Prophylactic Trials Research Articles

Rapid Development of a Registry to Accelerate COVID-19 Vaccine Clinical Trials.

The unprecedented scientific response to the SARS-Cov-2 pandemic in 2020 required the rapid development and activation of extensive clinical trial networks to study vaccines and therapeutics. The COVID-19 Prevention Network (CoVPN) coordinated hundreds of sites conducting phase 2 and 3 clinical trials of vaccines and antibody therapeutics. To facilitate these clinical trials, the CoVPN Volunteer Screening Registry (VSR) was created to collect volunteer information at scale, identify volunteers at risk of COVID-19 who met enrollment criteria, distribute candidates across clinical trial sites, and enable monitoring of volunteering and enrollment progress. We developed a secure database to support three primary web-based interfaces: a national volunteer questionnaire intake form, a clinical trial site portal, and an Administrative Portal. The Site Portal supported filters based on volunteer attributes, visual analytics, enrollment status tracking, geographic search, and clinical risk prediction. The Administrative Portal supported oversight and development with pre-specified reports aggregated by geography, trial, and trial site; charts of volunteer rates over time; volunteer risk score calculation; and dynamic, user-defined reports. Over 650,000 volunteers joined the VSR, and 1094 users were trained to utilize the system. The VSR played a key role in recruitment for the Moderna, Oxford-AstraZeneca, Janssen, and Novavax vaccine clinical trials, provided support to the Pfizer and Sanofi vaccine and prophylactic antibody clinical trials, and enhanced the diversity of trial participants. Clinical trial sites selected 166,729 volunteer records for follow-up screening, and of these 47·7% represented groups prioritized for increased enrollment. Despite the unprecedented urgency of its development, the system maintained 99·99% uptime. The success of the VSR demonstrates that information tools can be rapidly yet safely developed through a public-private partnership and integrated into a distributed and accelerated clinical trial setting. We further summarize the requirements, design, and development of the system, and discuss lessons learned for future pandemic preparedness.

Dynamic borrowing of historical controls adjusting for covariates in vaccine efficacy clinical trials.

Traditional vaccine efficacy trials usually use fixed designs and often require large sample sizes. Recruiting a large number of subjects can make the trial expensive, long, and difficult to conduct. A possible approach to reduce the sample size and speed up the development is to use historical controls. In this paper, we extend the robust mixture prior (RMP) approach (a well established approach for Bayesian dynamic borrowing of historical controls) to adjust for covariates. The adjustment is done using classical methods from causal inference: inverse probability of treatment weighting, G-computation and double-robust estimation. We evaluate these covariate-adjusted RMP approaches using a comprehensive simulation study and demonstrate their use by performing a retrospective analysis of a prophylactic human papillomavirus vaccine efficacy trial. Adjusting for covariates reduces the drift between current and historical controls, with a beneficial effect on bias, control of type I error and power.

Association Between Early External Ventricular Drain Insertion and Functional Outcomes 6 Months Following Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading global cause of morbidity and mortality. Intracranial hypertension following moderate-to-severe TBI (m-sTBI) is a potentially modifiable secondary cerebral insult and one of the central therapeutic targets of contemporary neurocritical care. External ventricular drain (EVD) insertion is a common therapeutic intervention used to control intracranial hypertension and attenuate secondary brain injury. However, the optimal timing of EVD insertion in the setting of m-sTBI is uncertain and practice variation is widespread. Therefore, we aimed to assess if there is an association between timing of EVD placement and functional neurological outcome at 6 months post m-sTBI. We pooled individual patient data for all relevant harmonizable variables from the Erythropoietin in Traumatic Brain Injury (EPO-TBI) and Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomized control trials, and the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) Core Study version 3.0 and Australia-Europe NeuroTrauma Effectiveness Research in TBI (Oz-ENTER) prospective observational studies to create a combined dataset. The Glasgow Coma Scale (GCS) score was used to define TBI severity and we included all patients admitted to an intensive care unit with a GCS ≤12, who were 15 years or older and underwent EVD placement within 7 days of injury. We used hierarchical multi-variable logistic regression models to study the association between EVD insertion within 24 h of injury (early) compared with EVD insertion more than 24 h after injury (late) and 6-month functional neurological outcome measured using the Glasgow Outcome Score Extended (GOSE). In total, 2536 patients were assessed. Of these, 502 (20%) underwent early EVD insertion and 145 (6%) underwent late EVD insertion. Following adjustment for the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) score extended (Core + CT), sex, injury severity score, study and treatment site, patients receiving a late EVD had higher odds of death or severe disability (GOSE 1-4) at 6 months follow-up than those receiving an early EVD adjusted odds ratio; 95% confidence interval, 2.14; 1.22-3.76; p = 0.008. Our study suggests that in patients with m-sTBI where an EVD is needed, early (≤ 24 h post-injury) insertion may result in better long-term functional outcomes. This finding supports future prospective investigation in this area.

HTA91 Health Impact of a Potential HIV Vaccine Among Men Who Have Sex with Men in the United States

70% of new HIV infections in the United States (U.S.) occur among men who have sex with men (MSM). Ongoing prophylactic HIV vaccine efficacy trials for MSM may provide efficacy evidence, but the long-term impact of future HIV vaccines is not clear. This study aims to evaluate the long-term health outcomes of a potential HIV vaccine in the U.S. MSM population under different scenarios of efficacy, durability, and coverage.

A RANDOMISED CONTROL TRIAL TO ASCERTAIN IF POSTOPERATIVE ANTIBIOTICS ARE NECESSARY FOLLOWING LAPAROSCOPIC APPENDICECTOMY IN NONPERFORATED APPENDICITIS

Background: The most frequent cause of severe abdominal discomfort is acute appendicitis. Prophylactic antibiotics should be used as directed to reduce the risk of postoperative surgical site infections (SSIs). There is no denitive recommendation, though, for how long to use antibiotics. There has only been one preoperative prophylactic dose several randomised control trials strongly suggest. Therefore, the goal of the study was to ascertain if postoperative antibiotics were necessary following laparoscopic appendix surgery for nonperforated appendicitis. Methods: A total of 52 nonperforated appendicitis patients were separated into two groups and underwent laparoscopic appendectomy. Patients in group B (n=26) received three postoperative doses of antibiotics in addition to the one preoperative dose given to group A's (n=26) patients. Regular investigations, such as Complete blood count, blood urea, serum creatinine, and other tests like an abdominal ultrasound were also carried out. After a laparoscopic appendicectomy, the surgical incision was examined to check for any evidence of postoperative SSI after 48, 72, and 7 days. Results: Group A had a mean age of 30.6± 10.5 years compared to group B's mean age of 30.7 ±9.5 years (p=0.75). Right iliac fossa pain was the initial complaint of every subject in the research. Grade III SSIs occurred in 0ne patient in group A (4%) and one patient in group B (4%) and were treated conservatively. The difference in the incidence of SSIs between the two groups was statistically negligible (p=1.000). Conclusions: After a laparoscopic appendicectomy, prophylactic postoperative doses of antibiotics offer no additional advantage over a single preoperative dosage in terms of preventing postoperative SSIs

PHARMACOKINETICS OF PHVS719, EXTENDED-RELEASE TABLET FORMULATION OF PHA121, A FIRST-IN-CLASS ORAL HUMAN BRADYKININ B2-RECEPTOR ANTAGONIST

<h3>Introduction</h3> PHA121 is an orally bioavailable potent, competitive and selective antagonist of the human bradykinin B2 receptor (B2R) being developed in two formulations for treatment of hereditary angioedema (HAE): PHVS416 soft capsule for treatment of acute attacks and PHVS719 extended-release tablet for prophylaxis. <h3>Methods</h3> Bioavailability of the extended-release formulation PHVS719 in comparison with PHVS416 was evaluated in an open-label, crossover single-dose study. Eight healthy volunteers received treatment with PHVS416 (2x soft capsules each containing 10 mg-of PHA121) and PHVS719 (1x extended-release tablet containing 40 mg of PHA121) in randomized order and in variable experimental conditions. <h3>Results</h3> Administration of PHVS416 resulted in rapid clinically relevant exposure of PHA121 active ingredient above EC₈₅ determined from the bradykinin challenge (13.8 ng/mL) within 15 minutes. A single dose of PHVS719 yielded exposure of PHA121 above EC₈₅ by the 3-hour timepoint and maintained it for at least 28 hours with or without food. The 24-hour area under the curve exposure of PHA121 using PHVS719 was similar to that observed in studies with PHVS416 soft capsules dosed 20 mg twice a day with food (being investigated in the ongoing CHAPTER-1 prophylactic trial). PHVS416 and PHVS719 were well tolerated. <h3>Conclusions</h3> Findings from this study confirmed rapid achievement of clinically relevant exposure of PHA121 after administration of PHVS416. The observed pharmacokinetic of PHVS719 is consistent with the extended-release formulation designed to provide long-term exposure to PHA121. PHVS719 appears to be suitable for once-daily prophylactic dosing in HAE.

Declining Epstein-Barr Virus Antibody Prevalence in College Freshmen Strengthens the Rationale for a Prophylactic EBV Vaccine

Background: To better understand the epidemiology of primary Epstein-Barr virus (EBV) infection and to identify EBV-naïve candidates eligible to receive a prophylactic EBV vaccine, we screened freshmen from the University of Minnesota Class of 2025 for circulating EBV antibody, which is indicative of previous infection. This permitted us to compare their EBV antibody prevalence with that of 4 other freshman classes (Classes of 2010, 2011, 2016, 2021) that have been previously published. Methods: Freshman students were recruited during screening sessions in the residence halls. Venous blood was collected and the serum fraction tested for IgG antibody against EBV viral capsid antigen (VCA IgG) using commercial enzyme immunoassays. Results: All classes combined, 1196 participants were tested (female, 677; male, 513; did not identify gender, 6) who were 18–23 years old (median, 18; mean, 18.37). The EBV VCA IgG antibody prevalence was 58% (689/1196) and was higher in women than men. The EBV antibody prevalence of 64% (170/267) in the 2010 freshman class versus 52% (78/150) in the Class of 2025 was statistically significantly different (p = 0.0223, Fisher exact test).” Conclusions: Sufficient participants are available for a prophylactic vaccine trial. Antibody prevalence decreased over 15 years from 64% to 52%. If this trend continues, the number of EBV-naïve adolescents and young adults who are in the age group most susceptible to infectious mononucleosis will increase, strengthening the rationale to develop an effective prophylactic EBV vaccine.

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

BackgroundCarriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention.MethodsThis was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm “converters,” 15 Pm “nonconverters,” 15 Nc) that were one-one matched on age, education, and socioeconomic status.ResultsCompared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters.ConclusionsAccelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.

Prophylactic efficacy of Unani herbal and herbo-mineral preparations in population at risk of COVID-19 – A randomised controlled prospective field trial

Present study was aimed to evaluate the efficacy of Unani poly-herbal decoction and Khamira Marvareed (herbo-mineral preparation) in COVID-19 susceptible population. This study was conducted as prospective, open label, randomized Controlled, prophylactic Community-based clinical trial. Four thousand five hundred healthy adults from containment zone were allocated randomly into intervention (n=2250) and control group (n=2250). The intervention group was given a combination of herbal drugs namely Unnab ( Zizyphus jujube Mill.), 5 pieces; Sapistan ( Cordia myxa L . ), 9 pieces; Behidana ( Cydonia oblonga Mill.), 3gms in decoction form and Khameera Marwareed , 5gms as semisolid preparation, orally once daily in the morning for 20 days. No drug was given in the control group. The subjects were assessed on 0, 20 th and 35 th day. The prophylactic effect of the Unani intervention was evaluated on the basis of difference of COVID-19 incidence between the groups, COVID-19 like symptoms, scores of immunity status questionnaire and WHOQOL-BREF scale after completion of 35 th day of study. The study remained inconclusive to find any difference in COVID-19 incidence, but showed highly significant result (p&lt;0.001) in favour of Unani intervention in containing all COVID-19 like symptoms except cough; highly significant results (p&lt;0.001) in score of immunity status questionnaire and highly significant results (p&lt;0.001) in scores of physical and psychological domains of WHOQOL-BREF scale. The highly significant results in almost all secondary outcomes suggest the efficacy of the Unani intervention in control of COVID-19 like symptoms and may be beneficial in prevention of COVID-19 infection.

A Phase II Study of Prophylactic Anakinra to Prevent CRS and Neurotoxicity in Patients Receiving CD19 CAR T Cell Therapy for Relapsed or Refractory Lymphoma

A Phase II Study of Prophylactic Anakinra to Prevent CRS and Neurotoxicity in Patients Receiving CD19 CAR T Cell Therapy for Relapsed or Refractory Lymphoma

The DAPA Trial in the Context of Previous Prophylactic ICD Landmark Trials.

In patients with ischaemic cardiomyopathy and severely reduced left ventricular ejection fraction (LVEF), an arrhythmogenic milieu is created by a complex interplay between myocardial scarring (assessed by cardiac MRI) and multiple other factors (ventricular ectopy, ischaemia and autonomic imbalance), favouring the occurrence of arrhythmic sudden cardiac death (SCD). Currently, a dynamic and robust model of dichotomised SCD risk assessment after primary percutaneous coronary intervention (PCI) is lacking, underlining the urgent need for further refinement of the widely accepted and guidelines-based criteria (ischaemic cardiomyopathy, LVEF ≤35%) for primary prevention. This review addresses the potential additional value of the recently published Defibrillator After Primary Angioplasty (DAPA) trial results. The DAPA trial conveys important messages and provides novel perspectives regarding left ventricular function post-primary PCI as an (early) risk marker for SCD and the impact of prophylactic ICD implantation on survival in this cohort. In the context of other previous primary prevention trials, DAPA was the first trial including only ST-elevation MI patients all treated with acute PCI.

The impact of an online adult headache guideline on headache referrals to the neurology clinic

Headache is a common problem in primary care and one of the main reasons general practitioners (GP) consult the neurology service. We developed an online adult headache guideline (Supporting Information Appendix S1) for the greater Wellington Region as a resource for GP to guide identification of concerning headaches, initiation of prophylactic medications for migraine and management of analgesic overuse headache. To examine the effectiveness of this adult headache guideline in reducing demand on the neurology outpatient service for headache patients that could readily be managed in primary care. We reviewed electronic referrals to Wellington Hospital's neurology department before and after the implementation of the online headache guideline. The primary outcome was the proportion of referrals for headache. Secondary outcomes included proportion of referrals requiring clinic review, rate of pre-referral trial of headache prophylactic medication and medication overuse headache diagnosed at neurological consultation. Nine hundred neurology referrals before and 801 referrals after the publication of the online headache guideline were included. There was a statistically significant reduction in proportion of referrals for headache (15.4% vs 11.7%; P = 0.026). There was neither an increased rate of pre-referral adequate prophylactic medication trial (33.8% vs 27.7%; P = 0.320) nor fewer medication overuse headaches diagnosed during the neurology assessment (21.9% vs 25.0%; P = 0.674). The launch of an online headache guideline was associated with a reduction in demand on neurology service. Further education could improve the utilisation of this guideline, to avoid delays in prophylactic treatment and reduce the harm of medication overuse.

Protective Effect of Baicalin against Clostridioides difficile Infection in Mice.

This study investigated the prophylactic and therapeutic efficacies of baicalin (BC), a plant-derived flavone glycoside, in reducing the severity of Clostridioides difficile infection (CDI) in a mouse model. In the prophylactic trial, C57BL/6 mice were provided with BC (0, 11, and 22 mg/L in drinking water) from 12 days before C. difficile challenge through the end of the experiment, whereas BC administration started day 1 post challenge in the therapeutic trial. Both challenge and control groups were infected with 106 CFU/mL of hypervirulent C. difficile BAA 1803 spores or sterile PBS, and the clinical and diarrheal scores were recorded for 10 days post challenge. On day 2 post challenge, fecal and tissue samples were collected from mice prophylactically administered with BC for microbiome and histopathologic analysis. Both prophylactic and therapeutic supplementation of BC significantly reduced the severity of colonic lesions and improved CDI clinical progression and outcome compared with control (p < 0.05). Microbiome analysis revealed a significant increase in Gammaproteobacteria and reduction in the abundance of protective microbiota (Firmicutes) in antibiotic-treated and C. difficile-infected mice compared with controls (p < 0.05). However, baicalin supplementation favorably altered the microbiome composition, as revealed by an increased abundance in beneficial bacteria, especially Lachnospiraceae and Akkermansia. Our results warrant follow-up investigations on the use of BC as an adjunct to antibiotic therapy to control gut dysbiosis and reduce C. difficile infection in humans.

Abstract SY17-03: Tumor-associated antigen MUC1 vaccine for colon cancer prevention

Abstract For most human cancers, infectious etiology is unknown and preventative vaccines based on viral antigens, such as HPV for cervical cancer, are not a possibility. However, non-viral cancer-associated antigens, self-antigens abnormally expressed on tumors, have been identified as candidates for vaccines. In patients diagnosed with cancer, preexisting immunity to some of these antigens correlates with better disease outcome or reduced risk of recurrence. In transgenic mice or other animal models where they are expressed as self-antigens, immune responses induced to their tumor forms protect from tumor challenge without causing autoimmunity. Therapeutic vaccines that have utilized these antigens have had only marginal efficacy, which extensive research has now attributed to the presence of many immunosuppressive influences in the tumor microenvironment. MUC1 is one such antigen that has been shown effective as a vaccine in preclinical animal models but has had limited immunogenicity and little efficacy as a therapeutic vaccine in numerous clinical trials in many epithelial tumors, including cancer. Hypothesizing that the major difference between the outcome of the vaccine in preclinical models and in clinical trials is likely to be the high level of immune suppression in cancer patients, we began to develop models and MUC1 vaccines for cancer prevention in patients at risk, before immune suppression develops. We determined first that the tumor form of MUC1 was expressed on early premalignant lesions as well and chose premalignant colonic polyps as the first setting for testing the preventative vaccine. Data will be reviewed from a published feasibility study confirming immunogenicity and safety of the MUC1 vaccine in healthy individuals at risk for colon cancer. Data will then be presented from a recently completed unpublished randomized, double blind placebo controlled multi-center prophylactic MUC1 vaccine trial in the same patient population, those with a history of advanced colonic polyps and therefore at increased risk of developing colon cancer. Citation Format: Olivera (Olja) J. Finn. Tumor-associated antigen MUC1 vaccine for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-03.

Abstract 20: Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet)

Abstract Purpose: Persons living with HIV have elevated risks of HPV-related cervical, anogenital, and oropharyngeal cancers. Yet, research on optimization and implementation of prevention interventions (prophylactic HPV vaccination, cervical and anogenital cancer screening and triage, and precancer therapeutics) for HPV-related cancers among persons living with HIV has been limited. With a goal to expand this evidence, and building on strong academic research partnerships developed for HIV research between institutions in the US and the Latin American and the Caribbean (LAC) region, the US National Cancer Institute (NCI) initiated ULACNet, a new Cooperative Agreement clinical trials network in 2019. Methods: ULACNet comprises of three Partnership Centers each led by US-based institutions (University of California San Francisco, Weill Medical College of Cornell University, and Fred Hutchinson Cancer Research Center), working collaboratively with US and LAC institutions and with the NCI to develop and conduct multicenter prevention clinical trials focused on filling key scientific gaps and evaluating novel interventions. Results: ULACNet encompasses six countries (US, Mexico, Puerto Rico, Brazil, Peru, and Dominican Republic), twenty partner institutions, and over 100 collaborating scientific investigators, clinical and public health practitioners, research staff, and patient advocates. ULACNet will collaboratively conduct nine prevention clinical trials (two prophylactic HPV vaccine trials in adults and perinatally-HIV infected adolescents, three trials for clinical validation of molecular biomarkers and imaging technologies for screening and triage, two candidate HPV therapeutic vaccine trials, and two trials of topical therapeutic agents). Facilitation across network partners is achieved via a Coordinating Committee and three Working Groups (focused on HPV testing and screening, precancer treatment, and recruitment and retention activities). Conclusion: ULACNet seeks to leverage established academic global health partnerships to conduct high quality collaborative clinical trials to inform clinical practice and ultimately reduce the burden of highly preventable HPV-related cancers in persons living with HIV worldwide. Citation Format: Emma Brofsky, Margaret House, Brandy Heckman-Stoddard, Mostafa Nokta, Satish Gopal, Vikrant Sahasrabuddhe. Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet) [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 20.

Mycafungin Prophylaxis for Adult Acute Leukemia Patients Undergoing Induction Chemotherapy

BackgroundMicafungin is a tolerable and effective prophylactic antifungal agent used during allogeneic stem cell transplantation. In this prospective single arm trial, we aimed to evaluate the potential efficacy and safety of micafungin as a prophylactic agent during first induction chemotherapy in acute leukemia patients.Materials and MethodsPatients received 50mg of micafungin intravenously once daily from initiation of induction chemotherapy to recovery of neutrophil count (absolute neutrophil count > 500/μg for consecutive days) or suspected fungal infection or occurrence of drug-related toxicity. Primary end point was the incidence of invasive fungal infection and secondary end point was overall survival and non-relapse mortality (ClinicalTrials. Gov number, NCT02440178).ResultA total of 65 patients (median age 51.0 years, male:female = 34:31) were enrolled in this study; 33 (50.8%) acute myeloid leukemia (AML), 31 (47.7%) acute lymphoblastic leukemia, and 1 acute biphenotypic leukemia, respectively. The median treatment duration of micafungin was 24 days (range 1.0-68 days). Proven invasive fungal disease occurred in 1/65 patients (1.5%) and possible fungal infection occurred in 2/65 patients (4.6%). Overall, 19/65 patients (29.2%) discontinued prophylactic micafungin and 18/65 patients (27.7%) changed micafungin to other antifungal agents; 2 patients (3.1%) for fungal infection and 15 patients (23.1%) for prolonged neutropenic fever of unknown cause. For safety, 3/65 patients (4.6%) experienced adverse events: 2 liver function abnormality (Grade 2 and 3 respectively) and 1 grade 2 allergic reaction. Induction-related mortality occurred in 3 patients, where 1 event was caused by invasive aspergillosis pneumonia. The period of from initiation of micafungin to change to other antifungal agents was 46 days (95% CI 27-64 days). There were no significant differences in adverse events and fungal infections between AML and ALL (2/33 for AML vs. 1/31 for ALL patients, p=1.000). In addition, the occurrence of fungal infection during induction therapy was associated with poor overall survival (hazard ratio 8.470, 95% confidence interval 1.048-68.465, p=0.045) in multivariable analysis. Additionally, there was no fungal infection caused by resistant organism after induction chemotherapy. Micafungin also prevented invasive fungal infection more effectively and adverse events were tolerable when compared to the results of previous prophylactic posaconazole trial (proven or probable invasive fungal infection: 2% (7/304); adverse events 19/304 (6%) in patients treated with prophylactic posaconazole) [1].ConclusionLikewise posaconazole, micafungin could be used effectively and safely as prophylactic regimen in both AML and ALL patients undergoing induction chemotherapy.Reference1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. The New England journal of medicine. 2007;356:348-59.Figure captionFigure 1. The period of from initiation of micafungin to change to other antifungal agents [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Systematic Review and Meta-Analysis on the Efficacy of Curcumin/Turmeric for the Prevention and Amelioration of Radiotherapy/Radiochemotherapy Induced Oral Mucositis in Head and Neck Cancer Patients.

Background:Oral Mucositis(OM) is an acute debilitating dose limiting toxicity of Radiotherapy/Radiochemotherapy(RT/RCT) in management of Head and Neck Cancer (HNC). Curcumin/Turmeric may reduce OM in patients. Aim: Efficacy of Curcumin/Turmeric for preventing and ameliorating the onset and severity of RT/RCT induced OM was analysed in this review. Methods:A systematic literature search with meta-analysis were performed using Mesh terms in PubMed, Google scholar, Science Direct, Cochrane library and manual searching, articles published from 2010 to April 2021 were included. Clinical trials that studied the efficacy/effects of turmeric / curcumin in management of RT/RCT induced OM in HNC patients were included. Statistical Analysis were done to calculate the pooled Risk ratio at 95%confidence interval with significance at p <0.05. Results:Nine studies with overall 582 patients with HNC undergoing RT/RCT were included qualitatively. From evidence, orally 1,500-2,000 mg/day of Curcumin/Turmeric, (80mg/day/0.1%mouthwash) of nanocurcumin, topically gel/mouthwash used with increase in frequency prior and the entire course of RT/RCT with long follow ups are beneficial with no serious adverse effects. Meta-analysis of 5 prophylactic trials favoured curcumin/turmeric in reducing the severity of OM (RR 0.48 at 95% CI=0.23,0.99,P=0.05), did not prevent the overall incidence of OM (RR 0.99 at 95%CI=0.95,1.03,P=0.67) but delayed the onset of OM (RR 0.38 at 95% CI=0.18,0.80, P=0.01) during RT/RCT compared to control. Mean mucositis grade (Grade 3) was reduced in curcumin/turmeric with a mean difference of (-0.85 at 95%CI=-1.02,0.67, P<0.00001) over control. Pooling of 2 therapeutic trials favoured Curcumin/Turmeric with significant reduction of pain score at a mean difference of -2.17 at 95%CI =-2.77, -1.58,P<0.00001 over chlorhexidine. Conclusion:Curcumin/Turmeric are safe, efficacious, well tolerated in preventing the delay in onset and severity of OM, therapeutically ameliorated pain in patients with cancer therapy induced OM. We recommend novel curcumin formulations, high quality randomised controlled trials to further improve its therapeutic effects.

Feline thelaziosis (Thelazia callipaeda) in Spain: state-of-the-art and first prophylactic trial in cats.

Thelaziosis caused by the nematode Thelazia callipaeda (Spirurida, Thelaziidae) affects the eyes of domestic and wild carnivores, lagomorphs and even humans. The role of cats in spreading thelaziosis remains unclear. The present study assesses the current status of feline T callipaeda infection in Spain and presents the results of the first prophylactic trial conducted in this species. We retrospectively analysed the occurrence of feline thelaziosis (study 1), examined its prevalence based on cross-sectional sampling of endemic areas (study 2), and assessed the therapeutic/prophylactic benefits of a spot-on (moxidectin) and therapeutic efficacy of an eye drop (ivermectin) formulation (study 3). In study 1, 69 Thelazia-infected cats were examined. Autochthonous cases were detected in 18/26 municipalities surveyed in Spain, which corresponds to 88.4% (n = 61/69) of the total number of cases. In study 2, 74 cats (20 from La Vera region and 54 from Orense province) were examined from 2011 to 2013. Ten of these cats (13.5%) were infected with T callipaeda. The infection prevalence was 40% (n = 8/20) in La Vera and 3.7% (n = 2/54) in Orense. The therapeutic efficacy of ivermectin was assessed over a summer (2011) in 12 cats, while that of moxidectin was examined over a 17-month period in seven cats. Four of these seven cats were subsequently included in an all-year-round prophylaxis trial. Treatment efficacy ranged from 91.7% (ivermectin) on day 28 after treatment to 100% (moxidectin) on day 14. Moxidectin prevented reinfections in cats. Our data confirm the endemic status of T callipaeda infection in Spain, revealing its high prevalence in cats living in known endemic areas. Moxidectin was effective in treating and preventing infection. We strongly recommend the inclusion of thelaziosis in the differential diagnosis of pets and humans presenting with ocular manifestations, along with adequate preventive measures.

Notable Developments for Vitamin D Amid the COVID-19 Pandemic, but Caution Warranted Overall: A Narrative Review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel contagion that has infected over 113 million people worldwide. It is responsible for the coronavirus disease (COVID-19), which has cost the lives of 2.5 million people. Ergo, the global scientific community has been scrambling to repurpose or develop therapeutics to treat COVID-19. Dietary supplements and nutraceuticals are among those under consideration due to the link between nutritional status and patient outcomes. Overall, poor vitamin D status seems to be associated with an increased risk of COVID-19. Severely ill COVID-19 patients appear to be deficient or have suboptimal levels of serum 25-hydroxyvitamin D, a measure of vitamin D status. Consequently, vitamin D is now the subject of several prophylactic and therapeutic clinical trials. In this review, the general status of nutraceuticals and dietary supplements amid the pandemic is appraised, with a particular focus on vitamin D. Consumers should be aware of misinformation and unsubstantiated promises for products marketed for COVID-19 protection. However, maintaining a healthy diet and lifestyle will likely maintain health including optimum immune function that may affect patient outcomes. Those who are deficient in key nutrients such as vitamin D should consider lifestyle changes and potentially supplementation in consultation with their physician and/or registered dieticians.

A 52-week prophylactic randomised control trial of omega-3 polyunsaturated fatty acids in bipolar disorder.

Previous work suggests supplementation with omega-3 polyunsaturated fatty acids (PUFAs) may improve mood symptoms in bipolar disorder (BD) although findings remain unclear. In this study, we assess the efficacy of omega-3 PUFA administration for prophylaxis in BD using a clinical trial design over 52-weeks (ClinicalTrials.gov Identifier: NCT04210804). Individuals with BD (n=80) were randomised to receive placebo (n=40) or 1g eicosapentaenoic acid (EPA) plus 1g docosahexaenoic acid (DHA; n=40) adjunctively for 52-weeks. The primary outcome measure comprised the number of mood episode relapses including hospital admissions and medication changes experienced. Secondary outcome measures included time to first mood episode relapse and change in psychometric measures of depression and elation (Hamilton Depression Rating Scale and Young Mania Rating Scale). No significant differences in the number of mood episode relapses (U=490.00, p=0.14) or the number of individuals requiring admission to hospital (χ2 =0.67, p=0.41) or medication adjustment in the omega-3 PUFA compared to the placebo group were noted. Time to relapse was not significantly different between groups (Log Rank χ2 =0.41, p=0.52). Change in Young Manic Rating Scale (F(3.12, 152.86)=2.71, p=0.05) was significantly different between treatment groups over 12-months, with scores at 9-months and 12-months significantly lower than those at 3-months in the omega-3 group and not in the placebo group. Change in Hamilton Depression Rating Scale, Global Clinical Impression and Global Assessment of Functioning were not different between groups. Despite a minor reduction in hypomania scores in the omega-3 PUFA group compared to placebo, we find little evidence that the supplementation of omega-3-PUFAs exhibits prophylactic benefit in BD.