Desfechos obstétricos adversos durante a COVID-19: uma série de casos retrospectiva / Adverse obstetric outcomes during COVID-19: a retrospective case series / Resultados obstétricos adversos durante el COVID-19: serie de casos retrospectiva

Objetivo: analisar as características e os desfechos obstétricos adversos em gestantes/puérperas infectadas pelo SARS-CoV-2 em serviço de referência. Método: série de casos retrospectiva entre gestantes com Covid-19 em um hospital universitário em Minas Gerais, Brasil, atendidas no serviço de 2020 a 2021, coletados em abril de 2022, empregando-se estatística descritiva para análise dos dados através do Statistical Package for the Social Science. Resultados: incluídas 26 gestantes, em sua maioria brancas, que tiveram como principais desfechos obstétricos adversos a internação em UTI (43,5%), parto prematuro (34,6%), dado reestratificado de semanas para dias para investigar o encurtamento da gestação, onde constatou-se média de 38,6 dias potenciais de gravidez perdidos dos 280 dias ideais, e ainda 15,4% evoluíram para óbito materno. Conclusão: o estudo proporcionou evidenciar a necessidade de vigilância e atenção às gestantes com foco nos principais desfechos adversos, podendo-se intervir em tempo oportuno para diminuir adversidades.

Objective: to analyze the characteristics and adverse obstetric outcomes in pregnant/puerperal women infected by SARS-CoV-2 at a reference service. Method: a retrospective case series conducted among pregnant women with Covid-19 in a university hospital from Minas Gerais, Brazil, treated at the service from 2020 to 2021. The cases were collected in April 2022 employing descriptive statistics for data analysis in the Statistical Package for the Social Science. Results: a total of 26 pregnant women were included, mostly white-skinned, whose main adverse obstetric outcomes were admission to the ICU (43.5%), premature birth (34.6%) and data restratified from weeks to days to investigate shortening of pregnancy, where a mean of 38.6 potential days of pregnancy were lost out of the ideal 280 days, and 15.4% resulted in maternal death. Conclusion: the study provided evidence of the need for surveillance and care for pregnant women with a focus on the main adverse outcomes, enabling timely intervention to reduce adversities.

Objetivo: analizar las características y resultados obstétricos adversos en gestantes/puérperas infectadas por SARS-CoV-2 en un servicio de referencia. Método: serie de casos retrospectiva entre gestantes con Covid-19 en un hospital universitario de Minas Gerais, Brasil, atendidas en el servicio de 2020 a 2021. Los datos se recolectaron en abril de 2022, se utilizó estadística descriptiva para analizar los datos mediante el Statistical Package for the Social Science. Resultados: se incluyeron 26 gestantes, la mayoría de raza blanca, cuyos principales resultados obstétricos adversos fueron ingreso a UCI (43,5%), parto prematuro (34,6%), dato reestratificado de semanas a días para investigar el acortamiento de la gestación, que arrojó como resultado un promedio de 38,6. Se comprobó que se perdieron en promedio 38,6 días potenciales de embarazo de los 280 días ideales, y muerte materna (15,4%). Conclusión: la evidencia que proporcionó el estudio indica que es necesario vigilar y atender a las gestantes enfocándose en los principales resultados adversos, lo que permite intervenir de forma oportuna para reducir adversidades.

All-cause mortality and cause-specific death in U.S. long-lived siblings: data from the Long Life Family Study.

BACKGROUND: This study compared the mortality risk of long-lived siblings with the U.S. population average and their spouse controls, and investigated the leading causes of death and the familial effect in death pattern. METHODS: In the Long Life Family Study (LLFS), 1,264 proband siblings (Mean age 90.1, SD 6.4) and 172 spouses (83.8, 7.2) from 511 U.S.-based families were recruited and followed over 12 years. Their survival function was compared with a birth cohort-, baseline age-, sex-, and race-matched pseudo sample from U.S. census data. To examine underlying and contributing causes, we examined in detail 338 deaths with complete death adjudication at the University of Pittsburgh Field Center through the year 2018. A familial effect on survival and death pattern was examined using mixed effect models. RESULTS: The LLFS siblings had better survival than the matched U.S. population average. They also had slightly but not significantly better survival than their spouses' (HR=1.18 [95%CI 0.94-1.49]) after adjusting for age and sex. Age at death ranged from 75-104 years, mean 91.4. The leading causes of death were cardiovascular disease (33.1%), dementia (22.2%), and cancer (10.7%). Mixed effect model shows a significant random effect of family in survival, with adjustment of baseline age and sex. There was no significant familial effect in the underlying cause of death or conditions directly contributing to death among siblings recruited by the University of Pittsburgh Field Center. CONCLUSION: Our findings demonstrate a higher survival in the LLFS siblings than the U.S. census data, with a familial component of survival. We did not find significant correspondence in causes of death between siblings within families.

Causes and investigation of stillbirths in Brazil: A multicentre cross-sectional study in 10 referral maternity hospitals.

OBJECTIVE: Understanding the local characteristics and statistics related to stillbirths may be the first step in a series of strategies associated with a reduction in stillbirth ratio. The aim of this study was to estimate the fetal mortality ratio and evaluate the investigation processes related to the causes of death, comparing the investigation according to the specific cause of death. METHODS: A cross-sectional study was retrospectively conducted in 10 tertiary obstetric care centers. Medical records of women with stillbirth managed between January 1, 2009 and December 31, 2018 were analyzed and classified, according to sociodemographic characteristics, and gestational and childbirth data, culminating in stillbirth. The stillbirth ratio and its causes were presented in proportions for the study period and individually for each health facility. RESULTS: Cases of 3390 stillbirths were analyzed. The stillbirth ratio varied from 10.74/1000 live births (LBs) in 2009 to 9.31/1000 in 2018. "Intrauterine hypoxia and asphyxia" (ICD-10 P20) and "unspecific causes of death" (ICD-10 P95) represented 40.8% of the causes of death. Investigation for TORCHS and diabetes occurred in 90.8% and 61.4% of deaths, respectively. Placental and necroscopic tests were performed in 36.6% of the cases. CONCLUSION: The adoption of a rational and standardized investigation of stillbirth remains an unmet need; the use of additional tests and examinations are lacking, especially when unspecific causes are attributed.

Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum-infected macrophages.

Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo. Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g, two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture. IMPORTANCE: The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates serpina3f and serpina3g and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth in vivo. The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.

Assessment of the Quality of Cause-of-Death Data in Serbia for 2005-2019 Vital Statistics Performance Index Estimation.

Background: We aimed to evaluate the quality of the cause of death (COD) concerning mortality patterns and completeness of death registration to identify areas for improvement in Serbia. Methods: COD data collected from the mortality register in Serbia from 2005 to 2019 (1540615 deaths) were analyzed with the software Analysis of National Causes of Death for Action. The Vital Statistics Performance Index for Quality (VSPI(Q)) is estimated for the overall COD data quality. Results: The completeness of death certification was higher than 98%. Usable underlying COD was registered in 57%, 24.1% with an unusable and 18.6% with insufficiently specified COD. The VSPI(Q) was 67.2%, denoting medium quality. The typical error was using intermediate COD (24.7% of all deaths), while 13.2% and 8.5% of all garbage codes (GC) belonged to the Very High and High Severity classes. The leading underlying COD is unspecified cardiomyopathy. The analysis revealed that 39.1% of GC has been redistributed to non-communicable diseases, 2.5% to external causes and 1.1% to communicable diseases. Conclusion: In the 15 years' worth of data analyzed, the true underlying COD, in many cases, was ill-defined, indicating that COD data at the national level could be distorted. The additional and continuous professional education of medical students as well as physicians is needed. It should focus on the most common GC among the leading COD and acquiring skills in certifying external causes of death.

Significantly Positive Impact of Nonsteroidal Anti-inflammatory Drugs Combined With Osmoprotectant (Osmolytes) in Cancer Treatment.

Osmoprotectant osmolyte and nonsteroidal anti-inflammatory drug (NSAID) coadministration can work synergistically in cancer chemotherapy since most tumors are inflammatory and cancer cells experience osmotic stress. NSAIDs have been shown to inhibit cyclooxygenase (COX) enzymes, which in turn reduces prostaglandin synthesis and prevents inflammation. They also encourage cell death to prevent tumor growth and its spread to other tissues and prevent the construction of new blood vessels, which contributes to the growth of cancer. Taurine belongs to the class of osmolytes since it has been shown to stabilize macromolecular structures and maintain cellular osmotic balance when combined with betaine and glycine. When these drugs are taken together, as opposed to separately, the effectiveness of cancer treatment is increased by increasing cancer cell death and suppressing tumor growth. Notable therapeutic benefits include the reduction of local inflammatory milieu by NSAIDs, which promotes tumor development, and the protection of surviving, normal cells and tissues from treatment-induced damage caused by cancer. By enhancing this synergy, side-effect risk can be decreased and treatment outcomes improved in terms of quality. Put another way, peptides can increase the therapeutic index of NSAIDs in cancer patients by preventing cell damage, which may lessen the gastrointestinal (GI), cardiovascular (CV), and renal side effects of the drug. However, there are drawbacks because using NSAIDs for an extended period of time is linked to serious side effects that call for strict supervision. More research is required because the usefulness and significance of osmolytes in cancer therapy are still very unclear, if not fragmented. In addition, people who live in places with limited resources may find it difficult to afford the possible expenditures associated with osmolytes and selective cyclooxygenase-2 (COX-2) inhibitors. Only the molecular mechanisms of the two drugs' interactions, the appropriate dosages for combination therapy, and clinical trials to validate the efficacy and safety of this dosage should be the focus of future research. The request is inviting because it presents hope for an extremely successful antiviral strategy; nevertheless, in order to implement this approach successfully, it is likely to be necessary to create affordable formulations and scalable solutions that do not necessitate excessive treatment regimen individualization. Due to their complementary capacities to demonstrate anti-inflammatory and cytoprotective effects, Akta and 5-aminosalicylic acid (5-ASA) administration may thus represent a significant advancement in the treatment of cancer.

E-mmortal: Death Anxiety is Related to Selfie Behaviors.

Given the widespread phenomenon of selfies, numerous studies are examining the motivations behind taking and sharing selfies. The current paper suggests an additional possible motivation, namely, decreasing death anxiety. People are motivated to decrease their death anxiety by preserving a fake feeling of immortality. One known way to achieve this goal is by using photography. Therefore, we suggest that selfie behaviors are a way to fulfill the need to remain immortal. A hundred undergraduate students (Mage = 22.33) answered self-reported questionnaires regarding selfie motivations, selfie-taking frequency, selfie-sharing frequency, and death anxiety. All of those selfie measurements were indeed positively related to death anxiety. Moreover, many previous studies suggested that narcissism motivates selfie behaviors. In an exploratory approach, we examined whether death anxiety mediates this relationship. Indeed, death anxiety fully mediated the relationships between narcissism and selfie motivations and between narcissism and selfie-taking frequency, suggesting that the well-documented association between selfie behaviors and narcissism might be driven by death anxiety. Those preliminary results indicate that death anxiety is associated with selfie behaviors, opening new avenues for understanding the motivations underlying selfie behaviors.

Alcohol use, civilian interference, and other possible risk factors for death during restraint.

Physical restraint is usually used when trying to control and terminate a violent episode. Many causes are possible behind aggressive, agitated, and violent behavior. Some of these are such factors that can either be detected in forensic autopsies or can be evident from the person's medical records. Various causes for deaths during physical restraint have been suggested. In this study, we wanted to review all incidents in which physical restraint was employed, ending in death of the restrained person, whether the restraint was applied by police officers, security guards, police custody personnel, health care personnel or ordinary civilians. The main aim was to see if this new kind of study design would increase our knowledge in circumstances and causes leading to death in restraint situations. Data was collected retrospectively from all forensic autopsies performed in the Southern Finland area during 2010-2015. We went through 21,036 forensic autopsy cases and found 12 cases (0.06 %) in which a physical restraint was employed before death. Police officers were involved in the physical restraint in 7/12 of the cases: in two of these cases, police alone; in three cases, police and guards; and in two cases, police and health care personnel. Civilians carried out the restraint in 5/12 cases. With civilians responsible for the restraint, the cause of death was more likely considered to be a result of the restraint itself than in cases where police and other authorities were responsible for the restraint. This could be because civilians aren't educated about safe restraint methods, and they might themselves be intoxicated. Alcohol was the most common psychoactive substance found in this study and could be a risk factor for not only aggressive behavior but also death, since alcohol use can provoke cardiac arrhythmias and even sudden death. Based on this study, and previously published studies, we see restraint deaths as a varying spectrum of deaths, in which the death is often possibly a result of many factors, including the effects of agitation and restraint, intoxication, and cardiac and other illnesses.

Viral infection and sudden non-cardiac death: A systematic review.

INTRODUCTION: Sudden non-cardiac death (SNCD) is a clinical entity comprising deaths lacking previous clinically significant symptoms, and in which the mechanisms of death do not involve the heart. Infection is a major cause of SNCD, particularly in children, and viruses are frequently involved in the disease process. Nevertheless, SNCD of viral infectious causes remains poorly characterized. Thus, a systematic review of the literature describing the association between viral infection and the development of SNCD was performed. METHODS: PRISMA statement guidelines were followed in this systematic review. A literature search was conducted across MEDLINE, Scopus and Web of Science databases. Studies considered eligible were autopsy series or cohort studies of sudden death cases, in which evidence of viral disease as a cause of death was demonstrated, along with identification of causative agents. RESULTS: Twelve studies published between 1996 and 2020 were included in this review. Selected studies were categorized into three groups according to the study population: infants and young children (up to four years of age); presumed sudden infant death syndrome patients; and older individuals (five years of age and older). SNCD with viral implication represents a minority of sudden death cases in all age groups, with infants and young children having a higher prevalence across studies. Respiratory infection was the main cause of viral SNCD, with influenza virus and respiratory syncytial virus being the most commonly identified agents in older individuals, and infants and young children respectively. Disseminated infection, gastrointestinal infection, and meningitis were other identified causes of SNCD in children. CONCLUSIONS: No studies have directly assessed the frequency and causes of viral SNCD. Infants and young children show a considerable, but variable, prevalence of this clinical entity. Wider implementation of post-mortem virological molecular testing may help uncover previously unknown cases. More research into viral SNCD is needed, especially in the adult population.

Clinical Effectiveness and Safety of Transarterial Chemoembolization: Hepatic Artery Infusion Chemotherapy Plus Tyrosine Kinase Inhibitors With or Without Programmed Cell Death Protein-1 Inhibitors for Unresectable Hepatocellular Carcinoma-A Retrospective Study.

BACKGROUND: Locoregional treatment with transarterial chemoembolization (TACE) or hepatic artery infusion chemotherapy (HAIC) and systemic targeted immunotherapy with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC) have achieved promising efficacy. The retrospective study aimed to evaluate the efficacy and safety of TACE and HAIC plus TKI with or without PD-1 for uHCC. PATIENTS AND METHODS: From November 2020 to February 2024, the data of 44 patients who received TACE-HAIC + TKI + PD-1 (THKP group) and 34 patients who received TACE-HAIC + TKI (THK group) were retrospectively analyzed. Primary outcomes were overall survival (OS) and progress-free survival (PFS), and secondary outcomes were objective response rate (ORR), disease control rate (DCR), conversion rates, and adverse events (AEs). RESULTS: A total of 78 patients were recruited in our single-center study. The patients in THKP group had prolonged median OS [25 months, 95% confidence interval (CI) 24.0-26.0 vs 18 months, 95% CI 16.1-19.9; p = 0.000278], median PFS [16 months, 95% CI 14.1-17.9 vs 12 months 95% CI 9.6-14.4; p = 0.004] and higher ORR (38.6% vs 23.5%, p = 0. 156) and DCR (88.6% vs 64.7%, p = 0.011) compared with those in THK group. Multivariate analysis showed that treatment option and alpha-fetoprotein (AFP) level were independent prognostic factors of OS and PFS. The frequency of AEs were similar between the two groups. CONCLUSIONS: The THKP group had better efficacy for uHCC than the THK group, with acceptable safety.

Wearable defibrillator to improve accuracy in selecting candidates to implantable defibrillator: A real-world experience.

AIMS: The indication for implantable cardioverter defibrillator (ICD) for sudden cardiac death (SCD) prevention relies mostly on left ventricular ejection fraction (LVEF) ≤ 35%. The use of a wearable cardioverter defibrillator (WCD) in the case of dynamic alterations of LVEF may help avoid an improper early ICD implant when a favourable evolution in the post-acute phase is observed and may help reduce costs. METHODS: This parallel cohort retrospective study included patients with heart failure with reduced ejection fraction (HFrEF) at high risk of arrhythmias recruited in the acute phase and divided into an early ICD cohort and a WCD cohort for primary prevention during the waiting period established by European Society of Cardiology guidelines. RESULTS: A total of 41 consecutive patients were enrolled: 26 in the WCD group and 15 in the early ICD group. Age, LVEF at baseline, causes of HFrEF and drug therapy in the two cohorts were similar. During the waiting period after the inclusion, three patients (11.5%) in the WCD cohort and four (26.7%) in the early ICD cohort developed relevant ventricular arrhythmias (P = 0.22); none of them had subsequent LVEF recovery. At the end of the waiting period, 13 patients (50%) in the WCD group and 7 (46.7%) in the early ICD group experienced LVEF recovery (P = 0.84). The average cost per patient at the end of the waiting period was €23 934 in the early ICD cohort versus €19 167 in the WCD cohort (-19.9%). This cost savings from WCD use appears even higher when projected over a 10 year period (-41.2%). CONCLUSIONS: WCD may represent a cost-effective strategy to more accurately select candidates for the primary prevention ICD implant among high-risk patients with HFrEF. ICD use provides effective protection from SCD and reduces costs compared with an extensive early ICD implant.

Influencing and prognostic factors of end-stage hypertrophic cardiomyopathy.

AIMS: End-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM. METHODS AND RESULTS: A total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF) < 50% were defined as having ES-HCM, and a control group (LVEF ≥ 50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF ≥ 50%. The mean age of the patients at enrolment was 62.5 ± 10.3 years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF ≥ 50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P < 0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR] = 0.95, 95% CI [0.90, 1.00], P = 0.042), New York Heart Association (NYHA) class (OR = 7.73, 95% CI [2.93, 20.41], P < 0.001), heart rate (OR = 1.07, 95% CI [1.02, 1.12], P = 0.003), QRS duration (OR = 1.03, 95% CI [1.00, 1.05], P = 0.020), left ventricular end-diastolic diameter (LVEDD) (OR = 1.15, 95% CI [1.04, 1.28], P = 0.006), left atrial anteroposterior diameter (LAD) (OR = 1.13, 95% CI [1.03, 1.24], P = 0.012), and maximum left ventricular wall thickness (MLVWT) (OR = 0.80, 95% CI [0.68, 0.93], P = 0.005). Among the 50 patients with ES-HCM, NYHA class (P < 0.001) and heart rate (P = 0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses. CONCLUSIONS: The influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM.

The clinicopathological significance and prognostic value of PD-L1 in oral squamous cell carcinoma.

OBJECTIVE: To investigate the relationship between the expression of PD-L1 in OSCC and the clinicopathological features and prognosis of patients. METHODS: We retrospectively analyzed the clinicopathological data and prognosis of 381 OSCC patients. Immunohistochemical staining was performed on OSCC tumor specimens, and the expression level of PD-L1 was evaluated according to the combined positive score (CPS). Kaplan-Meier analysis was used to identify the effect of PD-L1 expression and clinicopathological features on the prognosis of patients. Univariate and multivariate Cox regression analyses were conducted to determine the hazard factors affecting the prognosis of patients. RESULTS: PD-L1 overexpression was significantly associated with cervical lymph node metastasis (p = 0.018), worse clinical stage (p = 0.022), worse tumor differentiation (p = 0.046), and worse depth of invasion (DOI) (p = 0.003). Poorer clinical stage and degree of tumor differentiation were significantly associated with poorer OS and DSS in patients. PD-L1 expression was not associated with prognosis in patients with OSCC. CONCLUSIONS: High PD-L1 expression was significantly associated with higher tumor malignancy in OSCC patients. Poorer clinical stage and degree of tumor differentiation were associated with poor prognosis in OSCC patients. Our results may help clinicians develop more appropriate individualized treatment strategies for their patients, thus improving their outcomes.

Targeting endocytosis to sensitize cancer cells to programmed cell death.

Evading programmed cell death (PCD) is a hallmark of cancer that allows tumor cells to survive and proliferate unchecked. Endocytosis, the process by which cells internalize extracellular materials, has emerged as a key regulator of cell death pathways in cancer. Many tumor types exhibit dysregulated endocytic dynamics that fuel their metabolic demands, promote resistance to cytotoxic therapies, and facilitate immune evasion. This review examines the roles of endocytosis in apoptotic resistance and immune escape mechanisms utilized by cancer cells. We highlight how inhibiting endocytosis can sensitize malignant cells to therapeutic agents and restore susceptibility to PCD. Strategies to modulate endocytosis for enhanced cancer treatment are discussed, including targeting endocytic regulatory proteins, altering membrane biophysical properties, and inhibiting Rho-associated kinases. While promising, challenges remain regarding the specificity and selectivity of endocytosis-targeting agents. Nonetheless, harnessing endocytic pathways represents an attractive approach to overcome apoptotic resistance and could yield more effective therapies by rendering cancer cells vulnerable to PCD. Understanding the interplay between endocytosis and PCD regulation is crucial for developing novel anticancer strategies that selectively induce tumor cell death.

A disulfidptosis-related glucose metabolism and immune response prognostic model revealing the immune microenvironment in lung adenocarcinoma.

Background: Lung adenocarcinoma accounts for the majority of lung cancer cases and impact survival rate of patients severely. Immunotherapy is an effective treatment for lung adenocarcinoma but is restricted by many factors including immune checkpoint expression and the inhibitory immune microenvironment. This study aimed to explore the immune microenvironment in lung adenocarcinoma via disulfidptosis. Methods: Public datasets of lung adenocarcinoma from the TCGA and GEO was adopted as the training and validation cohort. Based on the differences in the expression of disulfidptosis -related genes, a glucose metabolism and immune response prognostic model was constructed. The prognostic value and clinical relationship of the model were further explored. Immune-related analyses were performed according to CIBERSORT, ssGSEA, TIDE, IPS. Results: We verified that the model could accurately predict the survival expectancy of lung adenocarcinoma patients. Patients with lung adenocarcinoma and a low-risk score had better survival outcomes according to the model. Moreover, the high-risk group tended to have an immunosuppressive effect, as reflected by the immune cell components, phenotypes and functions. We also found that the clinically relevant immune checkpoint CTLA-4 was significantly higher in low-risk group (P<0.05), indicating that the high-risk group may suffer worse tumor immunotherapy efficacy. Finally, we found that this model has accurate predictive value for the efficacy of immune checkpoint blockade in non-small cell lung cancer (P<0.05). Conclusion: The prognostic model demonstrated the feasibility of predicting survival and immunotherapy efficacy via disulfidptosis-related genes and will facilitate the development of personalized anticancer therapy.

TLR4 signalling in ischemia/reperfusion injury: a promising target for linking inflammation, oxidative stress and programmed cell death to improve organ transplantation outcomes.

Transplantations represent the principal therapeutic interventions for terminal organ failure, a procedure that has salvaged myriad lives annually. Ischemia/reperfusion injury (IRI) is frequently correlated with an unfavourable prognosis and is relevant for early graft dysfunction and graft survival. IRI constitutes a complex pathological state influenced by a series of factors such as oxidative stress, metabolic stress, leukocytic infiltration, programmed cell death pathways, and inflammatory immune responses. Reducing ischemia/reperfusion injury is one of the main directions of transplantation research. Toll-like receptors (TLRs) are important pattern-recognition receptors expressed on various organs that orchestrate the immune responses upon recognising PAMPs and DAMPs. Targeting the TLR4 signalling has recently been suggested as a promising approach for alleviating IRI by affecting inflammation, oxidative stress and programmed cell death (PCD). In this minireview, we summarise the role of TLR4 signalling in regulating inflammation, oxidative stress and PCD in organ transplantation and discuss their interactions during IRI. A detailed understanding of the multiple functions of TLR4 in IRI provides novel insights into developing therapies to improve organ transplantation outcomes.

Mistakes are not an option: aggression from peers and other correlates of anxiety and depression in pediatricians in training.

Introduction: Pediatricians in training are a population at risk for anxiety and depression: they face long working hours, they are confronted with the suffering and death of a vulnerable population and may have personal characteristics that put them in danger. Nonetheless, few studies have looked at their prevalence and associated factors. We aimed to compare demographic, professional activities, adversities and perfectionism personality features between a group of pediatricians in training with depression and/or anxiety and a group of pediatricians in training without depression nor anxiety and, to identify the variables that increase the probabilities of depression and/or anxiety in pediatricians in training. Methods: Pediatric residents who voluntarily answered an online survey distributed via personal and institutional social media channels from October 2019 to April 2021, as part of a cross-sectional study with medical specialists and residents from Mexico were included. Demographic information, professional activities and adversities, perfectionism personality features (Multidimensional Perfectionism Scale), depression and anxiety (ICD-11 PHC) were evaluated. For comparison purposes Chi-square tests (χ2) and independent sample t-tests were used. A logistic regression analysis was used to identify those variables that increase the probabilities of depression and/or anxiety. Results: 934 pediatric residents answered the survey. 11.6% reported having depression and 20% anxiety. Being single, a history of anxious or depressive episodes, being the resident in charge of a patient who died, aggressions from colleagues and a high concern for errors were associated with current depression and/or anxiety. Discussion: Screening for depressive and anxious symptoms should be routinely performed from entry to the residency to favor early intervention. A shift from promoting perfectionism to a more compassionate training could serve a population facing so many adversities.

Factors associated with mortality among laboratory-diagnosed drug-resistant tuberculosis patients on treatment, KwaZulu-Natal Province, 2017-2019.

Introduction: tuberculosis (TB) remains a leading cause of death in South Africa. KwaZulu-Natal (KZN) is one of the provinces with a high burden of TB/drug-resistant TB cases and deaths. We determined predictors for mortality among drug-resistant TB patients on treatment in KZN province. Methods: we conducted a retrospective cohort study using secondary data from the Electronic Drug-Resistant Tuberculosis Register. We used a modified Poisson regression model with robust standard errors to determine predictors for drug-resistant TB mortality. Results: of the 7,692 eligible patients, 1,234 (16.0%) died. Males predominated (707, 57.3%) and the median age was 36 years (Interquartlile Range: 29-45 years). The majority (978, 79.2%) were HIV-TB co-infected with 911 (93%) on antiretroviral treatment (ART). The predictors included HIV-TB co-infection without ART (aIRR 3.4; 95% CI: 2.3-5.1), unknown ART status (aIRR: 1.8; 95% CI: 1.4-2.3), aged ≥60 years (aIRR: 2.1; 95% CI: 1.6-2.7), previous drug-resistant TB (aIRR: 1.5; 95% CI: 1.2-1.8) and exposure to second-line drugs (aIRR: 1.7; 95% CI: 1.4-2.0). Other predictors were hospitalization during treatment initiation (aIRR 2.5; 95% CI 2.0-3.1), initiation in other treatment facilities (aIRR: 2.2; 95% CI: 1.6-2.9) and rifampicin-resistant (aIRR: 1.2; 95% CI: 1.1-1.4). Bedaquiline fumarate was a significant protective factor against death (aIRR: 0.5; 95% CI: 0.4-0.5). Conclusion: older age, HIV co-infection without ART, hospitalization for treatment initiation, exposure to second-line drugs and a previous episode of drug-resistant TB were predictors for DR-TB mortality. Early treatment initiation and provision of antiretroviral treatment for all co-infected patients may reduce DR-TB mortality in the Province.

Photothermal induction of pyroptosis in malignant glioma spheroids using (16-mercaptohexadecyl)trimethylammonium bromide-modified cationic gold nanorods.

Plasmonic photothermal therapy (PPTT) employing plasmonic gold nanorods (GNRs) presents a potent strategy for eradication of tumors including aggressive brain gliomas. Despite its promise, there is a pressing need for a more comprehensive evaluation of PPTT using sophisticated in vitro models that closely resemble tumor tissues, thereby facilitating the elucidation of therapeutic mechanisms. In this study, we exposed 3D glioma spheroids (tumoroids) to (16-mercaptohexadecyl)trimethylammonium bromide-functionalized gold nanorods (MTAB-GNRs) and a near-infrared (NIR) laser. We demonstrate that the photothermal effect can be fine-tuned by adjusting the nanoparticle concentration and laser power. Depending on the selected parameters, the laser can trigger either regulated or non-regulated cell death (necrosis) in both mouse GL261 and human U-87 MG glioma cell lines, accompanied by translocation of phosphatidylserine in the membrane. Our investigation into the mechanism of regulated cell death induced by PPTT revealed an absence of markers associated with classical apoptosis pathways, such as cleaved caspase 3. Instead, we observed the presence of cleaved caspase 1, gasdermin D, and elevated levels of NLRP3 in NIR-irradiated tumoroids, indicating the activation of pyroptosis. This finding correlates with previous observations of lysosomal accumulation of MTAB-GNRs and the known lysosomal pathway of pyroptosis activation. We further confirmed the absence of toxic breakdown products of GNRs using electron microscopy, which showed no melting or fragmentation of gold nanoparticles under the conditions causing regulated cell death. In conclusion, PPTT using coated gold nanorods offers significant potential for glioma cell elimination occurring through the activation of pyroptosis rather than classical apoptosis pathways.

Late Gadolinium Enhancement in Early Repolarization Syndrome.

BACKGROUND: In patients with Brugada syndrome, myocardial fibrosis can be identified through epicardial biopsy or cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). However, the myocardial alterations in patients with early repolarization syndrome (ERS) remain poorly elucidated. OBJECTIVE: To investigate the presence of myocardial fibrosis in patients with ERS using LGE in CMR. METHODS: We retrospectively evaluated 20 ERS patients, all of whom exhibited J waves in the contiguous two leads. The location of J waves was classified as in the septum (V1-V2), anterior (V3-V4), lateral (I, aVL, V5-V6), inferior (II, III, aVF), or posterior (V7-V9) regions. To compare the distribution of LGE in CMR with J waves, sections of short-axis view of left ventricle (LV) were categorized as located in either the septum, anterior, lateral, inferior, and posterior regions. RESULTS: Overall, 85% of ERS patients displayed LGE, which was more prevalent in the septum and posterior regions, followed by the inferior and lateral regions. The presences or absence of J waves and LGE coincided in 61% of LV areas, while discordance between the distributions of J waves and LGE was observed in 38%. LGE was most frequent in the septum (75%), where its reflection in J waves may be less robust. The appearance of LGE was not associated with symptoms, electrical storm, or VF occurrence during follow-up. CONCLUSIONS: LGE is common among patients with ERS, and the distribution of J waves and LGE coincides in approximately sixty percent of LV areas.