war ; armed conflicts ; Nuclear Energy ; Atomic Energy ; Radiation ; Nuclear Weapons

war ; Armed Conflicts ; Nuclear Energy ; Atomic Energy ; Radiation ; Nuclear Weapons

Objective: To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs (miRNAs) implicated in rheumatoid arthritis (RA) pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment. Methods: miRNA microarray data (CEL and TXT formats) were acquired from human and murine RA models, with the latter undergoing acupuncture treatment. Data were normalized using the robust multi-array average (RMA) method and analyzed for differential expression. Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues, acupuncture-treated murine RA models, and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment. Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins (STRING) and ShinyGO. Gene-drug interaction analysis was performed through Drug-Gene Interaction Database (DGIdb) screening. Interaction networks were constructed with the Cytoscape v3.10.3 software. Results: The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis, presenting 468 and 455 target genes, respectively. These genes were enriched in 20 signaling pathways, including Janus kinasa-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which have been associated with RA pathogenesis and progression. Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs, among which 13 genes interacted with members of the hsa-miR-125 family. Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways, including JAK-STAT, MAPK, PI3K-Akt, and NF-κB. Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases, including RA management. This suggests their potential roles as biomarkers for monitoring acupuncture treatment. Although existing evidence indicates that acupuncture can modify miRNA expression profiles, rigorous validation through biological models remains essential to confirm these results.

Over the past two decades, marked progress has been made in treating non-small cell lung cancer (NSCLC) patients with EGFR-, ALK-, ROS1- and KRAS^G12C-targeted inhibitors. NSCLC patients very often develop brain metastases. Despite the continuous development of newer and better inhibitors, the survival outcomes of NSCLC patients with brain metastases remain significantly worse than those of patients without. The main challenges in these pharmacotherapies are the development of resistance mutations, and, potentially, the presence of the blood-brain barrier (BBB). The outcomes of clinical studies show the improved efficacy of later-generation targeted inhibitors. The increase in progression free survival (PFS) in patients treated with these later-generation inhibitors is largely attributed to their efficacy against multiple resistance mutations, and possibly due to enhanced brain penetration. This review explores the different aspects hindering the targeted treatment of NSCLC and especially of brain metastases, focusing on recent clinical trials and emerging resistance mutations and the influence of the BBB on the efficacy of EGFR, ALK, ROS1 and KRAS^G12C inhibitors. The role of the ABCB1 and ABCG2 drug transporters in differential efflux of the targeted drugs at the BBB is also discussed, since preclinical studies indicate that they may reduce the efficacy of transported inhibitors.

Objective: : Trauma is a leading causes of death and disability in all ages. The aim of this study was to describe the demography and characteristics of paediatric head trauma in our institution and examine the predictors of outcome and incidence of injury related mortality. Methods: : We examined our institutional Trauma Registry over a 2 year period. Results: : A total of 1100 trauma patients were seen over the study period. Of the 579 patients who had head injury 99 were in the paediatric age group. Of the paediatric head trauma patients 79 had documented Glasgow coma score (GCS), 38 (48.1%), 17 (21.5%) and 24 (30.4%) had mild, moderate and severe head injury respectively. The percentage mortality of head injury in the paediatric age group was 6.06% (6/99). There is an association between mortality and GCS (p=0.008), necessity for intensive care unit (ICU) admission (p=0.0001), associated burns (p=0.0001) and complications such as aspiration pneumonia (p=0.0001). The significant predictors of outcome are aspiration (p=0.004), the need for ICU admission (p=0.0001) and associated burns (p=0.005) using logistic binary regression. During the study period 46 children underwent surgical intervention with extradural haematoma 16 (34.8%), depressed skull fracture 14 (30.4%) and chronic subdural haematoma five (10.9%) being the commonest indication for surgeries. Conclusion : Paediatric head injury accounted for 9.0% (99/1100) of all trauma admissions. Majority of patients had mild or moderate injuries. Burns, aspiration pneumonitis and the need for ICU admission were important predictors of outcome in children with traumatic brain injury.

The Russian military invasion of Ukraine on February 24, 2022, and Hamas’ terror attack on Israel on October 7, 2023, signaled the beginning of two of the most recent wars to make international headlines. To date, over 110 armed conflicts are taking place: over 45 in the Middle East and North Africa (Cyprus, Egypt, Iraq, Israel, Libya, Morocco, Palestine, Syria, Turkey, Yemen, Western Sahara); over 35 in Africa (Burkina Faso, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Ethiopia, Mali, Mozambique, Nigeria, Senegal, Somalia, South Sudan, Sudan); 21 in Asia (Afghanistan, India, Myanmar, Pakistan, the Philippines); seven in Europe (Russia, Ukraine, Moldova, Georgia, Armenia, Azerbaijan); and six in Latin America (three each in Mexico and Colombia); with two more international armed conflicts (between India and Pakistan, and between India and China) in Asia.1 This list does not even include such problematic situations as those involving China and the South East Asia region. As though these situations of armed violence were not enough, mankind has already passed or is on the verge of passing several climate tipping points – a recent review lists nine Global core tipping elements (and their tipping points) - the Greenland Ice Sheet (collapse); West Antarctic Ice Sheet (collapse); Labrador-Irminger Seas / SPG Convection (collapse); East Antarctic Subglacial Basins (collapse); Amazon Rainforest (dieback); Boreal Permafrost (collapse); Atlantic M.O. Circulation (collapse); Arctic Winter Sea Ice (collapse); and East Antarctic Ice Sheet (collapse); and seven Regional impact tipping elements (and their tipping points) – Low-latitude Coral Reefs (die-off); Boreal Permafrost (abrupt thaw); Barents Sea Ice (abrupt loss); Mountain Glaciers (loss); Sahel and W. African Monsoon (greening); Boreal Forest (southern dieback); and Boreal Forest (northern expansion).2 Closer to home, how can we forget the disaster and devastation wrought by Super Typhoon Haiyan (Yolanda) 10 years ago to date? Whether international or non-international, armed conflicts raise the risk of nuclear war. Russia has already “rehearsed its ability to deliver a ‘massive’ nuclear strike,” conducting “practical launches of ballistic and cruise missiles,” and stationed a first batch of tactical nuclear weapons in Belarus,3 and the possibility of nuclear escalation in Ukraine cannot be overestimated.4 Meanwhile, in a rare public announcement, the U.S. Central Command revealed that an Ohio- class submarine (560 feet long, 18,750 tons submerged and carrying as many as 154 Tomahawk cruise missiles) had arrived in the Middle East on November 5, 2023.5 Indeed, “the danger is great and growing,” as “any use of nuclear weapons would be catastrophic for humanity.”
Armed Conflicts ; Nuclear Energy ; Radiation ; Climate Change ; Global Warming

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 ^-/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 ^-/- background (TgCES1). Ces1 ^-/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 ^-/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 ^-/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 ^-/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

In this study, we aim to elucidate the clinical impact and long-term course of tricuspid regurgitation (TR), taking into account its dynamic nature, after biatrial orthotopic heart transplant (OHT). All consecutive adult patients undergoing biatrial OHT (1984-2017) with an available follow-up echocardiogram were included. Mixed-models were used to model the evolution of TR. The mixed-model was inserted into a Cox model in order to address the association of the dynamic TR with mortality. In total, 572 patients were included (median age: 50 years, males: 74.9%). Approximately 32% of patients had moderate-to-severe TR immediately after surgery. However, this declined to 11% on 5 years and 9% on 10 years after surgery, adjusted for survival bias. Pre-implant mechanical support was associated with less TR during follow-up, whereas concurrent LV dysfunction was significantly associated with more TR during follow-up. Survival at 1, 5, 10, 20 years was 97% ± 1%, 88% ± 1%, 66% ± 2% and 23% ± 2%, respectively. The presence of moderate-to-severe TR during follow-up was associated with higher mortality (HR: 1.07, 95% CI (1.02-1.12), p = 0.006). The course of TR was positively correlated with the course of creatinine (R = 0.45). TR during follow-up is significantly associated with higher mortality and worse renal function. Nevertheless, probability of TR is the highest immediately after OHT and decreases thereafter. Therefore, it may be reasonable to refrain from surgical intervention for TR during earlier phase after OHT.
Male ; Adult ; Humans ; Middle Aged ; Tricuspid Valve Insufficiency/diagnostic imaging* ; Heart Transplantation ; Echocardiography ; Ventricular Dysfunction, Left ; Retrospective Studies ; Treatment Outcome

The coronavirus disease 2019 (COVID-19) epidemic is evolving in Latin America despite implementation of government measures. We report a familial cluster in Lima, Peru, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Two young and two middle-aged adults with a wide range of COVID-19 manifestations experienced successful management under telehealth outpatient monitoring. Telehealth monitoring was scheduled as suggested by Peruvian Ministry of Health Guidelines and was performed by a designated physician who assessed the patients and prescribed treatment. On May 14, 2020, a 25-year-old male, who worked treating COVID-19 patients, reported constitutional symptoms and tested positive for SARS-CoV-2. Clinical improvement was achieved with azithromycin and ivermectin therapy. He had been in contact with his parents (Cases 2 and 3) and his sister (Case 4). Cases 2 and 3 developed moderate pulmonary compromise requiring oxygen supplementation and pharmacological therapy, including corticosteroids and anticoagulation, under home medical assessment and telehealth monitoring. Case 4 developed mild symptoms and periorbital rash, an atypical dermatological finding. To our knowledge this represents the first report of a familial cluster with COVID-19 that was successfully managed under scheduled telehealth outpatient monitoring in Latin America.
SARS-CoV-2 ; COVID-19 ; Telemedicine ; Remote Consultation