Prophylactic Administration Research Articles

The pharmacokinetic profile of brensocatib and its effect on pharmacodynamic biomarkers including NE, PR3, and CatG in various rodent species.

Brensocatib is a novel, oral, selective, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which activates several neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) in the bone marrow during the early stage of neutrophil maturation. These NSPs are associated with pathogen destruction and inflammatory mediation; their dysregulated activation can result in excess secretion of active NSPs causing damaging inflammation and contributing to neutrophil-mediated inflammatory and autoimmune diseases. Pharmacological inhibition of DPP1 in the bone marrow could therefore represent an attractive strategy for these neutrophil-driven diseases. A completed Phase 2 trial in non-cystic fibrosis bronchiectasis patients (ClinicalTrials.gov number NCT03218917; EudraCT number: 2017-002533-32) indeed demonstrated that administration of brensocatib attenuated the damaging effects of chronic inflammation by inhibiting the downstream activation of NSPs. To support a range of preclinical programs and further understand how rodent species and strains may affect brensocatib's pharmacokinetic (PK) profile and its pharmacodynamic (PD) effects on NE, PR3, and CatG, an extensive naïve dosing study with brensocatib at different dosing levels, frequencies, and durations was undertaken. Dose-dependent PK exposure responses (AUC and Cmax) were observed regardless of the rodent species and strain. Overall, mice showed greater reduction in NSP activities compared to rats. Both mice and rats dosed once daily (QD) had equivalent NSP activity reduction compared to BID (twice a day) dosing when the QD dose was 1.5-times the BID daily dose. For both mouse strains, CatG activity was reduced the most, followed by NE, then PR3; whereas, for both rat strains, PR3 activity was reduced the most, followed by CatG, and then NE. Maximum reduction in NSP activities was observed after ∼7 days and recoveries were nearly symmetrical. These results may facilitate future in vivo brensocatib study dosing considerations, such as the timing of prophylactic or therapeutic administration, choice of species, dosage and dosing frequency.

Prophylactic use of levosimendan in preoperative setting for surgical repair of congenital heart disease in children.

Low cardiac output syndrome (LCOS) is a significant cause of morbidity and the leading cause of mortality after pediatric cardiac surgery. Levosimendan has been shown safe and effective in pediatrics to treat LCOS. We aimed to review our local strategy with preoperative prophylactic Levosimendan infusion to minimize LCOS after heart surgery in identified high-risk patients. Retrospective monocentric study. As there is no reliable cardiac output measurement in children, we recorded hemodynamic parameters as surrogates of cardiac output after extracorporeal circulation through an electronic patient survey system at different time points. Seventy-two children received Levosimendan before surgery between 2010 and 2019. As expected, most patients were newborns and infants with prolonged open-heart surgeries. Median cardiopulmonary bypass time was 182 [137-234] min, and aortic clamping time was 95 [64-126] min. The postoperative hemodynamic parameters, vasoactive-inotropic score, and urine output remained stable throughout the first 48 h. Only a tiny portion of the patients had combined surrogate markers of LCOS with a maximal median arterial lactate of 2.6 [1.9-3.5] mmol/L during the first six postoperative hours, which then progressively normalized. The median arterio-venous difference in oxygen saturation was 31 [23-38] % between 12 and 18 h post-surgery and gradually decreased. The median venous-to-arterial CO2 difference was the highest at 10 [7-12] mmHg between 12 and 18 h post-surgery. Nine patients (13%) required extracorporeal membrane oxygenation. No patient required dialysis or hemofiltration. Mortality was 0%. Before congenital heart surgery, preoperative prophylactic administration of Levosimendan seems effective and safe for decreasing occurrence and duration of LCOS in high-risk children.

Efficacy of prophylactic intravenous dexamethasone on postoperative laryngotracheal symptoms after orotracheal extubation: A randomized study

Postoperative sore throat (POST) is not an uncommon complaint and has been described as one of the most undesirable outcomes during the postoperative period after orotracheal extubation, because it adversely affects the patient satisfaction and activities after discharge from hospital. Cough and hoarseness are other problems that follow intubation. The objective of this study was to determine the efficacy of prophylactic intravenous dexamethasone in reducing post postoperative sore throat, cough and hoarseness of voice in patients operated under general anaesthesia with orotracheal intubation.After obtaining approval from hospital ethical committee and informed consent from the patients. The patients were divided in to two groups of 40 each. Group C- patients who received a placebo (normal saline) Group D- patients who received a treatment drug (dexamethasone). Assessment of patients for post-operative sore throat, cough, and hoarseness of voice at 1, 6 and, 24 hours after surgery will be carried out by the investigator and anaesthesiologist in charge of the post anaesthesia care unit, who is blinded to the group allocation, using the questionnaire.There was significant reduction in scores of postoperative sore throat and cough in 1postoperative hour (p<0.005) than in 6 and 24 hours in comparison with placebo group (group C). from the present study, it can be concluded that prophylactic iv dexamethasone administration significantly reduces postoperative sore throat, cough when compared to control groups.

Prophylactic Administration of Vasopressors Prior to Emergency Intubation in Critically Ill Patients: A Secondary Analysis of Two Multicenter Clinical Trials.

A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors. Seven emergency departments and 17 ICUs across the United States. One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021. None. The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66). The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes.

Risk factors of preterm infants with CPAP intubated for mechanical ventilation

Early use of continuous positive airway pressure (CPAP) is equal to the prophylactic administration of a surfactant to prevent neonatal respiratory distress syndrome (nRDS) in high-risk infants. However, almost half of the smallest infants still require intubation and mechanical ventilation in the first 72 hours after birth. It is known that ineffective initial CPAP is associated with a poorer prognosis. Therefore, the search for reliable prognostic risk factors for ineffective CPAP in very preterm neonates whose respiratory support is started with CPAP is still relevant today. The results of a retrospective cohort study conducted at the Lviv Regional Clinical Hospital (Ukraine), which included 151 children with birth weight <1500 g and gestational age <32 weeks, showed that CPAP failure occurred at a median age of five hours in 31% of infants initially treated with CPAP and average (SD) FiO2, while the failure point was 0.48 (0.15). The prevalence of the main risk factors for severe nRDS did not differ significantly between two groups (CPAP success and CPAP failure). The risk of CPAP failure was significantly associated with surfactant treatment (OR – 7.46; 95% CI: 2.3–24.2), severe RDS (OR – 12.17; 95% CI: 3.8–39.3), requirement in resuscitation after birth (OR – 3.10; 95% CI: 1.2–8.1), initial CPAP pressure (OR – 0.38; 95% CI: 0.15–0.99). Earlier administration of exogenous surfactant to children at high risk of developing severe RDS could prevent the need for mechanical ventilation. Keywords: CPAP failure, neonatal respiratory distress syndrome mechanical ventilation, preterm infants, surfactant

Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.

Comparison of Short-Term Infectious Rates Related to Implantable Venous Port Placement With and Without Prophylactic Antibiotic Administration

Abstract The purpose of this study is to determine the rate of short-term central line-associated bloodstream infections (CLABSI) related to port placement in patients who received prophylactic intravenous antibiotics compared with those who did not receive prophylactic antibiotics. A retrospective review of 545 consecutive patients who underwent implantable port placement at Mayo Clinic, Rochester, Minnesota, from May 2020 to June 2021 was conducted. A total of 270 patients underwent port placement with prophylactic antibiotics administration. A total of 275 patients underwent port placement without the administration of antibiotics. The rate of short-term or 30-day CLABSI in both groups was reviewed. Indications for port placement included vascular access for chemotherapy and need for long-term vascular access for intravenous hydration, intravenous immunoglobulin infusion, electroconvulsive therapy, and photophoresis. Short-term infections occurred in a total of 3 of 545 patients (0.55%). Rate of short-term infection in patients who had port placement without prophylactic antibiotics was 2 of 275 (0.72%). Rate of short-term infection in patients who underwent port placement with prophylactic antibiotics was 1 of 270 (0.37). All 3 patients presented with bacteremia and were treated with port explantation and intravenous antibiotics. Overall, 30-day CLABSI in 545 patients who underwent port placement was 0.55%. There was no significant difference in the rate of short-term infections in the group who received prophylactic antibiotics (0.37%) compared with patients who did not receive any preprocedural antibiotics (0.72%).

RELATIONSHIP BETWEEN HAEMOSTATIC AND MACRO-MICROHEMODYNAMIC PARAMETERS IN RATS UNDER EXPERIMENTAL EXPOSURE TO CADMIUM. MEANS OF PREVENTION

In experiments on Wistar rats, it was shown that the prophylactic administration of melatonin at a dose of 5 mg/kg helps to reduce the manifestations of toxic coagulopathy, preventing the development of micro- and macrohemodynamic disorders in rats with chronic cadmium intoxication. Correlations between changes in indicators of the hemostasis system with the restoration of linear and volumetric blood flow rates and a decrease in the Pourcelot peripheral resistive index were revealed. These effects correlated with a decrease in the level of lipid peroxidation products and the activity of antioxidant enzymes in the blood under the influence of melatonin. The results of the experiments suggest further studies on using melatonin for the prevention and correction of the procoagulative and pathocirculatory effects of cadmium.

Evaluation of bacteriophage therapy of Aeromonas hydrophila infection in a freshwater fish, Pangasius buchanani

IntroductionThe present study aimed to optimize the doses and schedule of specific bacteriophage cocktails in freshwater fish infections as prophylactic and therapeutic measures.MethodsThe three most active phages against Aeromonas hydrophila (A. hydrophila) (φAHBHU12, φAHBHU16, and φAHBHU19) were characterized phenotypically and genotypically. Intramuscular and water immersion routes were used to calculate the absolute lethal dose of A. hydrophila in Pangasius buchanani. Phage therapy was given simultaneously and after 6, 12, and 24 h of bacterial challenge through intramuscular and water immersion routes.ResultsThe prophylactic and early phage administration could save the fish. Furthermore, the dose of intramuscular 1.0 × 104 plaque-forming unit (PFU)/fish and water immersion 1.0 × 106 PFU mL–1 of the phage cocktail was optimal.DiscussionThe efficacy of bacteriophage therapy as preventive or curative measures practical when administered simultaneously or early hours of A. hydrophila infection in aquaculture systems. Phage-based approaches may be used as an alternative to antibiotics in aquaculture to reduce antibiotic use as a part of the “One Health” approach.

Die perioperative Gabe von Tranexamsäure.

The application of tranexamic acid (TXA) during endoprosthetic surgical procedures has significantly increased in recent years. Due its ability to reduce perioperative blood loss and avert the need for blood transfusions as well as wound drainage, TXA is becoming part of a 'standard practice'. However, TXA is currently not approved for the application during endoprosthetic procedures and therefore, a benefit-risk analysis should always be conducted. Prophylactic administration of TXA without prior patient consent is only justified if fibrinolytic bleeding is expected and there are no contraindications or relevant risk factors for thromboembolic complications. Respectively, no patient consent is required when a therapeutic dose of TXA is administered in the context of fibrinolytic bleeding. The following guidelines provide updated recommendations based on the current state of knowledge on TXA optimal timing, routes of administration and dosing regimen.

STEROIDS IN CARDIAC SURGERY: A SYSTEMATIC REVIEW

Since there has been considerable research on the prophylactic administration of corticosteroids in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), there is limited evidence to suggest that steroid therapy substantially affects patient outcomes.
 Objective: This study aims to investigate the effects of administering steroids during cardiac surgery.
 Aim: This study complied with the PRISMA 2020 guidelines for systematic review and meta-analysis. The researchers verified the study's similarity to become feasible. Publications from 2015 to 2023 were searched using online reference databases, including Pubmed and SagePub. Review articles, previously published works, and incomplete articles were dismissed.
 Methods: The search identified 9,316 articles in PubMed and 7,654 articles in SagePub. In 2015, a search on PubMed identified 238 articles, and a search on SagePub yielded 121 articles. At last, 27 papers were selected, with 15 sourced from PubMed and 12 from SagePub. We included five studies that met the criteria.
 Conclusion: The relationship between prescribing steroids and surgical site infections is still debated. Corticosteroid therapy has been found to reduce the incidence of postoperative delirium.

Ibrutinib Delays ALS Installation and Increases Survival of SOD1G93A Mice by Modulating PI3K/mTOR/Akt Signaling.

Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 G93A mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 G93A mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.

The Effect of Prophylactic Steroids on Shivering in Adults Undergoing Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Shivering is common following anesthesia and surgery. Corticosteroids (steroids) have been tried to reduce the risk of shivering, but the evidence in favor of their use is uncertain. The primary objective of this review was to evaluate the effect of steroids on the risk of perioperative (intra- and postoperative) shivering versus controls (placebo and active controls). Additional objectives were to assess the risk of severity of shivering, patient satisfaction with shivering prophylaxis, quality of recovery (QoR), and the risk of steroid-related adverse effects. PubMed, Embase, Cochrane Central Registry of Trials, Google Scholar, and preprint servers were searched from inception until November 30, 2022. Randomized controlled trials (RCTs) published in the English language were retrieved, provided they reported on shivering either as a primary or secondary outcome following steroid prophylaxis in adult patients undergoing surgery under spinal or general anesthesia. A total of 3148 patients from 25 RCTs were included in the final analysis. The steroids used in the studies were either dexamethasone or hydrocortisone. Dexamethasone was administered intravenously or intrathecally, while hydrocortisone was administered intravenously. Prophylactic administration of steroids reduced the risk of overall shivering (risk ratio [RR], 0.65 [95% confidence interval {CI}, 0.52-0.82]; P = .0002; I2 = 77%) as well as the risk of moderate to severe shivering (RR, 0.49 [95% CI, 0.34-0.71]; P = .0002; I2 = 61%) in comparison to controls. Administration of intravenous dexamethasone (RR, 0.67 [95% CI, 0.52-0.87]; P = .002; I2 = 78%) and hydrocortisone (RR, 0.51 [95% CI, 0.32-0.80]; P = .003; I2 = 58%) were effective in shivering prophylaxis. For intrathecal dexamethasone (RR, 0.84 [95% CI, 0.34-2.08]; P = .7; I2 = 56%), the null hypothesis of no subgroup difference was not rejected ( P = .47), preventing definitive conclusions about the efficacy of this route of administration. The prediction intervals for both overall shivering risk (0.24-1.70) and risk of severity of shivering (0.23-1.0) precluded generalization of results in future studies. Meta-regression analysis was used to further explore heterogeneity. Factors like the dose and timing of administration of steroids or the type of anesthesia were not found to be significant. Patient satisfaction and QoR were higher in the dexamethasone groups versus placebo. No increased risk of adverse events of steroids was noted versus placebo or controls. Prophylactic steroid administration may be beneficial in reducing the risk of perioperative shivering. However, the quality of evidence in favor of steroids is very low. Further well-designed studies are needed for establishing generalization.

Novel Effect of p-Coumaric Acid on Hepatic Lipolysis: Inhibition of Hepatic Lipid-Droplets.

p-coumaric acid (p-CA), a common plant phenolic acid with multiple bioactivities, has a lipid-lowering effect. As a dietary polyphenol, its low toxicity, with the advantages of prophylactic and long-term administration, makes it a potential drug for prophylaxis and the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism by which it regulates lipid metabolism is still unclear. In this study, we studied the effect of p-CA on the down-regulation of accumulated lipids in vivo and in vitro. p-CA increased a number of lipase expressions, including hormone-sensitive lipase (HSL), monoacylglycerol lipase (MGL) and hepatic triglyceride lipase (HTGL), as well as the expression of genes related to fatty acid oxidation, including long-chain fatty acyl-CoA synthetase 1 (ACSL1), carnitine palmitoyltransferase-1 (CPT1), by activating peroxisome proliferator-activated receptor α, and γ (PPARα and γ). Furthermore, p-CA promoted adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and enhanced the expression of the mammalian suppressor of Sec4 (MSS4), a critical protein that can inhibit lipid droplet growth. Thus, p-CA can decrease lipid accumulation and inhibit lipid droplet fusion, which are correlated with the enhancement of liver lipases and genes related to fatty acid oxidation as an activator of PPARs. Therefore, p-CA is capable of regulating lipid metabolism and is a potential therapeutic drug or health care product for hyperlipidemia and fatty liver.

Effect of preoperative prophylactic intravenous tranexamic acid on perioperative blood loss control in patients undergoing cesarean delivery: a systematic review and meta-analysis

BackgroundPostpartum hemorrhage (PPH) is one of the important risk factors leading to maternal mortality and intervention is essential. Oxytocin therapy is widely used clinically, but the effect is unsatisfactory. The efficacy of tranexamic acid (TXA) in hemostasis is notable, whereas its use in preventing PPH warrants exploration.AimsTo evaluate the effect of prophylactic administration of TXA on perioperative blood loss in women undergoing cesarean section by systematic review and meta-analysis of published studies.MethodsBibliographic databases were screened from their inception to December 2022 to retrieve relevant studies. Study outcomes including blood loss during cesarean section, 2-h postpartum blood loss, total blood loss (during cesarean section and 2-h postpartum), and 6-h postpartum, as well as hemoglobin changes were extracted and compared.ResultsA total of 21 studies, nine randomized clinical trials and 12 cohort studies, involving 1896 patients given TXA prophylactically and 1909 patients given placebo or no treatment, were analyzed. Compared with the control group, the preoperative prophylactic intravenous administration of TXA significantly reduced the intraoperative (RCT: P < 0.00001, cohort studies: P < 0.00001), 2-h postpartum (RCT: P = 0.02, cohort studies: P < 0.00001) and total blood loss (RCT: P < 0.00001, cohort studies: P = 0.0002), and reduced the decline in hemoglobin (RCT: P < 0.00001, cohort studies: P = 0.0001), but did not significantly affect blood loss at 6-h postpartum (P = 0.05).ConclusionProphylactic intravenous TXA before cesarean section is helpful in preventing perioperative bleeding in women.Trial registrationhttp://www.crd.york.ac.uk/PROSPERO, identifier: CRD 42022363450.

Precision engineered peptide targeting leukocyte extracellular traps mitigate acute kidney injury in Crush syndrome

Crush syndrome induced by skeletal muscle compression causes fatal rhabdomyolysis-induced acute kidney injury (RIAKI) that requires intensive care, including hemodialysis. However, access to crucial medical supplies is highly limited while treating earthquake victims trapped under fallen buildings, lowering their chances of survival. Developing a compact, portable, and simple treatment method for RIAKI remains an important challenge. Based on our previous finding that RIAKI depends on leukocyte extracellular traps (ETs), we aimed to develop a novel medium-molecular-weight peptide to provide clinical treatment of Crush syndrome.We conducted a structure-activity relationship study to develop a new therapeutic peptide. Using human peripheral polymorphonuclear neutrophils, we identified a 12-amino acid peptide sequence (FK-12) that strongly inhibited neutrophil extracellular trap (NET) release in vitro and further modified it by alanine scanning to construct multiple peptide analogs that were screened for their NET inhibition ability. The clinical applicability and renal-protective effects of these analogs were evaluated in vivo using the rhabdomyolysis-induced AKI mouse model.One candidate drug [M10Hse(Me)], wherein the sulfur of Met10 is substituted by oxygen, exhibited excellent renal-protective effects and completely inhibited fatality in the RIAKI mouse model. Furthermore, we observed that both therapeutic and prophylactic administration of M10Hse(Me) markedly protected the renal function during the acute and chronic phases of RIAKI.In conclusion, we developed a novel medium-molecular-weight peptide that could potentially treat patients with rhabdomyolysis and protect their renal function, thereby increasing the survival rate of victims affected by Crush syndrome.

Prophylactic treatment of dacomitinib-induced skin toxicities in epidermal growth factor receptor-mutated non-small-cell lung cancer: A multicenter, Phase II trial.

Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to evaluate a prophylactic strategy for skin toxicity induced by dacomitinib. We performed a single-arm, prospective, open-label, multi-institutional phase II trial for comprehensive skin toxicity prophylaxis. Patients with NSCLC harboring EGFR-activating mutations were enrolled and received dacomitinib with comprehensive prophylaxis. The primary endpoint was the incidence of skin toxicity (Grade ≥2) in the initial 8 weeks. In total, 41 Japanese patients participated between May 2019 and April 2021 from 14 institutions (median age 70 years; range: 32-83 years), 20 were male, and 36 had a performance status of 0-1. Nineteen patients had exon 19 deletions and L858R mutation. More than 90% of patients were perfectly compliant with prophylactic minocycline administration. Skin toxicities (Grade ≥2) occurred in 43.9% of patients (90% confidence interval [CI], 31.2%-56.7%). The most frequent skin toxicity was acneiform rash in 11 patients (26.8%), followed by paronychia in five patients (12.2%). Due to skin toxicities, eight patients (19.5%) received reduced doses of dacomitinib. The median progression-free survival was 6.8 months (95% CI, 4.0-8.6 months) and median OS was 21.6 months (95% CI, 17.0 months-not reached). Although the prophylactic strategy was ineffective, the adherence to prophylactic medication was quite good. Patient education regarding prophylaxis is important and can lead to improved treatment continuity.

Antiviral treatment with valacyclovir reduces virus shedding in saliva of Antarctic expeditioners

IntroductionReactivation of herpes viruses, such as Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV1), and varicella zoster virus (VZV), increases in astronauts during spaceflight, compared with their preflight and postflight levels. Reactivations can increase the risk of associated clinical conditions, such as herpes zoster, chronic neuropathic pain, vision loss, stroke, cognitive impairment, and cold sores. Furthermore, continued viral shedding for longer periods after space travel may increase the risk of viral transmission to uninfected crew contacts, including, but not limited to, the immunocompromised and newborn infants. Thus, it is essential to develop spaceflight countermeasures to prevent herpes viral reactivations to ensure the health of crewmembers and their contacts. One such countermeasure is the prophylactic administration of an antiviral drug (valacyclovir) against the alpha herpesviruses (VZV and HSV1). To determine the effectiveness of this countermeasure, we studied the shedding of EBV, VZV, and HSV1 in Antarctic expeditioners, who have similar salivary viral shedding patterns during winter-over to astronauts during long spaceflights.MethodsThe efficacy of this antiviral drug as a countermeasure was determined using three major parameters in the saliva of expeditioners during winter-over with and without administration of this drug: (i) viral load and frequency, (ii) physiological stress biomarkers [i.e., levels of cortisol, dehydroepiandrosterone (DHEA), and amylase), and (iii) immune markers (i.e., inflammatory cytokines)]. Thirty-two volunteers from two Antarctic stations (McMurdo and South Pole) participated in this study. Participants were randomly assigned to either the treatment group (valacyclovir HCl: 1 g/day) or placebo group (oyster calcium: 500mg/day). ResultsViral shedding of EBV reduced significantly (&amp;gt; 24-fold) in the treatment group compared with the placebo group. HSV1 was also reduced by more than fivefold, but this was not statistically significant. No VZV shedding was observed in any of the participants. In the placebo group 50% of the saliva samples had measurable viral DNA (EBV, HSV1, or both), compared with 19% of the treatment group. There was no significant change in the ratio of cortisol to DHEA or levels of alpha-amylase, indicating that physiological stress was similar between the groups. No difference was detected in levels of salivary cytokines, except IL-10, which was found in significantly lower levels in the treatment group. DiscussionThese data indicate that valacyclovir is a safe and successful intervention to reduce EBV and HSV1 shedding in individuals subjected to extreme environments and stressors.

Sublingual prophylactic administration of OVA-loaded MSC-derived exosomes to prevent allergic sensitization

AimThis study evaluated the immunomodulatory and delivery potential of adipose tissue-isolated MSC-derived exosomes as a prophylactic regimen through a sublingual route in the ovalbumin (OVA)-induced allergic asthma murine model. Material and methodsBalb/c mice received 10 μg/dose of OVA-enriched MSC-derived exosomes as a prophylactic regimen in six doses during three weeks, and then OVA sensitization was conducted through intraperitoneal and aerosol administration of allergen. The total cells and eosinophils counted in nasal lavage fluid (NALF) and lung tissues were assessed for histopathological analysis. In addition, the secretion of IFN-γ, IL-4, and TGF-β by spleen cells and serum OVA-specific IgE levels were measured via ELISA. ResultsSignificant reduction in the IgE levels and IL-4 production, along with elevated TGF-β levels, were observed. Also, limited cellular infiltrations and perivascular and peribronchiolar inflammation in the lung tissues and normal total numbers of cells and eosinophils in the NALF were reported. ConclusionProphylactic regimen using OVA-enriched MSC-derived exosomes modulated immune responses and inhibited allergic OVA sensitization.

Comparative Evaluation of Preoperative Paracetamol and a Combination of Paracetamol with Nebulized or Intravenous Dexamethasone for Prevention of Postoperative Sore Throat

ABSTRACT Background and Aims: Postoperative sore throat (POST) is a common complication following general anesthesia with tracheal intubation that increases patient morbidity. We evaluated the effect of preoperative administration of IV paracetamol and a combination of paracetamol with nebulized or IV dexamethasone on the incidence of POST (primary objective), hoarseness of voice and cough (secondary objectives) in adult patients. Methods: In a randomized, double-blind study in a tertiary care hospital, 150 patients undergoing laparoscopic cholecystectomy under general anesthesia with tracheal intubation were divided into three groups (n = 50): Group P received IV paracetamol 1 g infusion; Group I received IV dexamethasone 8 mg and IV paracetamol 1 g infusion; and Group N received nebulized dexamethasone 8 mg and IV Paracetamol 1 g infusion. The incidence and severity of POST, hoarseness and cough were assessed at various time-points for 24 hours after surgery. Results: The overall incidence of POST was 72%, 18%, and 24% in groups P, I, and N, respectively; P &lt; .0001. The severity of POST was significantly less in groups I and N compared with group P; both P &lt; .0001. The incidence of postoperative hoarseness was comparable between the three groups; P = 0.216. The incidence and severity of postoperative cough were significantly higher in group P compared with group I; P = 0.016. Statistical calculations were done using SPSS 21 version program for Windows. Conclusions: Prophylactic administration of both nebulized and IV dexamethasone 8 mg in combination with IV paracetamol was effective in decreasing the incidence and severity of POST in adult patients undergoing laparoscopic cholecystectomy under general anesthesia with tracheal intubation.