Optimal Timing Of Administration Research Articles

Exploring optimal administration timing of pegylated recombinant human granulocyte colony-stimulating factor for chemotherapy-induced neutropenia in early breast cancer treated with pharmorubicin and endoxan: a prospective randomized controlled clinical trial.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. However, the optimal injection timing of PEG-rhG-CSF after chemotherapy is obscure. The trial was designed to explore the best administration timing of PEG-rhG-CSF when breast cancer patients could benefit most. Patients with early breast cancer were randomly assigned to receive a preventive injection on the 7th or 3rd day following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n = 80) received it on day 3. The occurrence of grades 3-4 neutropenia and FN in the first cycle was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction. In comparison to the control group, the experimental group exhibited higher white blood cell count (WBC) and absolute neutrophil count (ANC) on the 9th and 13th days following chemotherapy (P < 0.05). Additionally, the incidence of grade 3-4 neutropenia was significantly lower in the experimental group (P = 0.038). Furthermore, a greater proportion of patients in the experimental group met the criteria for reducing the PEG-rhG-CSF dose compared to the control group (69.74% vs. 35.06%, P < 0.001). In comparison with PEG-rhG-CSF injection on day 3 after chemotherapy, the incidence of grade 3-4 myelosuppression is lower, and the safety is more manageable after the injection on day 7. This approach potentially allows for a wider adoption of PEG-rhG-CSF dose reduction, leading to a consequential decrease in overall medical costs for patients. Clinical Trials: NCT04477616. Registered July 16, 2020.

Optimizing Chronotherapy in Psychiatric Care: The Impact of Circadian Rhythms on Medication Timing and Efficacy

In many medical settings, medications are typically administered in the morning or evening, aligning with patients’ daily routines. This practice does not stem from chronotherapy, which involves scheduling drug administration to enhance its effectiveness, but rather from the way clinical operations are structured. The timing of drug administration can significantly affect a medication’s effectiveness and side effects, with the impact varying by up to ten times based on circadian rhythms. Disorders such as major depression, bipolar disorder, and schizophrenia are linked to disruptions in these rhythms. Recent studies have found that circadian dysfunctions, including genetic and neurohumoral changes, underlie many psychiatric conditions. Issues such as an altered glucocorticoid rhythm due to impaired HPA axis function, disturbed melatonin balance, and sleep disturbances have been noted in psychotic disorders. Furthermore, mood disorders have been associated with changes in the expression of circadian rhythm genes such as Clock, Bmal1, and Per. Considering that the absorption, biodistribution, effects on target organs, half-life, metabolism, and elimination of drugs are all influenced by the body’s circadian rhythms, this narrative review explores the optimal timing of medication administration to maximize efficacy and minimize side effects in the treatment of psychiatric disorders. By closely monitoring circadian variations in cortisol, melatonin, and key clock genes, as well as by deepening our understanding of the metabolisms and pharmacokinetics of antipsychotic medications, we propose a chronotherapy approach for psychiatric patients that could significantly enhance patient care.

Multimodal spatiotemporal drug assessment platform based on a microelectrode neural network chip in Alzheimer’s disease

The pathogenesis of Alzheimer’s disease (AD) remains elusive. The development of new drugs is protracted, costly, and fraught with failure, largely due to the lack of convenient methods for dynamically studying the pathogenesis of AD and evaluating drug efficacy in vitro. There is a dearth of in vitro multi-site assay platforms capable of observing the therapeutic effects of AD drugs at the level of cellular and network. Consequently, an in vitro multimodal spatiotemporal drug assessment platform has been developed based on a neuronal network chip. It has a symmetric distribution of electrode points with two different sizes (10 μm and 30 μm), which are more suitable for the detection of neuronal connections. The multifaceted neurophysiological properties, including single neuron firing pattern, intercellular connection, transmission speed, and neural network communication, were detected in real time. The results demonstrated that the differences between experimental groups in electrophysiological properties, could significantly distinguish the effects of AD representative drug treatment after different levels of neurological injury. The administration of the drug at the initial stage of β-amyloid oligomers (AβOs) toxicity was found to effectively retard the deterioration of neurons and network (early stage: firing rate increased by 8 %; middle stage: cross-correlation coefficient decreased by 27 %; late stage: similarity index remained positive and relative transmission speed decreased by 11 %). The neurophysiological mechanism of drug interaction was further elucidated, which may provide the guidance for the optimal timing of drug administration. Following the further extension of biosensor longevity and the expansion of synchronous multidimensional parameter detection, including impedance and electrochemistry, it is anticipated that this will become a novel platform for the preclinical evaluation and screening of AD drugs.

Effect of low-dose aspirin intervention on pre-eclampsia prevention in high-risk pregnant women and its impact on postpartum hemorrhage.

Pre-eclampsia, characterized by hypertension and organ dysfunction during pregnancy, poses significant risks to both maternal and fetal health. Aspirin, known for its antiplatelet properties, has been extensively utilized to mitigate pregnancy-related complications. However, the efficacy of low-dose aspirin in managing pre-eclampsia among high-risk pregnant women and its potential impact on postpartum hemorrhage remain contentious topics. A retrospective analysis was conducted on 344 pregnant women diagnosed with high-risk factors for pre-eclampsia. Among them, 152 received intervention with low-dose aspirin, while the rest did not receive it. The incidence of pre-eclampsia, as well as related complications and outcomes associated with bleeding, were compared and evaluated between the two groups. The study findings indicate a significant reduction in the incidence of pre-eclampsia among pregnant women receiving low-dose aspirin intervention, along with a significantly reduced risk of complications. Additionally, there was no significant statistical difference in postpartum hemorrhage between the two groups (p > 0.05). The safety profile of aspirin usage was found to be favorable. Low-dose aspirin demonstrates promising efficacy as an intervention strategy for high-risk preeclamptic women. It does not increase the risk of postpartum hemorrhage and reduces the occurrence of complications associated with preeclampsia. Therefore, low-dose aspirin presents a potential preventive measure against adverse outcomes associated with high-risk pregnancies related to preeclampsia. Further research is necessary to validate and elucidate the optimal dosage and timing of administration for maximal benefits.

Pharmacological Prevention of Postoperative Delirium in Adults: A Review of Recent Literature.

Postoperative delirium (POD) is a common complication that has important implications for surgical patients, often leading to both short- and long-term cognitive deficits, worse outcomes, and increased healthcare costs. Given these implications, there may be a benefit in reducing the incidence of POD. Pharmacologic interventions may have the potential to reduce the risk of a patient developing POD. Recently studied therapies include dexmedetomidine, propofol, haloperidol, ketamine, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, acetaminophen, melatonin/ramelteon, corticosteroids, midazolam, physostigmine, and neostigmine. In addition, the implementation of regional anesthesia and reduction of overall anesthetic depth have been examined. Of these therapies, dexmedetomidine has been studied the most and has the most supporting evidence for prevention of POD, but current studies lack clarity on optimal dosing and timing of dexmedetomidine administration. Acetaminophen, corticosteroids, and melatonin/ramelteon are other plausible medications that have potential for reducing POD incidence, but they all require further investigation. Reduction of anesthetic depth and regional anesthetics are options for anesthetic management that show promise but still lack enough supporting evidence in recent literature to receive a strong recommendation. Future research should focus on identifying optimal strategies for the implementation of the pharmacological options listed, including doses and timing of administration. Attention should be given to dexmedetomidine given its promise demonstrated by recent literature.

Efficacy of timing‑dependent infusion of nivolumab in patients with advanced gastric cancer.

Although an association exists between the timing of immune checkpoint inhibitor (ICI) administration and therapeutic efficacy in several types of cancer, to the best of our knowledge, no reports exist regarding this relationship in gastric cancer (GC). The present study aimed to evaluate the optimal timing of ICI (nivolumab) administration in patients with advanced GC. A total of 58 consecutive patients with advanced GC who received nivolumab monotherapy after ≥2 chemotherapy regimens were retrospectively evaluated. These patients were divided into two groups according to the median time of nivolumab administration: i) Early-timing and (ii) late-timing groups, and the efficacy was assessed in both groups. The early-timing group had significantly longer overall survival (OS) than the late-timing group [median OS 8.2 months; 95% confidence interval (CI), 4.2-12.9 vs. median OS 5.4 months; 95% CI, 3.6-6.1]. Moreover, patients in the early-timing group had significantly longer progression-free survival (PFS) than those in the late-timing group (median PFS 2.6 months; 95% CI, 1.3-3.9 months vs. median PFS 1.6 months; 95% CI, 0.9-2.1 months). Furthermore, univariate analysis showed that early timing, immune-related adverse events and nonsteroidal anti-inflammatory drug administration were associated with longer OS and PFS. Cutoff Finder analysis revealed that the optimal timing of nivolumab administration for achieving better outcomes was before 12:06 p.m. Nivolumab administration in the morning, especially before 12:06 p.m., had a better clinical impact on patients with advanced GC.

Investigating the Optimal Time of Administration of Heparin that will Improve Survival in a Murine Model of Sepsis

Investigating the Optimal Time of Administration of Heparin that will Improve Survival in a Murine Model of Sepsis

Impact of different intravenous bolus rates on fluid and electrolyte balance and mortality in critically ill patients.

The effect of intravenous bolus rates on patient outcomes is a complex and crucial aspect of critical care. Fluid challenges are commonly used in critically ill patients to manage their hemodynamic status, but there is limited information available on the specifics of when, how much, and at what rate fluids should be administered during these challenges. The aim of this review is to thoroughly examine the relationship between intravenous bolus rates, fluid-electrolyte balance, and mortality and to analyze key research findings and methodologies to understand these complex dynamics better. Fluid challenges are commonly employed in managing hemodynamic status in this population, yet there is limited information on the optimal timing, volume, and rate of fluid administration. Utilizing a narrative review approach, the analysis identified nine relevant studies that investigate these variables. The findings underscore the importance of a precise and individualized approach in clinical settings, highlighting the need to tailor intravenous bolus rates to each patient's specific needs to maximize outcomes. This review provides valuable insights that can inform and optimize clinical practices in critical care, emphasizing the necessity of meticulous and exact strategies in fluid administration.

Current Trends in the Imaging Diagnosis of Neonatal Respiratory Distress Syndrome (NRDS): Chest X-ray Versus Lung Ultrasound.

Neonatal respiratory distress syndrome (NRDS) is a major cause of morbidity and mortality in newborns, particularly in neonatal intensive care units (NICUs). Until recently, its diagnosis had been based on clinical signs, arterial blood gas analysis, and chest X-ray (CXR). However, the frequent use of CXR exposes newborns to ionizing radiation, which can have long-term negative effects, including an increased risk of cancer, especially among premature infants. Lung ultrasound (LUS) has been proposed as a promising alternative for diagnosing NRDS due to its many advantages: no exposure to radiation, the ability to be performed at the bedside, repeatability, and ease of use. This review compared the diagnostic accuracy of LUS with the reference standard, CXR, in evaluating NRDS in newborns admitted to the NICU. Studies have shown that LUS can identify specific signs of NRDS, such as bilateral "white lung," pleural line abnormalities, and lung consolidations. The method has high sensitivity and specificity for diagnosing this condition and offers several advantages over other diagnostic methods; it does not involve ionizing radiation, thereby eliminating the risk of radiation exposure; it is cost-effective, easy to use, and can be performed at the patient's bedside, making it a viable alternative to CXR for reducing ionizing radiation exposure. Additionally, LUS can be used to monitor the progression of respiratory diseases and guide clinical management, especially in determining the optimal timing for surfactant administration in newborns with respiratory distress syndrome (RDS). We conclude that LUS is an effective and non-invasive alternative method for diagnosing and managing NRDS, with the potential to improve the safety and quality of care in the NICU, where rapid and safe diagnostic tools are essential for managing the health of newborns.

Methylxanthine use in infants with hypoxic-ischemic encephalopathy: a retrospective cohort study

Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration.

Optimal timing of antibiotic administration in septic patients: The need to reformulate this question

Optimal timing of antibiotic administration in septic patients: The need to reformulate this question

The effect of early versus late remdesivir treatment in hospitalized mild to moderate COVID-19 patients in the Omicron era: A retrospective study.

Although real-world studies have found that remdesivir is effective in preventing poor prognosis, more information is needed on the optimal timing of remdesivir administration in high-risk coronavirus disease 2019 (COVID-19) patients in the Omicron era. From February 2022 to January 2023, a single-center retrospective study was performed in Korea. We compared the clinical characteristics and treatment outcomes between early (remdesivir treatment within 0-3 days from symptom onset) and late (≥ 4 days from symptom onset) treatment groups of patients who received remdesivir monotherapy. Of 284 patients, 225 were classified into the early treatment group and 59 were classified into the late treatment group. The early treatment group had a lower rate of 28-day progression to severe disease than the late treatment group (1.4% vs 7.4%, P = .03). Delaying remdesivir treatment ≥ 4 days from symptom onset (adjusted odds ratio [aOR], 6.17; 95% CI, 1.18-32.44; P = .03) and Charlson comorbidity index ≥ 3 (aOR, 9.62; 95% CI, 1.65-56.10; P = .01) were independent risk factors for 28-day progression to severe disease. Our results suggest that early administration of remdesivir could be associated with better prognosis in COVID-19 patients with the Omicron variant, and within 3 days from symptom onset seems to be the appropriate timing.

When Are Pregnant Patients Receiving Tranexamic Acid during Delivery Hospitalization in the United States?

The World Health Organization recommends tranexamic acid (TXA) in the management of postpartum hemorrhage (PPH). However, the role of TXA in PPH prevention and the optimal timing of TXA administration remain unknown. Our objective was to describe the timing of TXA administration, differences in timing of TXA administration by mode of delivery, and current trends in TXA administration in the United States. We conducted a descriptive study of trends in TXA administration using the Cerner Real-World Database. We identified 1,544,712 deliveries occurring at greater than 24 weeks' gestation from January 1, 2016, to February 21, 2023. Demographic data were collected including gestational age, mode of delivery, and comorbidities. The timing of TXA administration and differences in TXA timing by mode of delivery were also collected. In our cohort, 21,433 patients (1.39%) received TXA. The majority of patients who received TXA were between ages 25 and 34 years old (55.3%), White (60.7%), and delivered between 37 and 416/7 weeks (81.4%). The TXA group had a higher prevalence of medical comorbidities including obesity (32.9 vs. 19.0%, p < 0.00001), preeclampsia (19.6 vs. 6.81%, p < 0.00001), and pregestational diabetes (3.27 vs. 1.36%, p < 0.00001). Among women who received TXA, 15.4% received it within 3 hours before delivery. Among patients who received TXA after delivery, 23.6% received TXA within 3 hours after delivery, whereas 35.7% received TXA between 10 and 24 hours after delivery. A total of 80.4% of patients who received TXA before delivery had a cesarean delivery. While TXA is most commonly administered after delivery, many patients are receiving TXA prior to delivery in the United States without clear evidence to guide the timing of administration. A randomized trial is urgently needed to determine the safety and efficacy of TXA when administered prior to delivery. · TXA is used in the treatment of PPH.. · The role of TXA in prevention of PPH is unclear.. · Fewer than 2% of patients in the United States receive TXA at delivery.. · TXA administration before delivery in the United States is rising..

A Retrospective Exploration of Pre-operative Antibiotic Prophylaxis with Cefazolin in Cesarean Sections: Implications for Obstetrics and Gynecologic Surgery.

Background: Post-partum infection is a major contributor to maternal mortality and is responsible for approximately 10% of maternal fatalities worldwide. The risk of infection is substantially higher in cesarean section procedures. Approximately 8% of women who undergo cesarean sections are susceptible to infection. Although the body of evidence supporting the regular pre-operative utilization of prophylactic antibiotic treatment is steadily expanding, its usefulness in cesarean sections has not yet been standardized, and post-partum infection is still a serious medical challenge. We aimed to retrospectively assess the prophylactic effectiveness of cefazolin in combination with other antibiotic agents in cesarean sections. Materials and Methods: Both uni-variable and multi-variable analyses were conducted to identify factors that may affect cefazolin pre-operative antibiotic prophylaxis in elective cesarean section operations. The uni-variable analysis included timing of administration, operation duration, body mass index (BMI), and wound type. A multi-variable logistic regression model was then created to determine which variables provide independent information in the context of other variables. Results: Time of administration did not affect prophylactic cefazolin efficacy. However, prophylactic cefazolin was 1.43 and 1.77 times more effective when the operation lasted for 45 minutes or more, compared with operations that were shorter than 45 minutes. Patients with a BMI ranging from 18 to 29 kg/m2 showed increased efficacy of prophylactic cefazolin compared with obese patients with a BMI exceeding 30 kg/m2. The effectiveness of prophylactic cefazolin decreased by 95% in patients with clean-contaminated surgical incisions compared with those with clean surgical incisions. Conclusions: Our findings demonstrate that administering pre-operative prophylactic antibiotic agents to women undergoing cesarean section resulted in a reduction in post-partum infections, thereby reducing maternal mortality. Furthermore, optimal timing of administration, re-dosing if necessary, length of prophylactic medication, and dosing adjustments for obese patients are crucial factors in preventing surgical site infections and promoting antimicrobial stewardship.

Intravaginal probiotics before embryo transfer do not improve pregnancy rates in recurrent implantation failure cases: An RCT.

Considering the considerable influence of the vaginal microbiome on endometrial receptivity and embryo implantation, we hypothesized that cases of recurrent implantation failure (RIF) might benefit from the intravaginal probiotic administration. Evaluation of the effects of intravaginal probiotic administration before frozen embryo transfer (FET) on the rates of pregnancy and the status of vaginal lactobacillary flora in cases of RIF. This was a randomized, parallel-group, clinical trial conducted at an infertility clinic in Tehran, Iran between January 2021 and September 2022. A total of 166 reproductive-aged women with a history of unexplained RIF were randomly assigned to either the probiotic group or the control group (n = 83/each group). The probiotic group received intravaginal probiotics (LactoVagⓇ) daily for 2 wk from the second day of the menstrual cycle along with the routine treatment of FET. The control group received only the routine treatment of FET. The primary outcome was the chemical pregnancy rate, and the secondary outcomes were the clinical pregnancy rate and the status of vaginal lactobacillary flora. A total of 163 participants were included in the final analysis. The probiotic group had a slightly higher chemical pregnancy rate than the control group (39.02% vs. 33.33%), but the difference was not statistically significant (risk ratio: 1.71, 95% CI: 0.77-1.76; p = 0.449). The clinical pregnancy rate was also non-significantly higher in the probiotic group than the control group (37.80% vs. 33.33%; RR: 1.14, 95% CI: 0.76-1.74; p = 0.623). Intravaginal probiotic administration did not significantly improve the pregnancy rates in RIF cases undergoing FET. Further studies are needed to explore the optimal dose, duration, and timing of probiotic administration, as well as the mechanisms of action and the potential adverse effects of probiotics on the vaginal microbiome and the implantation process.

Development, Characterization, and Evaluation of Potential Systemic Toxicity of a Novel Oral Melatonin Formulation.

The need to create safe materials for biomedical and pharmaceutical applications has become a significant driving force for the development of new systems. Therefore, a chitosan-coated copolymer of itaconic acid, acrylic acid, and N-vinyl caprolactam (IT-AA-NVC) was prepared by radical polymerization and subsequent coating via nanoprecipitation to give a system capable of sustained delivery of melatonin. Although melatonin brings undoubted benefits to the human body, aspects of the optimal dose, route, and time of administration for the obtaining of suitable treatment outcomes remain under discussion. The entrapment of melatonin in biocompatible polymeric systems can prevent its oxidation, decrease its toxicity, and provide an increased half-life, resulting in an enhanced pharmacokinetic profile with improved patient compliance. The structures of the biopolymer and conjugate were proven by FTIR, thermal properties were tested by DSC, and the morphologies were followed by SEM. The loading efficiency and in vitro release profile were studied by means of HPLC, and a delayed release profile with an initial burst was obtained. The potential systemic toxicity of the formulation was studied in vivo; a mild hepatotoxicity was observed following administration of the melatonin-loaded formulation to mice, both by histopathology and blood clinical biochemistry. Histopathology showed a mild nephrotoxicity as well; however, kidney clinical biochemistry did not support this.

Timing of P2Y12 Inhibitor Administration in Patients With STEMI Undergoing Primary PCI

BackgroundThe optimal timing of P2Y12 inhibitor administration in patients with ST-segment elevation myocardial infarction (STEMI) has not been completely elucidating. ObjectivesThis analysis from a prospective multicenter registry sought to assess the safety and effectiveness of P2Y12 inhibitor pretreatment in patients transferred for primary percutaneous coronary intervention (PCI) within a regional STEMI network. MethodsPretreatment was defined as P2Y12 inhibitor administration before coronary angiography. Endpoints were major adverse cardiac events (MACE), major bleeding, and net adverse clinical events, a composite of MACE or major bleeding, within 30 days of index admission. Association of P2Y12 inhibitor pretreatment with outcomes was modeled using doubly robust weighted estimators based on propensity score analysis. ResultsOf 1,624 patients included, 1,033 received P2Y12 inhibitors before angiography and 591 in the catheterization laboratory (cath lab). The non-pretreated cohort more often had history of coronary artery disease and were more likely to receive antiplatelet therapy before the index admission. After adjustment for confounding and dependent censoring, pretreatment with P2Y12 inhibitors predicted lower risk of MACE (adjusted HR: 0.53; 95% CI: 0.37-0.76), without increasing bleeding risk (adjusted HR: 0.62; 95% CI: 0.36-1.05), resulting in superior net clinical benefit (adjusted HR: 0.47; 95% CI: 0.26-0.86) compared with in-cath lab administration of P2Y12 inhibitors. There was a significant treatment-by-time interaction for MACE risk, whereby the observed benefits of pretreatment only became apparent when time between P2Y12 inhibitor administration and PCI was longer than 80 minutes. ConclusionsIn contemporary patients with STEMI transferred for primary PCI, pretreatment with P2Y12 inhibitors was associated with a significant time-dependent reduction of 30-day MACE without increasing bleeding risk.

Molecular Mechanisms of N-Acetylcysteine in RSV Infections and Air Pollution-Induced Alterations: A Scoping Review.

N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models (n = 18), animal models (n = 7), and mixed models (n = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.

Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets.

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.

PHARMACOLOGICAL INTERVENTIONS FOR THE PREVENTION OF BLEEDING IN PEOPLE UNDERGOING ELECTIVE HIP OR KNEE SURGERY: A COCHRANE SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Preoperative anaemia and intraoperative blood loss result in ∼90% of individuals being anaemic following hip and knee arthroplasty. Reducing blood loss offers the opportunity to improve outcomes and reduce the risk of transfusion and costs. This review's aim was to determine the effectiveness of drugs for preventing blood loss, and identify optimal dose, route, and timing of administration.Cochrane network meta-analysis of randomised controlled trials was conducted. Inclusion criteria: adults undergoing primary or revision elective hip or knee arthroplasty. Drugs studied: tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid, desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants. Primary outcomes: need for allogenic blood transfusion, all• cause mortality (within 30 days). Secondary outcomes: mean number of transfusion episodes, re-operation, length of hospital stay and adverse events (DVT, PE, CVA, MI).102 studies with 8418 participants. Trials included more women (63%). 47 studies (4398 participants) were included within the blood transfusion NMA. TXA given intra-articularly and orally at a total dose of greater than 3g pre-incision, intraoperatively and postoperatively ranked the highest, with anticipated absolute effect of 147 fewer transfusions per 1000 (53% chance ranking 1st) (relative risk(RR) 0.02, 95% credible interval(CrI) 0–0.31); moderate-certainty). Aprotinin (RR 0.59, 95%:CrI 0.36–0.86; low certainty evidence), fibrin (RR 0.86, CrI 0.25–2.93; very-low certainty) and EACA (RR 0.60, 95%:CrI 0.29–1.27; very-low certainty) were not shown to be as effective as TXA.TXA was the most effective drug for preventing bleeding in lower limb arthroplasty. Aprotinin and EACA were not as effective. Currently, the optimal dose, route and timing of administration of TXA is unclear. However, TXA given at higher doses and via mixed routes ranked higher in the treatment hierarchy. Oral TXA may be as effective as intavenous. There was no evidence of harm associated with higher doses of TXA.