Rechallenges without desensitization following platinum-based chemotherapy reactions.

BACKGROUND: There is increasing interest in non-desensitization protocols as a potential way to reintroduce chemotherapy following hypersensitivity reactions (HSR). OBJECTIVE: To provide insight into the potential utility of non-desensitization reintroduction, particularly at institutions where allergy consultation may not be available. METHODS: For 70 patients with platinum HSR who underwent rechallenge with standard (≤2 hours), extended (1-bag, 1-step, 4-6 hours), or titrated (4-to-5-bag and -step, 6-7.5 hours) infusions between 1/2014 and 7/2019, demographics and clinical characteristics were reviewed and initial and breakthrough reactions (BTR) were graded using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tolerance (no BTR) and completion (dose completed despite BTR) were compared using Fisher's exact test. RESULTS: Patients (mean [standard deviation] age 57 [13] years, initial HSR grade 2 [1]), were rechallenged with standard (n = 8), extended (n = 23), or titrated (n = 22) infusions after oxaliplatin HSR; and standard (n = 5) or titrated (n = 12) after carboplatin HSR. Tolerance and completion were higher for extended versus (vs) standard (tolerance-87%-vs-8%, p < 0.005; completion-96%-vs-38%, p < 0.005) and titrated versus standard (tolerance-76%-vs-8%, p < 0.005; completion-79%-vs-38%, p < 0.05) infusions. CONCLUSIONS: Extended and titrated infusions may increase reintroduction safety compared to standard infusions. Further investigation into extended infusions may provide a safe alternative to standard infusions in patients who may not have access to desensitization at their institution.

Thoracic Society of Australia and New Zealand Position Statement on Acute Oxygen Use in Adults: 'Swimming between the flags'.

Oxygen is a life-saving therapy but, when given inappropriately, may also be hazardous. Therefore, in the acute medical setting, oxygen should only be given as treatment for hypoxaemia and requires appropriate prescription, monitoring and review. This update to the Thoracic Society of Australia and New Zealand (TSANZ) guidance on acute oxygen therapy is a brief and practical resource for all healthcare workers involved with administering oxygen therapy to adults in the acute medical setting. It does not apply to intubated or paediatric patients. Recommendations are made in the following six clinical areas: assessment of hypoxaemia (including use of arterial blood gases); prescription of oxygen; peripheral oxygen saturation targets; delivery, including non-invasive ventilation and humidified high-flow nasal cannulae; the significance of high oxygen requirements; and acute hypercapnic respiratory failure. There are three sections which provide (1) a brief summary, (2) recommendations in detail with practice points and (3) a detailed explanation of the reasoning and evidence behind the recommendations. It is anticipated that these recommendations will be disseminated widely in structured programmes across Australia and New Zealand.

Titrated oral misoprostol versus static regimen of oral misoprostol for induction of labour: a systematic review and meta-analysis.

We aimed to conduct a systematic review and meta-analysis to compare the efficacy and safety of titrated oral misoprostol versus static oral misoprostol for labour induction. We searched for the available randomised clinical trials (RCTs) in the Cochrane Library, PubMed, ISI web of science, Scopus, and ClinicalTrials.gov. We included RCTs compared titrated oral misoprostol versus static regimen of oral misoprostol during labour induction. Our main outcomes were vaginal and caesarean delivery rates, uterine tachysystole, misoprostol side effects, and neonatal adverse events. Three RCTs met our inclusion criteria with a total number of 360 patients. The vaginal delivery rate did not significantly differ between both groups (p = 0.49). Titrated oral misoprostol was associated with significant increase in the caesarean delivery rate compared to static oral misoprostol (p = 0.04). Moreover, titrated oral misoprostol led to significant increase in the uterine tachysystole and misoprostol side effects (p = 0.01 & p = 0.003, respectively). There were no differences among both groups regarding different neonatal adverse events. In conclusion, titrated oral misoprostol increases the incidence of caesarean delivery, uterine tachysystole, and misoprostol side effects with a similar vaginal delivery rate compared to static dose misoprostol. Thus, static oral misoprostol should be used instead of titrated oral misoprostol during labour induction. Impact StatementWhat is already known on this subject? Different studies have evaluated titrated oral misoprostol administration for induction of labour and proved their efficacy in comparison with other induction methods. However, there is controversy among the published studies between titrated oral misoprostol and static oral misoprostol during induction of labour. A recent study concluded that hourly titrated misoprostol and static oral misoprostol are equally safe and effective when utilised for induction of labour with no fear of any adverse events. However, another study recommended static oral misoprostol administration for labour induction as it was linked to a lower caesarean section incidence, fewer drug side effects, and decline in complication rates in comparison with titrated oral misoprostol.What the results of this study add? Titrated oral misoprostol increases the incidence of caesarean delivery, uterine tachysystole, and misoprostol side effects with a similar vaginal delivery rate compared to static dose misoprostol.What the implications are of these findings for clinical practice and/or further research? Static oral misoprostol should be used instead of titrated oral misoprostol during labour induction. More future trials are required to confirm our findings.

Reliability of a New Symptom Score in a Titrated Quantitative Conjunctival Provocation Test Supported by an Objective Photodocumentation.

BACKGROUND: Allergen provocation tests are useful methods for proving the clinical relevance of an allergen-specific sensitization. Among these methods, the conjunctival provocation test (CPT) represents an easy-to-use tool. However, its readout parameters have not yet been internationally standardized or validated. Photodocumentation has been shown as a good option for objectifying a CPT reaction, supporting the local investigator assessment. Based on test-retest reliability of the score and an objective digital photoanalysis of the conjunctival redness, this study aimed to prove the reproducibility of a new CPT scoring system for use in clinical trials (ClinicalTrials.gov identifier: NCT02690740). METHODS: A titrated quantitative CPT was conducted outside of the pollen season in a final cohort of 23 adult patients with birch or grass pollen-induced allergic rhinoconjunctivitis. Conjunctival symptoms were analyzed using a standardized symptom score. Conjunctival redness was also evaluated by an external observer and correlated with a digital photoanalysis using MATLAB software. RESULTS: A test-retest correlation of 0.6 (p < 0.01) was found for the symptom score results. Likewise, a correlation of 0.65 (p < 0.01) was observed in the digital photoanalysis. The total symptom score showed a decrease in the mean value of 0.48 score points in the retest. CONCLUSIONS: This study reveals both a valuable test-retest correlation of the proposed score as well as a good correlation of eye redness with the (objective) photodocumentation. Based on our results, we can recommend the use of this scoring system as a valuable clinical protocol for future clinical trials.

Randomized clinical trial between hourly titrated and 2 hourly static oral misoprostol solution for induction of labor.

BACKGROUND: Misoprostol is an effective agent for the induction of labor. Existing guidelines recommend oral misoprostol solution 25 µg every 2 hours. However, more research is required to optimize the use of oral misoprostol solution for the induction of labor. OBJECTIVE: The purpose of this study was to compare efficacy and safety of hourly titrated-dose oral misoprostol solution with static-dose oral misoprostol solution every 2 hours for labor induction. STUDY DESIGN: In this randomized controlled study, oral misoprostol solution was administered as (1) 20 µg hourly (≤4 doses) that was increased in the absence of regular uterine contractions to 40 µg hourly (≤4 doses) and then to 60 µg hourly (≤16 doses) or (2) 25 µg every 2 hours until active labor began (≤12 doses). A sample size of 146 women was planned with the use of a projected 95% rate for the primary endpoint (vaginal delivery within 24 hours) for hourly titrated-dose misoprostol and 80% rate for static-dose misoprostol every 2 hours. Safety outcomes included maternal morbidity and adverse neonatal outcomes. RESULTS: From December 2013 to July 2015, 146 women were assigned randomly to treatment. Demographic and clinical factors were similar between groups, except for age. Vaginal delivery was achieved within 24 hours in 47 women (64.4%) who received hourly titrated-doses of misoprostol solution and 48 women (65.8%) who received 2-hourly static-dose misoprostol solution (P=1.00). Rates of vaginal delivery within 24 hours did not differ significantly between treatment groups for women who were nulliparous (P=1.00) or who had postterm pregnancies (P=.66), a Bishop score of ≤3 (P=.84), or oxytocin augmentation (P=.83). Cesarean deliveries were performed within 24 hours in 9 women who received hourly titrated-dose misoprostol solution and 2 women who received 2-hourly static-dose misoprostol solution (P=.056). Pyrexia and meconium-stained liquor occurred more frequently with the hourly titrated-dose regimen. CONCLUSION: The static-dose oral misoprostol solution every 2 hours has similar efficacy as hourly titrated-dose misoprostol solution but with fewer side-effects and lower complication rates.

Titrated extract of Centella asiatica increases hair inductive property through inhibition of STAT signaling pathway in three-dimensional spheroid cultured human dermal papilla cells.

Dermal papilla (DP) is a pivotal part of hair follicle, and the smaller size of the DP is related with the hair loss. In this study, we investigated the effect of titrated extract of Centella asiatica (TECA) on hair growth inductive property on 3D spheroid cultured human DP cells (HDP cells). Significantly increased effect of TECA on cell viability was only shown in 3D sphered HPD cells, not in 2D cultured HDP cells. Also, TECA treatment increased the sphere size of HDP cells. The luciferase activity of STAT reporter genes and the expression of STAT-targeted genes, SOCS1 and SOCS3, were significantly decreased. Also, TECA treatment increased the expression of the hair growth-related signature genes in 3D sphered HDP cells. Furthermore, TECA led to downregulation of the level of phosphorylated STAT proteins in 3D sphered HDP cells. Overall, TECA activates the potential of hair inductive capacity in HDP cells.

Anti-Inflammatory Effect of Titrated Extract of Centella asiatica in Phthalic Anhydride-Induced Allergic Dermatitis Animal Model.

Centella asiatica has potent antioxidant and anti-inflammatory properties. However, its anti-dermatitic effect has not yet been reported. In this study, we investigated the anti-dermatitic effects of titrated extract of Centella asiatica (TECA) in a phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. An AD-like lesion was induced by the topical application of five percent PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 µL of 0.2% and 0.4% of TECA (40 µg or 80 µg/cm²) was spread on the dorsum of the ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB activity, which were determined by electromobility shift assay (EMSA). We also measured TNF-α, IL-1ß, IL-6, and IgE concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). TECA treatment attenuated the development of PA-induced atopic dermatitis. Histological analysis showed that TECA inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. TECA treatment inhibited expression of iNOS and COX-2, and NF-κB activity as well as the release of TNF-α, IL-1ß, IL-6, and IgE. In addition, TECA (1, 2, 5 µg/mL) potently inhibited Lipopolysaccharide (LPS) (1 µg/mL)-induced NO production, expression of iNOS and COX-2, and NF-κB DNA binding activities in RAW264.7 macrophage cells. Our data demonstrated that TECA could be a promising agent for AD by inhibition of NF-κB signaling.

Comparative study of titrated oral misoprostol solution and vaginal dinoprostone for labor induction at term pregnancy.

OBJECTIVE: To evaluate effectiveness and safety of titrated oral misoprostol solution (OMS) in comparison with vaginal dinoprostone for cervix ripening and labor induction in term pregnant women. METHODS: A multicenter randomized controlled trial of women with term singleton pregnancy with indications for labor induction; 481 participants were allocated to receive titrated OMS with different doses by hourly administration according to the procedure or insert vaginal dinoprostone for cervix ripening and labor induction to compare maternal outcomes including indication of labor induction, mode of outcome of delivery, maternal morbidity, and neonatal outcomes between two groups for evaluating the efficacy and safety of titrated oral misoprostol induction. RESULT: Proportion of delivery within 12 h of titrated oral misoprostol is significantly less than vaginal dinoprostone (p = 0.03), but no difference of total vaginal delivery rate (p = 0.93); the mean time of first treatment to vaginal delivery was longer in OMS group (21.3 ± 14.5 h) compared with the vaginal dinoprostone group (15.7 ± 9.6 h). Although the proportion of cesarean section between the two groups showed no statistically significant difference, OMS group showed significantly lower frequency of uterine hyperstimulation, hypertonus, partus precipitatus and non-reassuring fetal heart rate than dinoprostone group. Neonatal outcomes were similar evaluating from Apgar score and NICU admission. Our study also showed that labor induction of women with cervix Bishop score ≤3 needed increased dosage of misoprostol solution. CONCLUSION: Titrated OMS is as effective as vaginal dinoprostone in labor induction for term pregnant women, with safer effect for its lower rate of adverse effect for women.

Randomized clinical trial between hourly titrated oral misoprostol and vaginal dinoprostone for induction of labor.

OBJECTIVE: The objective of the study was to compare the efficacy and safety of hourly titrated oral misoprostol with vaginal dinoprostone insert. STUDY DESIGN: Subjects were randomized into hourly titrated oral misoprostol or dinoprostone 10 mg vaginal insert. Misoprostol was given as 20 µg hourly for 2 doses. In the absence of regular uterine contractions, the dose was increased to 30 µg hourly for 3 doses and then 40 µg for 1 dose, 50 µg for 1 dose, and 60 µg hourly for 4 doses. Before the 40 and 50 µg doses, 1 more hour of observation was given. The primary outcome variable was vaginal delivery within 24 hours. Safety assessments included the incidence of maternal morbidity and adverse neonatal outcomes. RESULTS: A total of 160 women was enrolled in the study. The groups were similar for demographic and clinical factors. Vaginal delivery was achieved within 24 hours in 100 women (62.5%): 44 in the dinoprostone group (55.0%) and 56 in the misoprostol group (70.0%) (P = .05). The proportion of women who achieved vaginal delivery within 24 hours was significantly greater for nulliparous women in the misoprostol group (24 of 51, 58.5%) compared with the dinoprostone group (12 of 36, 33.3%; P = .0270). Significantly more women with baseline Bishop score of 3 or less in the misoprostol group had successful induction (43 of 59, 72.9%) compared with the dinoprostone group (27 of 60, 45.0%; P = .002). Frequencies of maternal adverse events were similar between groups. CONCLUSION: Hourly titrated oral misoprostol can provide an efficacious and safe substitute for the expensive dinoprostone vaginal insert.

Standard vs. targeted oxygen therapy prehospitally for chronic obstructive pulmonary disease (STOP-COPD): study protocol for a randomised controlled trial.

BACKGROUND: A high concentration of inspired supplemental oxygen may possibly cause hypercapnia and acidosis and increase mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Even so, patients with AECOPD are being treated with high oxygen flow rates when receiving inhalation drugs in the prehospital setting. A cluster-randomised controlled trial found that reduced oxygen delivery by titrated treatment reduced mortality-a result supported by observational studies-but the results have never been reproduced. In the STOP-COPD trial, we investigate the effect of titrated oxygen delivery compared with usual care consisting of high flow oxygen delivery in patients with AECOPD in the prehospital setting. METHODS: In this randomised controlled trial, patients will be blinded to allocation. Patients with suspected AECOPD (n = 1888) attended by the emergency medical service (EMS) and aged > 40 years will be allocated randomly to either standard treatment or titrated oxygen, targeting a blood oxygen saturation of 88-92% during inhalation therapy. The trial will be conducted in the Central Denmark Region and include all ambulance units. The power to detect a 3% 30-day mortality risk difference is 80%. The trial is approved as an emergency trial. Hence, EMS providers will include patients without prior consent. DISCUSSION: The results will provide evidence on whether titrated oxygen delivery outperforms standard high flow oxygen when used to nebulise inhaled bronchodilators in AECOPD treatment. The trial is designed to ensure unselected inclusion of patients with AECOPD needing nebulised bronchodilators-a group of patients that receives high oxygen fractions when treated in the prehospital setting where the only compressed gas is generally pure oxygen. Conducting this trial, we aim to improve treatment for people with AECOPD while reducing their 30-day mortality. TRIAL REGISTRATION: European Union Clinical Trials (EUCT) number: 2022-502003-30-00 (authorised 06/12/2022), ClinicalTrials.gov number: NCT05703919 (released 02/02/2023), Universal trial number: U1111-1278-2162.

Olive juice dry extract containing hydroxytyrosol, as a nontoxic and safe substance: Results from pre-clinical studies and review of toxicological studies.

Products derived from olives, such as the raw fruit and oils, are widely consumed due to their taste, and purported nutritional/health benefits. Phenolic compounds, especially hydroxytyrosol (HT), have been proposed as one of the key substances involved in these effects. An olive juice extract, standardized to contain 20% HT ("OE20HT"), was produced to investigate its health benefits. The aim of this study was to demonstrate the genotoxic safety of this ingredient based on in vitro Ames assay and in vitro micronucleus assay. Results indicated that OE20HT was not mutagenic at concentrations of up to 5000 µg/plate, with or without metabolic activation, and was neither aneugenic nor clastogenic after 3-hour exposure at concentrations of up to 60 µg/mL with or without metabolic activation, or after 24-hour exposure at concentrations of up to 40 µg/mL. To further substantiate the safety of OE20HT following ingestion without conducting additional animal studies, a comprehensive literature review was conducted. No safety concerns were identified based on acute or sub-chronic studies in animals, including reproductive and developmental studies. These results were supported by clinical studies demonstrating the absence of adverse effects after oral supplementation with olive extracts or HT. Based on in vitro data and the literature review, the OE20HT extract is therefore considered as safe for human consumption at doses up to 2.5 mg/kg body weight/day.

Daily Training efficiency during computerized cognitive rehabilitation training (CCRT): an analysis from a randomized trial in Ugandan children with and without severe malaria.

Children in Uganda are at risk for significant cognitive sequelae from severe malaria. Computerized cognitive rehabilitation training (CCRT) represents a potential method to improve working memory, behavior, and executive functioning, cognitive domains most at risk following severe malaria. The primary aim of this study was to complete a secondary analysis of data from a concluded CCRT randomized control trial in order to compare the training efficiency of a commonly used CCRT program under conditions of titrated (adaptive) or non-titrated (non-adaptive) training and with children with increasing malaria severity to determine how various factors may affect potential CCRT improvement. A total of 201 school-aged children (66.2% boys) who were either healthy (n = 102) or previously diagnosed with severe or cerebral malaria (n = 99) were randomized into two active treatment arms (titrated and non-titrated learning). Each child received 24 one-hour sessions of training over 8 weeks using Captain's Log® CCRT by BrainTrain, which includes a comprehensive set of CCRT tasks. Children generally benefited from CCRT over the 24 training sessions, but titrated CCRT showed a clear advantage over non-titrated. Severity of illness or factors such as BMI, did not moderate CCRT performance indicators. These findings support our hypothesis that titrated CCRT would result in steeper improvement in learning, but do not support our hypothesis that history of recent significant illness would affect learning proficiency. Findings were evident across all CCRT performance scores, even given that children were from generally rural, low-resource settings and were generally unfamiliar with computers.ABBREVIATIONS:Computerized Cognitive Rehabilitation Training (CCRT); Mental Processing Index (MPI); Home Observation for the Measurement of the Environment (HOME); Socioeconomic Status (SES); least square means (LSM).

Management of Hemorrhagic Shock: Physiology Approach, Timing and Strategies.

Hemorrhagic shock (HS) management is based on a timely, rapid, definitive source control of bleeding/s and on blood loss replacement. Stopping the hemorrhage from progressing from any named and visible vessel is the main stem fundamental praxis of efficacy and effectiveness and an essential, obligatory, life-saving step. Blood loss replacement serves the purpose of preventing ischemia/reperfusion toxemia and optimizing tissue oxygenation and microcirculation dynamics. The "physiological classification of HS" dictates the timely management and suits the 'titrated hypotensive resuscitation' tactics and the 'damage control surgery' strategy. In any hypotensive but not yet critical shock, the body's response to a fluid load test determines the cut-off point between compensation and progression between the time for adopting conservative treatment and preparing for surgery or rushing to the theater for rapid bleeding source control. Up to 20% of the total blood volume is given to refill the unstressed venous return volume. In any critical level of shock where, ab initio, the patient manifests signs indicating critical physiology and impending cardiac arrest or cardiovascular accident, the balance between the life-saving reflexes stretched to the maximum and the insufficient distal perfusion (blood, oxygen, and substrates) remains in a liable and delicate equilibrium, susceptible to any minimal change or interfering variable. In a cardiac arrest by exsanguination, the core of the physiological issue remains the rapid restoration of a sufficient venous return, allowing the heart to pump it back into systemic circulation either by open massage via sternotomy or anterolateral thoracotomy or spontaneously after aorta clamping in the chest or in the abdomen at the epigastrium under extracorporeal resuscitation and induced hypothermia. This is the only way to prevent ischemic damage to the brain and the heart. This is accomplishable rapidly and efficiently only by a direct approach, which is a crush laparotomy if the bleeding is coming from an abdominal +/- lower limb site or rapid sternotomy/anterolateral thoracotomy if the bleeding is coming from a chest +/- upper limbs site. Without first stopping the bleeding and refilling the heart, any further exercise is doomed to failure. Direct source control via laparotomy/thoracotomy, with the concomitant or soon following venous refilling, are the two essential, initial life-saving steps.

What is better for psychiatry: Titrated or fixed concentrations of nitrous oxide?

Medication dosages are crucial-no single dose fits all. My paper compares the safety, scientific and practical applicability of fixed 25-50% concentrations of nitrous oxide (N2O) with the variable titrated concentrations of Psychotropic Analgesic N2O (PAN), as used in dentistry, and neuropsychiatry. A crucial difference is that PAN is always titrated, via an open circuit (nasal mask), to the minimum concentration (dose), which ensures full consciousness, cooperation, comfort and relaxation. With PAN, the goal is subject comfort, not dose. In contrast, fixed goal concentrations are usually given via relatively closed circuits (full facial mask/similar) without account for individual patient's dose-response. Hence, fixed concentrations, in N2O sensitive subjects, could result in unconsciousness and other adverse effects (nausea, vomiting, anxiety, aspiration, might occur; requiring an anaesthesiologist for patient safety. PAN is titrated using each subject's subjective and objective responses as the guide to the ideal concentration. Thus, when PAN is used, there is no fixed concentration even for a single subject, nor is an anaesthesiologist required. Furthermore, there is a greater scientific rationale for using PAN, because the receptor systems involved are better known, whilst those for fixed concentrations are not. The PAN or dental titration method has been safely used in general dentistry for over 70 years and as an investigative, diagnostic and therapeutic tool for neuropsychiatry for over 40 years. Clinical applications include substance abuse detoxification, ameliorating depression, and investigations of schizophrenia, human orgasm, pain perception and basic neuroscience. By contrast, the experience with fixed doses in psychiatry is limited.

Safety and efficacy of titrated oral misoprostol solution versus vaginal dinoprostone for induction of labor: A single-center randomized control trial.

OBJECTIVE: To compare the efficacy and safety of the hourly administration of titrated oral misoprostol solution (OMS) and vaginal dinoprostone for induction of labor. METHODS: Titrated OMS was administrated hourly for induction of labor, starting with a dose of 20 µg and terminating at a dose of 50 µg. The safety and efficacy of OMS were compared with that of vaginal dinoprostone for induction of labor. RESULTS: From June 2016 to October 2019, 2280 (78.3%) and 2115 (72.9%) women who received titrated OMS and vaginal dinoprostone, respectively, had a vaginal delivery (P = 0.005). Cesarean delivery was performed in 632 (21.7%) and 783 (27.0%) women who received titrated OMS and vaginal dinoprostone, respectively (P = 0.008). Tachysystole with changes in fetal heart rate (FHR) was seen in 104 (3.6%) and 249 (8.6%) women in the OMS and dinoprostone groups, respectively (P = 0.007). The frequency of non-reassuring FHR was lower in the OMS group compared to the dinoprostone group (P = 0.006). CONCLUSION: The titrated OMS has an efficacy comparable to vaginal dinoprostone. Moreover, it causes a lower incidence of cesarean delivery, lower frequency of tachysystole with changes in FHR, and non-reassuring FHR.

Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, is a widely used multiple sclerosis (MS) model. Unlike the spontaneous occurrence of MS, in EAE, external immunization with the MOG peptide (200-300 µg/mouse), emulsified in adjuvant enriched with Mycobacterium Tuberculosis (MT) H37Ra (100-500 µg mouse), and pertussis toxin (PTx, 200-500 ng/mouse) injections, are applied, which heavily boosts the immune system. NEW METHOD: A detailed and systematic titration of the MOG 35-55 EAE induction protocol in C57BL/6 mice reveals the minimal doses of the MOG 35-55 peptide, MT H37Ra, and PTx, required for disease manifestation. RESULTS: The amounts of MOG 35-55 peptide, MT H37Ra, and PTx can be drastically reduced from the standard protocol, to level of 5 µg MOG, 25 µg MT H37Ra, and 50 ng PTx, without affecting the clinical manifestations. The titrated protocols induced a high disease incidence and a consistent robust disease course, with full histopathological characteristics of the MOG model, inflammation, demyelination and axonal damage. COMPARISON WITH EXISTING METHODS: Similar disease incidences, day of symptoms appearance, maximal clinical score, and histopathology were obtained for the standard and the titrated protocols. CONCLUSIONS: Reducing the reagent dosages used for EAE induction, without attenuating the disease, can give a truer and less artificial perspective of MS. We propose an improved protocol for this extensively used model, with high disease incidence, a consistent robust course, and characteristic histological manifestations, which may be more sensitive for testing therapeutic modalities, cost-effective, and less distressing to the animals.

Oral misoprostol for induction of labor at term: a randomized controlled trial of hourly titrated and 2 hourly static oral misoprostol solution.

Background: Misoprostol has been shown to be effective in induction of labor (IOL) with different dosages and routes of administration.Objectives: This study compared the efficacy and safety of hourly titrated and 2-hourly static low dose oral misoprostol for IOL in Ekiti State University Teaching Hospital, Ado-Ekiti.Methods: One hundred fifty women with singleton pregnancy at term admitted for IOL were randomized into the two groups. Oxytocin augmentation was done as necessary. The primary outcome is rate of vaginal delivery within 24 hours. Data were analyzed using SPSS.Results: Vaginal delivery was achieved within 24 hours in 40 (67.8%) women who received hourly titrated-doses oral misoprostol and 42 (70.0%) women who received 2-hourly static-dose of oral misoprostol, p > .05. The rate of vaginal delivery, oxytocin augmentation, induction delivery time and cesarean section rate were similar in both groups, p > .05. Occurrence of uterine hyperactivity did not differ significantly among the women (p > .05) and no cases of uterine rupture were recorded. There were no adverse neonatal outcomes.Conclusions: The hourly titrated oral misoprostol is as effective and safe as the 2-hourly static oral misoprostol for IOL. Both can be utilized in IOL without the fear of adverse outcomes.

Automatic oxygen titration with O2matic® to patients admitted with COVID-19 and hypoxemic respiratory failure.

INTRODUCTION: Patients with coronavirus disease (COVID-19) and pneumonitis often have hypoxemic respiratory failure and a need of supplementary oxygen. Guidelines recommend controlled oxygen, for most patients with a recommended interval of SpO2 between 92 and 96%. We aimed to determine if closed-loop control of oxygen was feasible in patients with COVID-19 and could maintain SpO2 in the specified interval. METHODS: Patients were prospectively enrolled in an observational study on a medical ward dedicated to patients with COVID-19. Closed-loop controlled oxygen was delivered by O2matic® which can deliver 0-15 liters/min and adjusts flow every second based on 15 seconds averaging of SpO2 measured by pulse oximetry. Lung function parameters were measured at admission. RESULTS: Fifteen patients (six women, nine men) participated in the study. Average age was 72 years. Lung function was severely impaired with FEV1, FVC and PEF reduced to approximately 50%. The average stay on the ward was 3.2 days and O2matic was used on average for 66 hours, providing 987 hours of observation. O2matic maintained SpO2 in the desired interval for 82.9% of the time. Time with SpO2 > 2% below interval was 5.1% and time with SpO2 > 2% above interval was 0.6%. CONCLUSION: Closed-loop control of oxygen to patients with COVID-19 is feasible and can maintain SpO2 in the specified interval in the majority of time. Closed-loop automated control could be of particular benefit for patients in isolation with decreased visibility, surveillance and monitoring. Further studies must examine the clinical benefits.

Combination Effect of Titrated Extract of Centella asiatica and Astaxanthin in a Mouse Model of Phthalic Anhydride-Induced Atopic Dermatitis.

PURPOSE: In our previous study, we demonstrated that both titrated extract of Centella asiatica (TECA) and astaxanthin (AST) have anti-inflammatory effects in a 5% phthalic anhydride (PA) mouse model of atopic dermatitis (AD). The increasing prevalence of AD demands new therapeutic approaches for treating the disease. We investigated the therapeutic efficacy of the ointment form of TECA, AST and a TECA + AST combination in a mouse model of AD to see whether a combination of the reduced doses of 2 compounds could have a synergistic effect. METHODS: An AD-like lesion was induced by the topical application of 5% PA to the dorsal ear and back skin of an Hos:HR-1 mouse. After AD induction, TECA (0.5%), AST (0.5%) and the TECA (0.25%) + AST (0.25%) combination ointment (20 µg/cm²) were spread on the dorsum of the ear or back skin 3 times a week for 4 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclocxygenase (COX)-2, and nuclear factor (NF)-κB activity. We also measured the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and immunoglobulin E (IgE) in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). RESULTS: PA-induced skin morphological changes and ear thickness were significantly reduced by TECA, AST and TECA + AST treatments, but these inhibiting effects were more pronounced in the TECA + AST treatment. TECA, AST and the TECA+AST reatments inhibited the expression of iNOS and COX-2; NF-κB activity; and the release of TNF-α, IL-6 and IgE. However, the TECA+AST treatment showed additive or synergistic effects on AD. CONCLUSIONS: Our results demonstrate that the combination of TECA and AST could be a promising therapeutic agent for AD by inhibiting NF-κB signaling.

Negative-Pressure Hydrocephalus: A Case Report on Successful Treatment Under Intracranial Pressure Monitoring with Bilateral Ventriculoperitoneal Shunts.

BACKGROUND: Negative-pressure hydrocephalus (NegPH), a very rare condition of unknown etiology and optimal treatment, usually presents postneurosurgery with clinical and imaging features of hydrocephalus, but with negative cerebrospinal fluid pressure. CASE DESCRIPTION: We describe a NegPH case of -3 mm Hg intracranial pressure that was successfully treated to achieve 5 mm Hg under continuous intracranial pressure monitoring with horizontal positioning, head down and legs elevated to 10°-15°, neck wrapping for controlled venous drainage, chest and abdomen bandages, infusion of 5% dextrose fluid to lower plasma osmolarity (Na+, 130-135 mmol/L), daily cerebrospinal fluid drainage >200 mL, and arterial blood gas partial pressure of carbon dioxide >40 mm Hg.