/legislação & jurisprudência , Serviço Hospitalar de Emergência , Médicos , Política Organizacional , Masculino
7.
Acta Trop ; 251: 107122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38246399

RESUMO

Strongyloidiasis, caused by the nematode Strongyloides stercoralis, remains a threat to global public health, and a vaccine would be useful to control the disease, especially in developing countries. This study aimed to evaluate the efficacy of recombinant proteins, A133 and Ss-IR, as potential vaccine candidates against strongyloidiasis by investigating the humoral and cellular immune responses in immunized mice. Respective antigens were adjuvanted with Complete Freund's Adjuvant (prime) and Incomplete Freund's Adjuvant (boost) and administered intraperitoneally (prime) and subcutaneously (boost) to female BALB/c mice. For antigen-only doses, only antigens were injected without adjuvants. Altogether, 1 prime dose, 4 booster doses, and 2 antigen-only doses were administered successively. ELISAs were conducted to assess the antibody responses, along with flow cytometry and cytokine ELISA to elucidate the cellular immune responses. Results showed that A133 and Ss-IR induced the production of IgG1 and IgG2a, with A133 generating more robust IgG2a responses than Ss-IR. Flow cytometry findings indicated that effector CD8+T-cells and memory B-cells activity were upregulated significantly for A133 only, whereas cytokine ELISA demonstrated that a Th1/Th2/Th17 mixed cell responses were triggered upon vaccination with either antigen. This preliminary study illustrated the good potential of recombinant A133 and Ss-IR as vaccine candidates against S. stercoralis. It provided information on the probable immune mechanism involved in host defence and the elicitation of protection against S. stercoralis.


Assuntos
Strongyloides stercoralis , Estrongiloidíase , Vacinas , Feminino , Animais , Camundongos , Strongyloides stercoralis/genética , Imunoglobulina G , Estrongiloidíase/prevenção & controle , Imunização , Vacinação , Adjuvantes Imunológicos , Citocinas/metabolismo , Camundongos Endogâmicos BALB C
8.
Bone Joint J ; 106-B(2): 144-150, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38425304

RESUMO

Aims: The aim of this study was to determine both the incidence of, and the reoperation rate for, postoperative periprosthetic femoral fracture (POPFF) after total hip arthroplasty (THA) with either a collared cementless (CC) femoral component or a cemented polished taper-slip (PTS) femoral component. Methods: We performed a retrospective review of a consecutive series of 11,018 THAs over a ten-year period. All POPFFs were identified using regional radiograph archiving and electronic care systems. Results: A total of 11,018 THAs were implanted: 4,952 CC femoral components and 6,066 cemented PTS femoral components. Between groups, age, sex, and BMI did not differ. Overall, 91 patients (0.8%) sustained a POPFF. For all patients with a POPFF, 16.5% (15/91) were managed conservatively, 67.0% (61/91) underwent open reduction and internal fixation (ORIF), and 16.5% (15/91) underwent revision. The CC group had a lower POPFF rate compared to the PTS group (0.7% (36/4,952) vs 0.9% (55/6,066); p = 0.345). Fewer POPFFs in the CC group required surgery (0.4% (22/4,952) vs 0.9% (54/6,066); p = 0.005). Fewer POPFFs required surgery in males with a CC than males with a PTS (0.3% (7/2,121) vs 1.3% (36/2,674); p < 0.001). Conclusion: Male patients with a PTS femoral component were five times more likely to have a reoperation for POPFF. Female patients had the same incidence of reoperation with either component type. Of those having a reoperation, 80.3% (61/76) had an ORIF, which could greatly mask the size of this problem in many registries.


Assuntos
Artroplastia de Quadril , Prótese de Quadril , Fraturas Periprotéticas , Humanos , Masculino , Feminino , Artroplastia de Quadril/efeitos adversos , Fraturas Periprotéticas/epidemiologia , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Prótese de Quadril/efeitos adversos , Reoperação/efeitos adversos , Fatores de Risco , Desenho de Prótese , Cimentos Ósseos , Estudos Retrospectivos
9.
Aust J Gen Pract ; 53(6): 371-378, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840375

RESUMO

BACKGROUND: Healthy sleep is vital for optimal child development, yet over 30% of Australian parents report having children with disrupted sleep affecting all family members. These sleep difficulties might co-exist with sleep breathing disorders, contributing to morbidity and reduced quality of life. OBJECTIVE: This article aims to provide general practitioners (GPs) with an evidence-based, biopsychosocial approach to managing common sleep problems in infants and preschool-aged children. DISCUSSION: Strategies and techniques are outlined to aid GPs in promoting healthy sleep during infancy, educating parents on typical sleep patterns and supporting families in managing problematic sleep patterns in toddlers. Emphasis is placed on a tailored approach to developing a healthy sleep environment to meet the child's needs and parental values. Valuable resources and indications for specialist consultation are included.


Assuntos
Transtornos do Sono-Vigília , Humanos , Lactente , Pré-Escolar , Austrália , Transtornos do Sono-Vigília/terapia , Transtornos do Sono-Vigília/fisiopatologia , Pais/psicologia , Sono/fisiologia , Qualidade de Vida/psicologia
10.
Aust J Gen Pract ; 53(6): 379-386, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840376

RESUMO

BACKGROUND: Adolescence is a stage of significant transition as children develop into young adults. Optimal sleep is crucial during this period to ensure physical, emotional and mental wellbeing. However, it is well recognised that insufficient quality and quantity of sleep is common among adolescents worldwide. OBJECTIVE: This article aims to provide general practitioners with an overview of the key issues encountered in adolescent patients relating to sleep and summarises approaches to assessment and evidence-based management of sleep problems in this population. DISCUSSION: This review highlights the physiological changes that affect sleep during adolescence and how other factors, including unhealthy sleep behaviours, influence these. It discusses the importance of healthy sleep and the consequences of sleep disturbance in adolescents. Management strategies are outlined, focusing on the key common issues that affect sleep in the teenage years, and guidance on when to consider co-management with specialist care is provided.


Assuntos
Sono , Humanos , Adolescente , Sono/fisiologia , Transtornos do Sono-Vigília/terapia , Transtornos do Sono-Vigília/fisiopatologia
11.
Trop Med Infect Dis ; 9(7)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058181

RESUMO

Heat shock protein 16-kDa (HSP 16-kDa) is essential for the survival of Mycobacterium tuberculosis (M. tuberculosis) during the latent period; hence, a peptide-MHC presentation of HSP 16-kDa could be a potential diagnostic and therapeutic target for latent tuberculosis (LTB). This study aimed to generate a TCR-like single-domain antibody (sDAb)-human IgG1 antibody and subsequently investigate its diagnostic and therapeutic potential in LTB, utilizing a model cell presenting the target peptide. A previously generated TCR-like sDAB that can bind to HSP 16-kDa was first fused to a human IgG1 Fc-receptor via a linker. The fusion product, sDAb-IgG1, was expressed with HEK293-F and was subsequently purified. Its diagnostic potential was investigated via cell-based ELISA utilizing MCF-7 cells peptide-pulsed with HSP 16-kDa peptides. Investigation into the antibody-dependent cell-mediated cytotoxicity (ADCC) of MCF-7 cells was also conducted to investigate its therapeutic potential. Finally, TCR-like sDAb-IgG1 was successfully produced transiently with HEK-293F and was purified using protein A chromatography. The generated antibody was tested using cell-based ELISA, which demonstrated the effective binding of the TCR-like sDAb-IgG1 to the 16-kDa peptide-MHC on the cell surface. The ADCC assay also showed that the antibody effectively mediated the ADCC of MCF-7 cells with the help of 16-kDa peptide-MHC. This allows us to hypothesize the possible utility of the said antibody for both diagnostics and therapeutics of latent tuberculosis after more investigations with clinical samples.

12.
J Thorac Dis ; 16(6): 3844-3853, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38983144

RESUMO

Background: Surgical resection is the primary treatment for early-stage lung cancer, but little is known about the outcomes that truly matter to patients. This aim of our study was to identify the aspects of postoperative outcomes that matter most to patients undergoing lung cancer surgery and explore the influence of clinical and demographic factors on their importance ratings. Methods: We performed a cross-sectional study of patients undergoing lung resection for non-small cell lung cancer at our institution from November 2021 to May 2022. Patients were surveyed using a self-developed questionnaire and the European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire (EORTC QLQ-C30) prior to surgery. Ordinal logistic regression was performed to determine associations between individual patient factors and outcome importance ratings. Results: Forty patients completed the survey during the study period. Patients prioritized oncologic outcomes, with 95% rating R0 resection and cancer recurrence as "very important". Other important factors included overall survival (90%), postoperative complications (e.g., myocardial infarction: 92.5%, infection: 87.5%), and the need for reoperation (82.5%). Health-related quality of life factors, such as chronic pain (77.5%) and the ability to return to normal physical and exercise levels (75%), were also highly valued. Certain patient clinical and demographic factors demonstrated significant associations with importance placed on certain outcomes. Preoperative health-related quality of life scores did not influence outcome importance ratings. Conclusions: This study provides insights into the outcomes that matter most to patients undergoing lung cancer surgery. Oncologic outcomes and postoperative complications were prioritized, while scar-related factors were less important. Patient preferences varied based on demographic and clinical factors. Understanding these preferences can enhance shared decision-making and improve patient-centered care in thoracic surgical oncology.

13.
Pediatr Pulmonol ; 59(7): 1885-1893, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38560779

RESUMO

BACKGROUND: Longitudinal measurements of intrabreath respiratory impedance (Zrs) in preschool-aged children may be able to distinguish abnormal lung function trajectories in children with a history of wheezing compared to healthy ones. METHODS: Children from a prospective, longitudinal community-based cohort performed annual intrabreath oscillometry (IB-OSC) measurements from age 3- to 7-years. IB-OSC was performed using a single 10 Hz sinusoid while clinically asymptomatic. Linear mixed-effects models were developed to explore the effects of wheezing phenotypes, growth, and sex on seven IB-OSC outcome variables over time: resistance at end-expiration (ReE), resistance at end-inspiration (ReI), the tidal change in resistance (∆R=ReE-ReI), reactance at end-expiration (XeE), reactance at end-inspiration (XeI), the tidal change in reactance (∆X=XeE-XeI), and ∆X normalized by tidal volume (∆X/VT). RESULTS: Eighty-five children produced 374 acceptable IB-OSC measurements. Subjects were classified into one of three wheeze groups: never (n = 36), transient (n = 34), or persistent (n = 15). After adjusting for height, children with persistent wheezing, compared to those who never wheezed, had +0.814 hPa s L-1 ReE (95% confidence interval [CI] +0.178 to +1.451, p = 0.015), -0.792 hPa s L-1 XeE (95% CI -1.203 to -0.381, p = 0.003), -0.538 hPa s L-1 ∆X (95% CI -0.834 to -0.242, p = 0.007) and -1.672 hPa s L-2 ∆X/VT (95% CI -2.567 to -0.777, p < 0.001). Increasing height had a significant effect on all IB-OSC resistance and reactance variables when adjusted for the effect of preschool wheezing. CONCLUSIONS: IB-OSC is feasible for tracking lung function growth in preschool-aged children and may allow abnormal lung function to be identified early in asymptomatic preschoolers with a history of persistent wheezing.


Assuntos
Sons Respiratórios , Humanos , Masculino , Pré-Escolar , Feminino , Estudos Prospectivos , Sons Respiratórios/fisiopatologia , Estudos Longitudinais , Criança , Oscilometria/métodos , Resistência das Vias Respiratórias/fisiologia , Testes de Função Respiratória/métodos , Volume de Ventilação Pulmonar/fisiologia
14.
Pediatr Pulmonol ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953717

RESUMO

BACKGROUND: Several techniques can be used to assess bronchodilator response (BDR) in preschool-aged children, including spirometry, respiratory oscillometry, the interrupter technique, and specific airway resistance. However, there has not been a systematic comparison of BDR thresholds across studies yet. METHODS: A systematic review was performed on all studies up to May 2023 measuring a bronchodilator effect in children 2-6 years old using one of these techniques (PROSPERO CRD42021264659). Studies were identified using MEDLINE, Cochrane, EMBASE, CINAHL via EBSCO, Web of Science databases, and reference lists of relevant manuscripts. RESULTS: Of 1224 screened studies, 43 were included. Over 85% were from predominantly European ancestry populations, and only 22 studies (51.2%) calculated a BDR cutoff based on a healthy control group. Five studies included triplicate testing with a placebo to account for the within-subject intrasession repeatability. A relative BDR was most consistently reported by the included studies (95%) but varied widely across all techniques. Various statistical methods were used to define a BDR, with six studies using receiver operating characteristic analyses to measure the discriminative power to distinguish healthy from wheezy and asthmatic children. CONCLUSION: A BDR in 2- to 6-year-olds cannot be universally defined based on the reviewed literature due to inconsistent methodology and cutoff calculations. Further studies incorporating robust methods using either distribution-based or clinical anchor-based approaches to define BDR are required.

15.
Nutr Rev ; 2024 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-38219239

RESUMO

CONTEXT: Despite recent advances in antidepressants in treating major depression (MDD), their usage is marred by adverse effects and social stigmas. Probiotics may be an efficacious adjunct or standalone treatment, potentially circumventing the aforementioned issues with antidepressants. However, there is a lack of head-to-head clinical trials between these 2 interventions. OBJECTIVE: A systematic review and network meta-analysis was conducted to compare the efficacy and acceptability of these 2 interventions in treating MDD. DATA SOURCES: Six databases and registry platforms for the clinical trial were systematically searched to identify the eligible double-blinded, randomized controlled trials published between 2015 and 2022. DATA EXACTION: Two authors selected independently the placebo-controlled trials of antidepressants and microbiota-targeted interventions (prebiotics, probiotics, and synbiotics) used for the treatment of MDD in adults (≥18 years old). Standardized mean differences (SMDs) of depressive symptom scores from individual trials were pooled for network meta-analysis (PROSPERO no. CRD42020222305). RESULTS: Forty-two eligible trials covering 22 interventions were identified, of which 16 were found to be effective in MDD treatment and the certainty of evidence was moderate to very low. When all trials were considered, compared with placebo, SMDs of interventions ranged from -0.16 (95% credible interval: -0.30, -0.04) for venlafaxine to -0.81 (-1.06, -0.52) for escitalopram. Probiotics were superior to brexpiprazole (SMD [95% credible interval]: -0.42 [-0.68, -0.17]), cariprazine (-0.44 [-0.69, -0.24]), citalopram (-0.37 [-0.66, -0.07]), duloxetine (-0.26, [-0.51, -0.04]), desvenlafaxine (-0.38 [-0.63, -0.14]), ketamine (-0.32 [-0.66, -0.01]), venlafaxine (-0.47 [-0.73, -0.23]), vilazodone (-0.37 [-0.61, -0.12]), vortioxetine (-0.39 [-0.63, -0.15]), and placebo (-0.62 [-0.86, -0.42]), and were noninferior to other antidepressants. In addition, probiotics ranked the second highest in the treatment hierarchy after escitalopram. Long-term treatment (≥8 weeks) using probiotics showed the same tolerability as antidepressants. CONCLUSION: Probiotics, compared with antidepressants and placebo, may be efficacious as an adjunct or standalone therapy for treating MDD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020222305.

16.
Cancer Discov ; 14(7): 1161-1175, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38588588

RESUMO

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.


Assuntos
Antibacterianos , Microbioma Gastrointestinal , Melanoma , Humanos , Melanoma/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Biomarcadores Tumorais , Vancomicina/uso terapêutico , Adulto , COVID-19/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia
17.
Br J Ophthalmol ; 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38164563

RESUMO

BACKGROUND: Large language models (LLMs) are fast emerging as potent tools in healthcare, including ophthalmology. This systematic review offers a twofold contribution: it summarises current trends in ophthalmology-related LLM research and projects future directions for this burgeoning field. METHODS: We systematically searched across various databases (PubMed, Europe PMC, Scopus and Web of Science) for articles related to LLM use in ophthalmology, published between 1 January 2022 and 31 July 2023. Selected articles were summarised, and categorised by type (editorial, commentary, original research, etc) and their research focus (eg, evaluating ChatGPT's performance in ophthalmology examinations or clinical tasks). FINDINGS: We identified 32 articles meeting our criteria, published between January and July 2023, with a peak in June (n=12). Most were original research evaluating LLMs' proficiency in clinically related tasks (n=9). Studies demonstrated that ChatGPT-4.0 outperformed its predecessor, ChatGPT-3.5, in ophthalmology exams. Furthermore, ChatGPT excelled in constructing discharge notes (n=2), evaluating diagnoses (n=2) and answering general medical queries (n=6). However, it struggled with generating scientific articles or abstracts (n=3) and answering specific subdomain questions, especially those regarding specific treatment options (n=2). ChatGPT's performance relative to other LLMs (Google's Bard, Microsoft's Bing) varied by study design. Ethical concerns such as data hallucination (n=27), authorship (n=5) and data privacy (n=2) were frequently cited. INTERPRETATION: While LLMs hold transformative potential for healthcare and ophthalmology, concerns over accountability, accuracy and data security remain. Future research should focus on application programming interface integration, comparative assessments of popular LLMs, their ability to interpret image-based data and the establishment of standardised evaluation frameworks.

18.
JTCVS Open ; 16: 931-937, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38204618

RESUMO

Objective: Surgical mortality has traditionally been assessed at arbitrary intervals out to 1 year, without an agreed optimum time point. The aim of our study was to investigate the time-varying risk of death after lobectomy to determine the optimum period to evaluate surgical mortality rate after lobectomy for lung cancer. Methods: We performed a retrospective study of patients undergoing lobectomy for lung cancer at our institution from 2015 to 2022. Parametric survival models were assessed and compared with a nonparametric kernel estimate. The hazard function was plotted over time according to the best-fit statistical distribution. The time points at which instantaneous hazard rate peaked and stabilized in the 1-year period after surgery were then determined. Results: During the study period, 2284 patients underwent lobectomy for lung cancer. Cumulative mortality at 30, 90, and 180 days was 1.3%, 2.9%, and 4.9%, respectively. Log-logistic distribution showed the best fit compared with other statistical distribution, indicated by the lowest Akaike information criteria value. The instantaneous hazard rate was greatest during the immediate postoperative period (0.129; 95% confidence interval, 0.087-0.183) and diminishes rapidly within the first 30 days after surgery. Instantaneous hazard rate continued to decrease past 90 days and stabilized only at approximately 180 days. Conclusions: In-hospital mortality is the optimal follow-up period that captures the early-phase hazard during the immediate postoperative period after lobectomy. Thirty-day mortality is not synonymous to "early mortality," as instantaneous hazard rate remains elevated well past the 90-day time point and only stabilizes at approximately 180 days after lobectomy.

19.
An. otorrinolaringol. mex ; 38(2): 73-7, mar.-mayo 1993. tab
Artigo em Inglês | LILACS | ID: lil-121236

RESUMO

Se comparan tres pruebas de función vestibular, electronistagmografía (ENG), electronistagmografía de aceleración (AENG) y posturografía (EQT) en 83 pacientes com mareo, vértigo o trastornos del equilibrio. Treinta y uno (37.4 por ciento) presentaban mareo postraumático, 18 (21.7 por ciento) vértigo postural paroxístico benigno, 11 (13.3 por ciento) fístula perilinfática, 6 (7,2 por ciento) neuronitis vestibular, 4 (4.8 por ciento) emfermedad de Menière, 4 (4.8 por ciento) se diagnosticaron como vestibulopatía de origen desconocido y 9 (10.8 por ciento) pacientes se consideraron sin anormalidad vestibular. La ENG se practicó con electrodos superficiales para registrar los movimientos oculares. Incluyó las pruebas de nistagmus espontáneo, de reojo, optoquinético y postural, así como pruebas térmicas con estímulo a 30-C y 44-C. La AENG se estudió usando un sillón rotatorio alternante montado en una plataforma motorizada, en un cuarto oscuro aislado electricamente. El reflejo vestíbulo-oculomotor (VOR) se registró en tres condiciones: rotando sinusoidalmente el sillón en la oscuridad para probar el VOR, rotando el sillón con luz, rodeado por un tambor optoquinético estacionario para probar el reflejo oculmotor optovestibular (OVOR) y rotando sinusoidalmente el sillón en la obscuridad junto con un diodo luminoso frente a los ojos abiertos, para probar la supresión visual (VS). Los resultados revelaron que la ENG fue la prueba mas sensitiva para revelar anomalías (56.6 por ciento), la AENG un poco menos sensitiva (44.6 por ciento) y la EQT la menos sensitiva. Además, solo la ENG mostró especificidad respecto al sitio y al lado de la lesión. los resultados de la ENG y de la AENG se correlacionaron mejor en pacientes con mareo postraumático, vértigo postural paroxístico benigno, neuronitis vestibular, vestibulopatía de origen desconocido y enfermedad de Meniere. Esto puede ser debido porque ambas prueban respuestas del VOR en tanto que la EQT mide las respuestas del fascículo vestíbulo-espinal. Ninguna de las pruebas fue mejor que otra en el diagnóstico de fístula perilinfática. La EQT fue útil en la documentación del componente funcinal en los pacientes estudiados por mareo.


Assuntos
Humanos , Testes de Função Vestibular/instrumentação , Vertigem/diagnóstico , Testes de Função Vestibular/métodos
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