Administration Of Dose Research Articles

Heparin-binding epidermal growth factor-like growth factor improves erectile function in streptozotocin-induced diabetic mice.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) serves as a pro-angiogenic factor; however, there is to our knowledge currently no reported research on the relationship between HB-EGF and diabetic erectile dysfunction (ED). In this study we aimed to determine whether HB-EGF can improve the erectile function of streptozotocin-induced diabetic mice and to explore the related mechanisms. Eight-week-old male C57BL/6 mice were used for diabetes induction. Diabetes mellitus (DM) was induced by low-dose injections of streptozotocin (50mg/kg) for 5 consecutive days. Eight weeks after streptozotocin injections, DM was determined by measuring blood glucose and body weight. Diabetic mice were treated with two intracavernous administrations of phosphate-buffered saline (20μL) or various doses of HB-EGF (days -3 and 0; 1, 5, and 10μg in 20μL of phosphate-buffered saline). The angiogenesis effect of HB-EGF was confirmed by tube formation and migration assays in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was measured by electrical stimulation of the cavernous nerve, as well as histological examination and Western blot analysis for mechanism assessment. In vitro angiogenesis, cell proliferation, in vivo intracavernous pressure, neurovascular regeneration, cavernous permeability, and survival signaling were the outcomes measured. Expression of HB-EGF was reduced under diabetic conditions. Exogenous HB-EGF induced angiogenesis in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was decreased in the DM group, whereas administration of HB-EGF resulted in a significant improvement of erectile function (91% of the age-matched control group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal cells. Histological and Western blot analyses revealed a significant increase in the permeability of the corpus cavernosum in DM mice, which was attenuated by HB-EGF treatment. The protein expression of phospho-Akt Ser473 and phosphorylated endothelial nitric oxide synthase Ser1177 increased after HB-EGF treatment. The use of HB-EGF may be an effective strategy to treat ED associated with DM or other neurovascular diseases. Similarly to other pro-angiogenic factors, HB-EGF has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of HB-EGF in diabetic ED. In view of the properties of HB-EGF as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects. In the diabetic ED mouse model in this study erectile function was improved by HB-EGF, which may provide new treatment strategies for patients with ED who do not respond to phosphodiesterase 5 Inhibitors.

Recording of hippocampal activity on the effect of convulsant doses of caffeine

Seizures occur when there is a hyper-excitation of the outer layer of the brain, with subsequent excessive synchrony in a group of neurons. According to the World Health Organization (WHO), an estimated 50 million people are affected by this disease, a third of whom are resistant to the treatments available on the market. Caffeine (1,3,7-trimethylxanthine), which belongs to the purine alkaloid family, is the most widely consumed psychoactive drug in the world. It is ingested by people through drinks containing this substance, such as coffee, and as an adjuvant in analgesic therapy with non-steroidal antiflammatory drugs. The present study evaluated the electrocorticographic changes observed in the hippocampus of Wistar rats subjected to acute doses of caffeine (150 mg/kg i.p), which represents a toxic dose of caffeine corresponding to an estimated acute intake of more than 12 cups of coffee to record its convulsant activity. Our results showed, for the first time, that the administration of high doses of caffeine (150 mg/kg i.p.) in rats caused an increase in the spectral distribution of power in all frequency bands and suggested the appearance of periods of ictal and interictal peaks in the electrocorticogram (ECog). We have also shown that the anticonvulsants phenytoin, diazepam and phenobarbital have a satisfactory response when associated with caffeine.

Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A

BackgroundOnce-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited.MethodsWe conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics.ResultsA total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours.ConclusionsIn children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.)

Plasmodium falciparum infection status in children less than 10 years old under seasonal malaria chemoprevention and risk of clinical malaria in the Koulikoro health district, Mali.

Introduction: Seasonal malaria chemoprevention (SMC) with Sulfadoxine pyrimethamine plus amodiaquine (SP + AQ) consist of a monthly administration of therapeutic dose to children under five years of age during the high risk of malaria in area where malaria is highly seasonal. According to SMC recommendation, both non-infected and asymptomatic Plasmodium falciparum infected children will receive similar treatment. The gap in our knowledge is how the effect of asymptomatic infection on the efficacy of SMC in preventing clinical malaria over a four-week period. Thus, this study aimed to assess the risk of clinical malaria and its association with children's infection status when SMC treatment is given. Methodology: The study was carried out in the Koulikoro health district in Mali and concerned children under 10 years of age. A total of 726 and 1452 children were randomly selected and followed over the SMC campaign in the years 2019 and 2020 respectively. Prevalence of asymptomatic P. falciparum infection was determined each round by microscopy before SMC drugs intake. Children were passively followed over a four-week period to determine incidence of clinical malaria. R-Studio software was used for analysis. The risk of clinical malaria by infection status was estimated using a logistic regression. A Kaplan-Meier curve was used to determine the survival time between infected and uninfected children. The Pearson Chi-square test was used to compare proportions with the significant level at p< 0.05. Results: The average prevalence of asymptomatic infection was 11.0% both years, and it was higher among children aged 5 to 9 years old in 2019 (p<0.001) and 2020 (p=0.016). The risk of clinical malaria was significantly higher among asymptomatic infected children 2019: (RR =3.05, CI [2.04-4.72]) and 2020 (RR=1.43, CI [1.04-1.97]) transmission seasons. Likewise, the time of the first malaria occurrence was statistically lower among infected children regardless the year (p<0.001 in 2019 and p=0.01 in 2020). Conclusion: Results show a high risk of clinical malaria in asymptomatic infected children during SMC delivery. Screening for P. falciparum infection before the SMC treatment could significantly enhance the impact of the strategy on malaria morbidity in endemic areas.

The Impact of Gabapentinoids on Pain-Related Outcomes after Knee and Hip Surgery: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

Background: Postoperative pain remains a significant challenge after knee and hip surgeries, two of the most frequently performed procedures, preventing patients from seeking timely surgical help. Gabapentinoids, gabapentin, and pregabalin, have been gaining attention in postoperative pain management. Methods: We conducted a meta-analysis to evaluate the efficacy of gabapentinoids in pain management after knee and hip surgery. PubMed, Scopus, and Cochrane Library were searched for relevant randomized controlled trials (RCTs) published before January 2023. Results: Fifteen articles reporting 1320 patients were analyzed. Cumulative pain intensity at rest and on movement was lower in the experimental group with the mean difference (MD) = -0.30 [-0.55,-0.05], p-value = 0.02, and MD = -0.41 [-0.68,-0.13], p-value = 0.004, respectively. However, the difference was not clinically meaningful and lacked statistical significance at each time period. The gabapentinoid group required less opioid consumption in morphine equivalents (MD = -6.42 [-9.07, -3.78] mg, p-value < 0.001). There was a lower incidence of postoperative nausea in the experimental group with a risk ratio (RR) of 0.69 [0.55, 0.86], p-value < 0.001. A subgroup analysis showed that gabapentinoids reduced pain on movement on postoperative day two after total knee arthroplasty but not hip arthroplasty. There was insufficient data to examine the efficacy of gabapentinoids in the reduction of chronic postoperative pain in knee/hip surgery. Conclusions: Thus, gabapentinoids were associated with a reduction in postoperative pain intensity at rest and on movement, morphine consumption, and the incidence of postoperative nausea in the early postoperative period following knee and hip surgeries. However, pain reduction was not clinically relevant. Sedation has not been evaluated in this work and, if performed, this may have influenced the conclusions. An important limitation of this study is that different gabapentinoids, their administration times and dosages, as well as varying intraoperative management protocols, were pooled together.

The effect of sodium butyrate administered in ovo on the health status and intestinal response in broiler chicken

A healthy gut is one of the main factors influencing bird response. Over the years, efforts have been made to improve intestinal health. One of the supporting methods may be enriching the diet with bioactive ingredients, including sodium butyrate (SB). One of the possible ways of administering such supplementation is in ovo technology. Over the years, research has shown that administering bioactive substances this way has a positive effect on the health status of chickens. The current study aimed to modify the gut microbiota of broiler chickens by in ovo stimulation on d 12 of egg incubation with SB and to determine the changes occurring in intestines. One thousand eggs were incubated and injected with 0.1, 0.3, or 0.5% SB on d 12 of incubation. The control group was injected with physiological saline. Samples collected for analysis were obtained postmortem from 42-day-old ROSS 308 broiler chickens. Growth performance parameters were also monitored during broiler rearing. Gene expression analysis showed significant changes in the levels of IL4, IFNγ, AvBD1, TJAP and MUC6 genes in the ileum. However, the IL8, MUC2 and MUC6 genes were significantly expressed in the cecal mucosa. These changes depended on the administered dose of butyrate. There was no effect of in ovo administration of various doses of SB on digesta pH, SCFA level and histological parameters. However, a significant increase in Bifidobacterium bacteria was detected in the ileum after administration of a dose of 0.5% SB and in the cecum after administration of a dose of 0.3%. Administration of SB in ovo has the potential to support intestinal health in poultry. The effects depend on the administered dose, while the results indicate a dose of 0.3% as the most optimal.

Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC): study protocol for an adaptive randomised controlled clinical trial

BackgroundImmunocompromised hosts (ICH) experience more breakthrough infections and worse clinical outcomes following infection with COVID-19 than immunocompetent people. Prophylactic monoclonal antibody therapies can be challenging to access, and escape variants emerge rapidly. Immunity conferred through vaccination remains a central prevention strategy for COVID-19. COVID-19 vaccines do not elicit optimal immunity in ICH but boosting, through additional doses of vaccine improves humoral and cellular immune responses. This trial aims to assess the immunogenicity and safety of different COVID-19 vaccine booster strategies against SARS-CoV-2 for ICH in Australia.MethodsBringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC) is an adaptive randomised trial of one or two additional doses of COVID-19 vaccines 3 months apart in people living with HIV, solid organ transplant (SOT) recipients, or those who have haematological malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma or multiple myeloma). Key eligibility criteria include having received 3 to 7 doses of Australian Therapeutic Goods Administration (TGA)-approved COVID-19 vaccines at least 3 months earlier, and having not received SARS-CoV-2-specific monoclonal antibodies in the 3 months prior to receiving the study vaccine. The primary outcome is the geometric mean concentration of anti-spike SARS-CoV-2 immunoglobulin G (IgG) 28 days after the final dose of the study vaccine. Key secondary outcomes include anti-spike SARS-CoV-2 IgG titres and the proportion of people seroconverting 6 and 12 months after study vaccines, local and systemic reactions in the 7 days after vaccination, adverse events of special interest, COVID-19 infection, mortality and quality of life.DiscussionThis study will enhance the understanding of COVID-19 vaccine responses in ICH, and enable the development of safe, and optimised vaccine schedules in people with HIV, SOT, or haematological malignancy.Trial registrationClinicalTrials.gov NCT05556720. Registered on 23rd August 2022.

Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Colchicine-The Divine Medicine against COVID-19.

Colchicine has a number of effects that suggest it may be useful in the treatment of COVID-19. Myeloid cells are a major source of dysregulated inflammation in COVID-19. The hyperactivation of the NLRP3 inflammasome and the subsequent cytokine storm take place precisely inside them and can lead to multiorgan damage and death. NLRP3 inflammasome inhibition has been assessed at micromolar colchicine concentrations which cannot be achieved in serum. However, colchicine has remarkable ability to accumulate intensively in leukocytes, where the cytokine storm is generated. Over 50 observational studies and randomized clinical trials, small randomized non-controlled trials, and retrospective cohort studies were initiated to test its healing effect in vivo, leading to conflicting, rather disappointing results. The WHO gives a "Strong recommendation against" the use of colchicine for COVID-19 treatment. This is because low doses of colchicine are always used, where the concentrations required to inhibit the NLRP3 inflammasome in leukocytes cannot be reached. Considering this, from March 2020, we started the administration of higher doses of colchicine. Our assumption was that a safe increase in colchicine doses to reach micromolar concentrations in leukocytes will result in NLRP3 inflammasome/cytokine storm inhibition. We demonstrated that in 785 inpatients treated with increasing doses of colchicine, mortality fell between two and seven times. Our data, including a large number of COVID-19 outpatients, showed that nearly 100% of the patients treated with this therapeutic regimen escaped hospitalization. In addition, post-COVID-19 symptoms in those treated with colchicine were significantly rarer. As a large number of viruses can overactivate the NLRP3 inflammasome (like seasonal influenza), we are convinced that higher colchicine doses would be useful in these cases as well.

The Impact of Smoking on Long-Term Protection Following Hepatitis B Vaccination: A 24-Year Cohort Study.

The hepatitis B vaccination-induced immune response has been demonstrated to be associated with a number of factors, including age, sex, BMI, and the presence of comorbidities. Additionally, modifiable determinants such as smoking have been identified as influencing the response to vaccination. However, despite the evidence that smokers are at an increased risk of not responding to vaccination, the long-term effects of smoking on antibody persistence remain poorly understood. This study aims to assess the impact of smoking habits on long-term immunity following the primary vaccination cycle. Participants were required to have received a standard three-dose vaccine schedule in childhood, without subsequent doses, and to be between 18 and 24 years of age. Data on age, sex, BMI, age of administration of the first vaccine dose, and time between doses were collected. An antibody concentration < 10 IU/L was considered as non-protective. A total of 2133 individuals were included, 14.2% of whom were smokers. The mean age was 20.28 ± 0.92 years. The probability of having a non-protective antibody concentration was significantly higher in smokers than in non-smokers (AOR: 1.287; 95% CI: 1.002-1.652). The detrimental effects of smoking extend beyond the immediate effects on the vaccine response, also impairing the long-term immune response in individuals who received vaccinations during childhood.

Early Detection and Management of Lamanema chavezi infection in a llama (Lama glama) in Switzerland.

Lamanema chaveziis an entero-hepatic strongylid parasite specific to South American camelids. It has been reported only on few occasions outside South America. Due to its hepaticmigration, it can cause extensive liver damage, leading to granulomatous and fibrotic hepatitis and manifesting with lethargy, anorexia, and even death. We are reporting the second case ofL. chavezi infection in Europe and the first in Switzerland. The patient was a three-year old neutered male llama (Lama glama). Clinical examination revealed bloody mucous discharge from the anus. Fecal sedimentation/flotation revealed strongylid eggs consistent with L. chavezi, which were molecularly confirmed by a PCR targeting the ITS2 plus 5.8S and 28S rDNA flanking regions and amplicon sequencing. Eighteen weeks after administration of a single dose of eprinomectin (0.2mg/kg i.m.), no further L. chavezi eggs were detected in the feces. The source of infection could not be traced back. The entire herd consisted of llamas bred in Switzerland. L. chavezi has been rarely reported outside South America, but its potential for pathogenicity and establishment should not be underestimated. Fecal sedimentation/flotation techniques should be routinely performed to ensure early detection of the parasite.

The effect of carbohydrate adjuvants in the composition of the experimental hantavirus vaccine on the dynamics of neutralizing antibodies in the blood sera of guinea pigs

Introduction. Vaccination could be the most effective means of preventing hemorrhagic fever with renal syndrome (HFRS), which is one of the leading zoonoses and a major cause of natural disease in humans. Therefore, research to develop an effective vaccine and the search for new non-toxic and effective adjuvants that can enhance and prolong the immune response, reduce the antigen concentration and reduce the frequency of dose administration is an urgent task. The aim of the study was to determine the dependence of the immunogenic activity of an experimental hantavirus vaccine based on Puumala virus (HV) on the antigen dose both in native form and in combination with carbohydrate adjuvants. Materials and methods. The immunoadjuvant effect of Ac3-LPS S. sonnei and S. flexneri 1B and emulsions of nanoemulsified squalene Sepivac SWE (SWE) as part of HV at the optimal and minimal doses was investigated by induction of neutralising antibodies after 3-fold immunisation (day 0, 14, 182) of guinea pigs (Cavia porcellus). Differences in the immunogenic activity of HV were assessed in the neutralisation reaction by 50% suppression of focal units in Vero E6 cell cultures. Results. A statistically significant increase in neutralising antibodies levels was observed after immunization both with HV at the optimal dose and for its combination with adjuvants. Ac3-LPS S. sonnei and SWE showed the most pronounced immunoadjuvant effect at concentrations of 50 and 100 μg/dose, respectively. The immunoadjuvant effect of the combination of the hantavirus vaccine with Ac3-LPS S. sonnei and SWE contributed to both an enhanced immune response and its duration. The tenfold reduction of the antigen dose in the presence of SWE allows optimization of the immune response to the vaccine. Conclusion. The results of this study show the prospects of using Ac3-LPS S. sonnei and Sepivac SWE in the vaccine for the prevention of HFRS.

Construction of GSH-responsive polyethyleneimine-based delivery vector for effective gene transfection.

The rise of gene therapy has solved many diseases that cannot be effectively treated by conventional methods. Gene vectors is very important to protect and deliver the therapeutic genes to the target site. Polyethyleneimine (PEI) modified with mannitol could enhance the gene transfection efficiency reported by our group previously. In order to further control and improve the effective gene release to action site, disulfide bonds were introduced into mannitol-modified PEI to construct new non-viral gene vectors PeiSM. The degrees of mannitol linking with disulfide bonds were screened. Among them, moderate mannitol-modified polyethyleneimine with disulfide bonds (M-PeiSM) showed the best transfection efficiency, and significantly enhanced long-term systemic transgene expression for 72 hours in vivo even at a single dose administration, and could promote caveolae-mediated uptake through up-regulating the phosphorylation of caveolin-1 and increase the loaded gene release from the nanocomplexes in high GSH intracellular environment. This functionalized gene delivery system can be used as an potential and safe non-viral nanovector for further gene therapy.

Impact of COVID-19 vaccines in patients on hemodialysis: an Italian multicentre cohort study.

The aim of this study was to evaluate the impact on the national health system of COVID-19 infection in vaccinated patients undergoing haemodialysis. From the cohort of vaccinated dialysis patients enrolled in 118 dialysis centres, we calculated hospitalisation incidence in COVID-19-infected subjects. COVID-19-related hospitalisations and ICU admissions were analysed over two time periods (prior to administration of the third dose and following administration of the third dose of vaccine) and adjusted for several co-variates. Using the general population as the reference, we then calculated the Standardized Incidence Ratio (SIR) of hospitalisation. Eighty-two subjects out of 1096 infected patients were hospitalised (7.5%) and sixty-four hospitalisations occurred among the 824 infected persons after the third dose. Age ≥ 60years (Adj RR 2.91; 95% CI 1.34-6.30) and lung disease (Adj RR = 2.45; 95% CI 1.32-4.54) were the only risk factors associated with hospitalisation. The risk of ICU admission in the second time period (Time 2) was reduced by 86% (RR = 0.14; 95% CI 0.03-0.71) compared to the first time period (Time 1). The SIR of hospitalisation (SIR 14.51; 95% CI 11.37-17.65) and ICU admission (SIR 14.58; 95% CI 2.91-26.24) showed an increase in the number of events in dialysis patients compared to the general population. Our analysis revealed that while the second variant of the virus increased infection rates, it wasconcurrently associated withmitigated severity of infections. Dialysis patients exhibited a higher susceptibility to both COVID-19 hospitalisation and ICU admission than the general population throughout the pandemic.

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on haemoglobin levels in Ethiopia: a longitudinal cohort study

BackgroundTo interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency.MethodsAn observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone.ResultsA total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28–15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to − 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (− 0.60 g/dL) than in the G6PDd ACT alone group (− 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = − 0.00 to 0.20) and 0.05 g/dl (95% CI = − 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412).ConclusionsThis study’s findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

Food Effect and Pharmacokinetic Bridging of Avacopan in Caucasian and Japanese Healthy Participants.

Avacopan 30mg twice daily (BID) is approved for the treatment of severe active antineutrophil cytoplasmic autoantibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). Food effect on avacopan pharmacokinetics (PKs) and PK bridging in Japanese participants were examined through 2 phase 1 studies involving healthy adult participants. In Study 1, an open-label, crossover trial, participants received oral administration of a single 30-mg dose of avacopan under fasted and fed conditions. Study 2 was a randomized, single-blind, placebo-controlled trial in Caucasian and Japanese participants: Part A investigated single doses of 10 and 30mg of avacopan under fasted and fed conditions and Part B investigated 30 and 50mg BID avacopan. The PKs of single-dose administrations of 10 and 30mg in Japanese participants was compared with that in Caucasian participants under fasted conditions. Food substantially increased plasma avacopan area under the plasma concentration-time curve from time 0 to time infinity (AUC0-inf) by 1.72-fold, supporting the recommendation of taking avacopan with food. Maximum plasma concentration (Cmax) remained relatively unchanged. The median time to reach Cmax (tmax) was delayed by 3hours. No significant food effect was observed on the active metabolite CCX168-M1 (M1) AUC. Avacopan and M1 exposures were <1.5-fold higher in Japanese participants than in Caucasian participants following multiple-dose administration of avacopan.

Effects of Denosumab and Bisphosphonates on Glucocorticoid-induced Osteoporosis in Patients with Neuroimmunological Disorders.

Objective Although patients with neuroimmunological disorders often need to be treated with glucocorticoids and are at risk of developing glucocorticoid-induced osteoporosis, no research has focused on the treatment of glucocorticoid-induced osteoporosis in such patients. Methods We compared the efficacy of denosumab and bisphosphonates in glucocorticoid-induced osteoporosis in neuroimmunological diseases. In 57 patients with neuroimmunological disorders treated with corticosteroids (34 with neuromyelitis optica spectrum disorders, 16 with myasthenia gravis, and 7 with others), we retrospectively studied the long-term effects of denosumab (n=23) and bisphosphonates (n=34) on spine and total hip bone mineral density (BMD) measured by dual energy X-ray absorptiometry. Results There were no significant differences in the age, lumbar spine BMD, or mean dose or duration of prednisolone administration at baseline between the denosumab and bisphosphonate groups. During the follow-up period of up to 6 years, the increase in the lumbar spine and total hip BMD was greater in the denosumab group than in the bisphosphonate group (p<0.01). Insufficient bone fractures were observed in 2 (9%) of the 23 patients in the denosumab group and in 2 (6%) of the 34 patients in the bisphosphonate group (not significant). Conclusion Denosumab is more effective than bisphosphonates in increasing the BMD of patients with neuroimmunological disorders receiving glucocorticoids.

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits andminimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring. This paper aims to investigate the potentiality of coupling RL with population PK/PD models to develop precision dosing algorithms, reviewing the most relevant works in the field. Case studies in which PK/PD models were integrated within RL algorithms as simulation engine to predict consequences of any dosing action have been considered and discussed. They mainly concern propofol-induced anesthesia, anticoagulant therapy with warfarin and a variety of anticancer treatments differing for administered agents and/or monitored biomarkers. The resulted picture highlights a certain heterogeneity in terms of precision dosing approaches, applied methodologies, and degree of adherence to the clinical domain. In addition, a tutorial on how a precision dosing problem should be formulated in terms of the key elements composing the RL framework (i.e., system state, agent actions and reward function), and on how PK/PD models could enhance RL approaches is proposed for readers interested in delving in this field. Overall, the integration of PK/PD models into a RL-framework holds great promise for precision dosing, but further investigations and advancements are still needed to address current limitations and extend the applicability of this methodology to drugs requiring adaptive dosing strategies.

A Case Report on Granulomatosis with Polyangitis and Diffuse Alveolar Haemorrhage

Granulomatous polyangitis (GPA), formerly known as Wegener’s granulomatosis, is a rare form of small-vessel vasculitis. It has no gender predominance and tends to present between the ages of 40 and 55 years old in more than two-thirds of cases. GPA should be critically considered as a diagnosis when a presentation involves multiple systems, including joint, kidney, and lung. Lifesaving treatment of GPA is based on prompt and aggressive administration of pulse steroids and high doses of cyclophosphamide in repeat intervals.

The future of cancer treatment: combining radiotherapy with immunotherapy

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other’s beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell’s genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.