RESUMO
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
Assuntos
Morte Celular Imunogênica , Proteólise , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Humanos , Animais , Camundongos , Proteólise/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Morte Celular Imunogênica/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Necroptose/imunologia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Imunoterapia/métodosRESUMO
Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.
Assuntos
Caspase 8/metabolismo , Instabilidade Cromossômica , Neoplasias do Colo/enzimologia , Fibroblastos/enzimologia , Mitose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Aneuploidia , Animais , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibroblastos/patologia , Células HT29 , Humanos , Inflamação/enzimologia , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Quinase 1 Polo-LikeRESUMO
Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1-/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1-/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.
Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Metformina , Metformina/farmacologia , Metformina/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/metabolismo , Animais , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Camundongos , Masculino , Camundongos Knockout , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacosRESUMO
mRNA translation initiation plays a critical role in learning and memory. The eIF4F complex, composed of the cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A, and scaffolding protein eIF4G, is a pivotal factor in the mRNA translation initiation process. eIF4G1, the major paralogue of the three eIF4G family members, is indispensable for development, but its function in learning and memory is unknown. To study the role of eIF4G1 in cognition, we used an eIF4G1 haploinsufficient (eIF4G1-1D) mouse model. The axonal arborization of eIF4G1-1D primary hippocampal neurons was significantly disrupted, and the mice displayed impairment in hippocampus-dependent learning and memory. Translatome analysis showed that the translation of mRNAs encoding proteins of the mitochondrial oxidative phosphorylation (OXPHOS) system was decreased in the eIF4G1-1D brain, and OXPHOS was decreased in eIF4G1-silenced cells. Thus, eIF4G1-mediated mRNA translation is crucial for optimal cognitive function, which is dependent on OXPHOS and neuronal morphogenesis.
Assuntos
Fator de Iniciação Eucariótico 4G , Fosforilação Oxidativa , Animais , Camundongos , RNA Mensageiro , Iniciação Traducional da Cadeia Peptídica , Morfogênese , DNA HelicasesRESUMO
BACKGROUND: Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation. METHODS: Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions. RESULTS: Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients. CONCLUSIONS: Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios.
Assuntos
Conselheiros , Neoplasias , Humanos , Testes Genéticos , Neoplasias/genética , Predisposição Genética para Doença , Reino Unido , Células GerminativasRESUMO
Competence for DNA transformation is a major strategy for bacterial adaptation and survival. Yet, this successful tactic is energy-consuming, shifts dramatically the metabolism, and transitory impairs the regular cell-cycle. In streptococci, complex regulatory pathways control competence deactivation to narrow its development to a sharp window of time, a process known as competence shut-off. Although characterized in streptococci whose competence is activated by the ComCDE signaling pathway, it remains unclear for those controlled by the ComRS system. In this work, we investigate competence shut-off in the major human gut commensal Streptococcus salivarius. Using a deterministic mathematical model of the ComRS system, we predicted a negative player under the control of the central regulator ComX as involved in ComS/XIP pheromone degradation through a negative feedback loop. The individual inactivation of peptidase genes belonging to the ComX regulon allowed the identification of PepF as an essential oligoendopeptidase in S. salivarius. By combining conditional mutants, transcriptional analyses, and biochemical characterization of pheromone degradation, we validated the reciprocal role of PepF and XIP in ComRS shut-off. Notably, engineering cleavage site residues generated ultra-resistant peptides producing high and long-lasting competence activation. Altogether, this study reveals a proteolytic shut-off mechanism of competence in the salivarius group and suggests that this mechanism could be shared by other ComRS-containing streptococci.
Assuntos
Proteínas de Bactérias , Regulon , Proteínas de Bactérias/metabolismo , Competência de Transformação por DNA/genética , Regulação Bacteriana da Expressão Gênica , Humanos , Peptídeos/genética , Feromônios/genética , Feromônios/metabolismo , Regulon/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.
Assuntos
Aurora Quinase A , Neoplasias Colorretais , Humanos , Cetuximab/farmacologia , Cetuximab/metabolismo , Aurora Quinase A/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
OBJECTIVE: To determine the feasibility and effectiveness of a Hospital at Home (HaH) enabled early transfer pathways for surgical patients. BACKGROUND: HaH serves as a safe alternative to traditional hospitalization by providing acute care to patients in their homes through a comprehensive range of hospital-level interventions. To our knowledge, no studies have been published to date reporting a large cohort of early home-transferred patients after surgery through a HaH unit. METHODS: Cohort study enrolling every patient admitted to the HaH unit of a tertiary hospital who underwent any of 6 surgeries with a predefined early transfer pathway and fitting both general and surgery inclusion criteria (clinical and hemodynamic stability, uncomplicated surgery, presence of a caregiver, among others) from November 2021 to May 2023. Protocols were developed for each pathway between surgical services and HaH to deliver the usual postoperative care in the home setting. Discharge was decided according to protocol. An urgent escalation pathway was also established. RESULTS: During the study period, 325 patients were included: 141 were bariatric surgeries, 85 kidney transplants, 45 thoracic surgeries, 37 cystectomies, 10 appendicectomies, and 7 ventral hernia repairs. The overall escalation of care during HaH occurred in 7.3% of patients and 30-day readmissions in 7%. Most adverse events were managed at home and the overall mortality was zero. The total mean length of stay was 8 days (interquartile range 2-14), and patients with HaH were transferred home 3 days (interquartile range 1-6) earlier than the usual pathway; a total of 1551 bed-days were saved. CONCLUSIONS: The implementation of early home transfer pathways for surgical patients through HaH is feasible and effective, with favorable safety outcomes.
Assuntos
Hospitalização , Readmissão do Paciente , Humanos , Estudos de Coortes , Alta do Paciente , HospitaisRESUMO
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.
Assuntos
COVID-19 , Mitocôndrias , SARS-CoV-2 , Proteínas Virais , Humanos , Células A549 , COVID-19/metabolismo , COVID-19/virologia , COVID-19/patologia , Mitocôndrias/metabolismo , Fases de Leitura Aberta , SARS-CoV-2/genética , Transcriptoma , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Viroporinas/metabolismoRESUMO
OBJECTIVES: Membranous lupus nephritis (MLN) is thought to have a more benign course than proliferative lupus nephritis (PLN). We aimed to determine the differences in short and long-term outcomes between patients with MLN and PLN. METHODS: We included patients with first biopsy-proven MLN and PLN. Short-term outcomes included complete proteinuria recovery (CPR), complete renal response (CRR), and primary efficacy renal response (PERR). Long-term outcomes included a sustained ≥40% reduction in baseline estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular (CV) events, ≥2 increase in SDI, and death. Univariable and multivariable Cox proportional hazard models were used to examine the effect of baseline characteristics on long-term outcomes. RESULTS: Of 215 patients, 51 had pure MLN, and 164 had PLN. We found no significant differences between the two groups in achieving CPR, CRR, and PERR at 1 and 2 years. Median time to outcomes was slightly, but insignificantly, longer in the MLN group.For long-term outcomes, PLN was associated with worse renal and non-renal outcomes, but this was not statistically significant.In the multivariable Cox proportional hazard models, ESKD was associated with the following baseline variables: younger age (HR 0.92, 95% CI 0.87-0.97), higher creatinine (HR 1.01, 95% CI 1.01-1.02), low complement (HR 4.0, 95% CI 1.04-11.10), and higher chronicity index (HR 1.28, 95% CI 1.08-1.51). CONCLUSION: The resolution of proteinuria in LN is slow. MLN is not a benign disease and may be associated with deterioration of renal function, ESKD, damage, CV events, and death.
RESUMO
BACKGROUND: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. METHODS: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. RESULTS: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome. CONCLUSIONS: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.
Assuntos
Modelos Animais de Doenças , Microglia , Neurônios , Receptores Purinérgicos P2X7 , Convulsões , Animais , Microglia/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Masculino , Camundongos , Convulsões/metabolismo , Convulsões/genética , Neurônios/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Ácido Caínico , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/genética , Hipocampo/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/genética , Camundongos Knockout , Pentilenotetrazol , Transdução de Sinais , Neurônios GABAérgicos/metabolismo , Epilepsia/metabolismo , Epilepsia/genética , Encéfalo/metabolismoRESUMO
BACKGROUND: Subjective orgasm experience (SOE) refers to the perception, assessment, and/or sensation of orgasm on a psychological level, with the particularity that the study of SOE in nonheterosexual populations is currently very scarce. AIM: The study sought to analyze differences in SOE dimensions, comparing the intensity of each adjective of the Orgasm Rating Scale (ORS) and creating a ranking of the adjectives that better represent it in LGB men and women. METHODS: In a sample of 1475 adults organized into 4 groups according to the type of sexual relationships reported, comparisons were made using multivariate analysis of variance and chi-square tests. OUTCOMES: Differences were obtained in the intensity of all the SOE dimensions, and in 23 of the 25 ORS adjectives. RESULTS: Lesbians and bisexual women reported higher intensity in SOE compared with bisexual and gay men. CLINICAL IMPLICATIONS: Because the ORS has been established as a good tool for detecting orgasmic difficulties in nonheterosexual populations, this study could provide LGBT affirmative psychotherapy with evidence on how these individuals evaluate their orgasms in a relational context. STRENGTHS AND LIMITATIONS: This study extends prior limited knowledge about how LGB people evaluate their orgasmic experiences in the context of sexual relationships. Despite this, the study poses limitations such as nonprobability sampling or the inclusion of exclusively cisgender and young individuals, making it difficult to generalize the results. CONCLUSION: Although significant differences were found between LGB men and women, all groups agree on the adjectives they use to describe the subjective experience of orgasm in the context of sexual relationships; therefore, evidence is provided about how LGB people evaluate their orgasmic experiences in this context.
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Homossexualidade Feminina , Minorias Sexuais e de Gênero , Adulto , Masculino , Humanos , Feminino , Orgasmo , Comportamento Sexual , BissexualidadeRESUMO
OBJECTIVE: Ustekinumab was recently approved for the treatment of moderate-to-severe ulcerative colitis (UC). Although data from the UNIFI clinical trial are encouraging, real-world data assessing effectiveness and safety are scarce. The aim of this study was to assess the effectiveness, safety and pharmacokinetics of ustekinumab in a large cohort of refractory UC patients. METHODS: Multicenter observational study of UC patients who received ustekinumab for active disease. The Partial Mayo Score (PMS), endoscopic activity, C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at different time points. Demographic and clinical data, adverse events (AEs) and surgeries were documented. RESULTS: A total of 108 patients were analyzed from 4 referral Spanish hospitals. The clinical remission rates were 59%, 56.5%, 57% and 69% of patients at weeks 8, 16, 24 and 52, respectively. Normalization of FC was achieved in 39.6%, 41% and 51% at weeks 8, 24 and 52, respectively. CRP normalization was observed in 79%, 75% and 76.5% of patients at weeks 8, 24 and 52, respectively. Fewer previous anti-TNF agents and loss of response to anti-TNF were associated with clinical response and normalization of FC, respectively. AEs were observed in 5 patients, and 9 underwent colectomy. Ustekinumab persistence rates were 91%, 83% and 81% at 24, 48 and 96 weeks, respectively. CONCLUSIONS: Ustekinumab demonstrated, in the real-world setting, long-term effectiveness and a favorable safety profile in a cohort of refractory UC patients.
Assuntos
Colite Ulcerativa , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Colite Ulcerativa/cirurgia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Resultado do Tratamento , Indução de Remissão , Proteína C-ReativaRESUMO
OBJECTIVES: The identification of changes in tumor markers (TMs) in cancer patients that indicate response to treatment, stabilization or disease progression is a challenge for laboratory medicine. Several approaches have been proposed: assessing percentage increases, applying discriminant values, and estimating half-life (t1/2) or doubling time (DT). In all of them it is assumed that the TM is a surrogate of the variation in tumor size. In general this variation is time-dependent, but this is not the case of intraindividual biological variability (CVi), which can range from 6â¯% in CA15-3 to 22â¯% in CA125. When decisions are made on the basis of DT or t1/2, these values can be affected by the CVi; if it is very large, the growth rate very slow and the period of time between determinations very short, the result obtained for DT may be due mainly to the CVi. The aim of this study is to establish the relationship between the CVi and temporal variables. METHODS: We related equations for calculating DT and t1/2 to the reference change values in tumor markers. RESULTS: The application of the formula obtained allows the calculation of the optimal time between measurements to ensure that the influence of the CVi is minimal in different types of tumors and different scenarios. CONCLUSIONS: Intraindividual variation affects the calculation of DT and t1/2. It is necessary to establish the minimum time between two measurements to ensure that the CVi does not affect their calculation or lead to misinterpretation.
Assuntos
Biomarcadores Tumorais , Neoplasias , Humanos , Neoplasias/patologia , Biomarcadores Tumorais/sangue , Variação Biológica Individual , Meia-VidaRESUMO
BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. In the last few years, after the publication of the consensus guidelines, with refined diagnostic criteria and improved awareness, FPIES is diagnosed with increased frequency. However, despite having a background of immune dysregulation, this complication has just been described once in the posttransplant setting, in an adult patient. To the best of our knowledge, there are no reports of pediatric patients developing FPIES after a hematopoietic stem cell transplant (HCT). METHODS: Retrospective review of a pediatric patient who developed severe FPIEs after a HCT. RESULTS: In this case report, the clinical presentation and diagnosis challenges of a pediatric patient who developed severe FPIES after HCT are described. The patient developed severe vomiting, diarrhea, lethargy, and shock and required admission to the pediatric intensive care unit in three occasions before the diagnosis was made. CONCLUSIONS: To the best of our knowledge, this is the first report of severe FPIES post-HCT in a pediatric patient. Physicians who are looking after pediatric patients in the post-HCT setting need to be aware of this possibility and include this entity in the differential diagnosis in order to reduce its associated morbidity.
Assuntos
Enterocolite , Hipersensibilidade Alimentar , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Enterocolite/etiologia , Enterocolite/diagnóstico , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/etiologia , Masculino , Proteínas Alimentares , Síndrome , Estudos Retrospectivos , Feminino , Pré-Escolar , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapiaRESUMO
The case report describes a 65-year-old man with arterial hypertension and a metallic aortic valve who presented to the emergency room for a loss of consciousness event and memory impairment. The electroencephalographic recording showed right temporal epileptiform activity followed by a 9 s asystole with quick consciousness recovery. The patient was diagnosed with right temporal epilepsy with asystole and was prescribed levetiracetam to prevent new events. A pacemaker was indicated in the follow-up for the long duration of the asystole, preventing major morbidity. Ictal asystole (IA) is a rare phenomenon of epilepsy that leads to syncope. It is observed in focal epilepsy, especially in left temporal epilepsy. Underlying cardiac pathology may facilitate IA, especially when the onset of the epilepsy is new. Knowledge of focal temporal semiology is key, concerning our case report, the memory impairment points to temporal pathology, and ictal vomiting in the non-dominant hemisphere. Anti-seizures drugs must be initiated in all patients, and there is a recommendation to avoid those with negative inotropic and arrhythmogenic effects (such as phenytoin, carbamazepine, and lacosamide). There is a discussion about pacemaker indication, however, it is highly recommended in non-controlled epilepsy and in ictal asystoles that last for more than 6 s to reduce morbidity.
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Eletroencefalografia , Parada Cardíaca , Humanos , Masculino , Idoso , Parada Cardíaca/etiologia , Parada Cardíaca/complicações , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/diagnóstico , Anticonvulsivantes/uso terapêutico , Levetiracetam/uso terapêuticoRESUMO
Rheumatoid arthritis causes progressive joint destruction in the long term, causing a deterioration of the foot and ankle. A clinical practice guideline has been created with the main objective of providing recommendations in the field of podiatry for the conservative management of rheumatoid arthritis. Thus, healthcare professionals involved in foot care of adults with rheumatoid arthritis will be able to follow practical recommendations. A clinical practice guideline was created including a group of experts (podiatrists, rheumatologists, nurses, an orthopaedic surgeon, a physiotherapist, an occupational therapist and patient with rheumatoid arthritis). Methodological experts using GRADE were tasked with systematically reviewing the available scientific evidence and developing the information which serves as a basis for the expert group to make recommendations. Key findings include the efficacy of chiropody in alleviating hyperkeratotic lesions and improving short-term pain and functionality. Notably, custom and standardized foot orthoses demonstrated significant benefits in reducing foot pain, enhancing physical function, and improving life quality. Therapeutic footwear was identified as crucial for pain reduction and mobility improvement, emphasizing the necessity for custom-made options tailored to individual patient needs. Surgical interventions were recommended for cases which were non-responsive to conservative treatments, aimed at preserving foot functionality and reducing pain. Moreover, self-care strategies and education were underscored as essential components for promoting patient independence and health maintenance. A series of recommendations have been created which will help professionals and patients to manage podiatric pathologies derived from rheumatoid arthritis.
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Artrite Reumatoide , Humanos , Artrite Reumatoide/terapia , Órtoses do Pé , Articulação do Tornozelo , Pé , Podiatria/normas , ConsensoRESUMO
BACKGROUND: Risk scores (RS) evaluate the likelihood of short-term mortality in patients diagnosed with community-acquired pneumonia (CAP). However, there is a scarcity of evidence to determine the risk of long-term mortality. This article aims to compare the effectiveness of 16 scores in predicting mortality at three, six, and twelve months in adult patients with CAP. METHODS: A retrospective cohort study on individuals diagnosed with CAP was conducted across two hospitals in Colombia. Receiver Operating Characteristic (ROC) curves were constructed at 3, 6, and 12 months to assess the predictive ability of death for the following scoring systems: CURB-65, CRB-65, SCAP, CORB, ADROP, NEWS, Pneumonia Shock, REA-ICU, PSI, SMART-COP, SMRT-CO, SOAR, qSOFA, SIRS, CAPSI, and Charlson Comorbidity Index (CCI). RESULTS: A total of 3688 patients were included in the final analysis. Mortality at 3, 6, and 12 months was 5.2%, 8.3%, and 16.3% respectively. At 3 months, PSI, CCI, and CRB-65 scores showed ROC curves of 0.74 (95% CI: 0.71-0.77), 0.71 (95% CI: 0.67-0.74), and 0.70 (95% CI: 0.66-0.74). At 6 months, PSI and CCI scores showed performances of 0.74 (95% CI: 0.72-0.77) and 0.72 (95% CI: 0.69-0.74), respectively. Finally at 12 months, all evaluated scores showed poor discriminatory capacity, including PSI, which decreased from acceptable to poor with an ROC curve of 0.64 (95% CI: 0.61-0.66). CONCLUSION: When predicting mortality in patients with CAP, at 3 months, PSI, CCI, and CRB-65 showed acceptable predictive performances. At 6 months, only PSI and CCI maintained acceptable levels of accuracy. For the 12-month period, all evaluated scores exhibited very limited discriminatory ability, ranging from poor to almost negligible.
Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Curva ROC , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Colômbia/epidemiologia , Infecções Comunitárias Adquiridas/mortalidade , Infecções Comunitárias Adquiridas/diagnóstico , Pneumonia/mortalidade , Pneumonia/diagnóstico , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
OBJECTIVE: For many health care providers, an umbilical venous catheter (UVC) may be a contraindication for skin-to-skin contact (SSC). Our aim was to compare the frequency of adverse events between preterm infants who were on SSC with UVC and those who remained in an incubator. STUDY DESIGN: Prospective observational study in newborns less than 35 weeks gestation. UVC-related adverse events were compared between neonates who performed SSC and those who did not. The incidence of catheter-related displacement, leak, loss, hemorrhage, malfunction, and bloodstream infection was studied. RESULTS: From 226 patients, 171 performed SSC with UVC. Their first contact was earlier than in those who remained in an incubator (SSC-UVC, 29 hours [interquartile range (IQR): 21-53] vs. no SSC-UVC, 132 hours [IQR: 96-188]; p < 0.001). Both groups were similar in gestational age (SSC-UVC, 30 weeks vs. no SSC-UVC, 30.3 weeks; p = 0.331) and birth weight (SSC-UVC, 1,285 g vs. no SSC-UVC, 1,355 g; p = 0.2). Studied complications were not more frequent in patients who performed SSC. In fact, although it was not statistically significant, a lower overall incidence of adverse events (SSC-UVC, 13.5% vs. no SSC-UVC, 20%; p = 0.237) and catheter-related bloodstream infection (SSC-UVC, 4.7% vs. no SSC-UVC, 10.9%; p = 0.111) was observed in this group. CONCLUSION: SSC with a UVC is a safe procedure and there are no more complications in newborns who perform SSC compared to those who remain in the incubator. Due to its demonstrated benefits, SSC should be promoted in premature newborns regardless of the presence of a UVC. KEY POINTS: · SSC in preterm infants with UVCs is safe.. · Early SSC does not increase UVC-related bloodstream infection.. · Early SSC should be promoted in stable patients regardless of the presence of a UVC..
RESUMO
Body temperature must be monitored in patients receiving Hospital-at-Home (HaH) care for COVID-19 and other infectious diseases. Continuous temperature telemonitoring (CTT) detects fever and patient deterioration early, facilitating decision-making. We performed a validation clinical study assessing the safety, comfort, and impact on healthcare practice of Viture®, a CTT system, compared with a standard digital axillary thermometer in 208 patients with COVID-19 and other infectious diseases treated in HaH at the Navarra University Hospital (HUN). Overall, 3258 pairs of measurements showed a clinical bias of -0.02 °C with limits of agreement of -0.96/+0.92 °C, a 95% acceptance rate, and a mean absolute deviation of 0.36 (SD 0.30) °C. Viture® detected 3 times more febrile episodes and revealed fever in 50% more patients compared with spot measurements. Febrile episodes were detected 7.23 h (mean) earlier and modified the diagnostic and/or therapeutic approach in 43.2% of patients. Viture® was validated for use in a clinical setting and was more effective in detecting febrile episodes than conventional methods.