Background/Aims:Non-adherence is a significant issue in clinical trials of new therapeutics; and Alcohol Use Disorder (AUD) studies are particularly vulnerable to discontinuation. Moreover, clinical trials involving behavioral intervention over time may be even more difficult to complete. Digital therapeutics make participation in treatment much more accessible and may therefore reduce one of the barriers to study participation. This study aims to investigate predictors of treatment adherence in a clinical trial that collected data over 13 weeks involving a digital therapeutic Cognitive Remediation Therapy (CRT) and donepezil for patients with AUD, focusing on (1) CRT adherence (total hours completed); (2) medication adherence (pill count) and (3) total adherence that combines 1 and 2. Methods:Baseline data including demographics, illness characteristics, cognitive assessments, self-reports of functioning and disability, psychiatric symptoms and personality traits were collected on 52 participants. Exploratory analyses included parametric and non-parametric analyses of baseline variables to predict adherence over 13 weeks. Results:Of the 52 participants who were randomized, 49 completed baseline assessments and entered the study. The mean CRT hours was 29.49 hours (SD=27.90) out of a possible 65 hours (45.37%). Mean weekly medication adherence was 48.78 (SD=38.81) out of 84 pills (58.02%). Medication adherence was correlated with younger age and Total Adherence was negatively correlated with WHODAS 2.0 Self-care indicating that greater adherence is associated with lower self-care dysfunction. Medication adherence was significantly related to physical ability on the VR-12 but with none of the other variables. CRT adherence was not directly related to any baseline variables. A linear regression analysis was performed to predict Total Adherence. A significant model was obtained with WHODAS 2.0 Self-care and Age as significant variables. No relationship was found between Self-care and substance abuse or craving variables, or with cognitive measures, but there were some significant relationships with psychiatric symptoms and relatedness variables. A linear regression of Self-care Predictors produced a significant model with Alienation as the only predictor. Conclusions:This study showed a relatively high rate of adherence: over two-thirds of participants completed the 13-week protocol, with substantial engagement in both digital therapeutics and medication. The findings highlight the importance of Self-care, as a predictor of adherence, whereas illness-specific characteristics did not predict adherence, suggesting that adherence may not vary by AUD characteristics. While Self-care was the best predictor of Total Adherence, we found that psychiatric symptoms and relatedness variables were predictors of Self-care. Regression analysis indicates that Alienation captures the most variance in Self-care, suggesting the importance of therapeutic alliance in clinical trials.
Objective:The COVID-19 pandemic led to immediate changes in cancer clinical trial conduct. The primary aims of this study were to summarize the impact of the pandemic on Alliance for Clinical Trials in Oncology (Alliance) enrollment, protocol deviations, COVID-19 events (positive or presumptive-positive COVID test), and premature study discontinuation rates. Methods:Enrollment trends were examined from January 2019 (pre COVID-19 pandemic) through 2022. Data were captured for protocol deviations and premature treatment and study discontinuation events across all Alliance protocols using a centralized Medidata Rave database, and summarized from January 1, 2020, through June 30, 2022. Descriptive statistics and graphical techniques are used to summarize observed trends. Results:Overall enrollment across Alliance trials decreased during the COVID-19 pandemic and remained below pre-pandemic levels in 2022. Racial and ethnic demographics of enrolled patients did not change substantially. 4805 protocol deviations were reported on 2745 unique patients, with at least one protocol deviation reported by 618 sites and 77 unique trials. Commonly reported deviations were telemedicine visits (n=2167, 45%) and late/missed study procedures (n=2150, 45%). A total of 826 COVID-19 events were reported in 659 unique patients. Of an estimated 18,000 enrolled patients, only 68 withdrew from treatment and 45 withdrew from study due to COVID-19. Conclusion:A centralized COVID-19 database enabled a comprehensive assessment of the impact of the pandemic across Alliance trials. COVID-19 led to an immediate decline in enrollment across all patient populations. While the number of trials open to patient accrual remained stable, several large, adjuvant studies completed accrual during this period, which contributed to accrual decline. Telemedicine usage was notable, and both COVID-19 events and study discontinuation due to COVID-19 were rare.
Background:The safety and efficacy of mycophenolate mofetil (MMF) for lupus nephritis (LN) treatment is established in adults and in some children. MMF is rapidly converted to the biologically active metabolite mycophenolic acid (MPA) whose pharmacokinetics (PK) is characterized by large inter- and intra-individual variability. Methods/Design:This randomized, double-blind, active comparator, controlled clinical trial of pediatric subjects with proliferative LN compares pharmacokinetically-guided precision-dosing of MMF (MMFPK, i.e. the dose is adjusted to the target area under the concentration-time curve (AUC0-12h) of MPA ≥ 60-70 mg*h/L) and MMF dosed per body surface area (MMFBSA, i.e. MMF dosed 600 mg/m2 body surface area), with MMF dosage taken about 12 hours apart. At baseline, subjects are randomized 1:1 to receive blinded treatment with MMFPK or MMFBSA for up to 53 weeks. The primary outcome is partial clinical remission of LN (partial renal response, PRR) at week 26, and the major secondary outcome is complete renal response (CRR) at week 26. Subjects in the MMFBSA arm with PRR at week 26 will receive MMFPK from week 26 onwards, while subjects with CRR will continue MMFBSA or MMFPK treatment until week 53. Subjects who achieve PRR at week 26 are discontinued from study intervention. Discussion:The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) study will provide a thorough evaluation of the PK of MMF in pediatric LN patients, yielding a head-to-head comparison of MMFBSA and MMFPK for both safety and efficacy. This study has the potential to change current treatment recommendations for pediatric LN, thereby significantly impacting childhood-onset SLE (cSLE) disease prognosis and current clinical practice.
Introduction:Erectile Dysfunction (ED) is a common challenge post Radical Prostatectomy (RALP), affecting men's sexual health after undergoing definitive cancer therapy. Despite employing nerve-sparing techniques, ED remains a prevalent issue in this population. Studies indicate that approximately 70%-85% of men experience varying degrees of ED following RALP. The existing treatment landscape for post-RALP-ED presents limitations, and a discernible knowledge gap persists. To address this, our study aims to investigate the efficacy of Shockwave Therapy (SWT) as a potential intervention for managing ED after RALP. Methods:This prospective, randomized, sham-controlled clinical trial aims to recruit 189 eligible patients post-RP and assess the effects of SWT. Comprehensive screening, including medical history, physical examinations, and biochemical evaluations, will be conducted to confirm eligibility. The intervention involves utilizing a device to administer focal shockwaves targeted at cavernosal tissue. Safety measures include continuous monitoring for adverse events and rigorous reporting protocols. The primary endpoint assesses changes in participants' ability to engage in penetrative intercourse from baseline to study completion, while secondary endpoints encompass various measures of erectile function, including questionnaire-based assessments, ultrasound parameters, and clinical outcomes. Results:Statistical analysis, encompassing ANOVA for continuous variables and Fisher's exact test for categorical ones, will evaluate demographic characteristics, baseline data, and primary as well as secondary outcomes for statistical significance. Detailed analysis of trends, subgroup comparisons, and treatment effects will provide a comprehensive understanding of the impact of SWT on post-RP ED. Conclusion:This study protocol represents a rigorous investigation into the potential therapeutic role of SWT in managing post-RP ED. The outcomes from this study aim to contribute valuable insights into the efficacy, safety, and potential improvements in erectile function following SWT, providing significant guidance for future interventions aimed at addressing this challenging condition affecting men's health and quality of life.
Introduction:The SARS-CoV-2 pandemic has spurred the development of numerous Point of Care (POC) immunoassays. Previous studies assessing performance of these available kits occurred in a laboratory setting, raising concerns of translating findings for POC use. We aim to assess the performance of a lateral flow immunoassay for the detection of SARS-CoV-2 antibodies using samples collected at POC. Method:One lateral flow immunoassay (Humasis® COVID-19 IgG/IgM) was tested. Fifty PCR RT-PCR positive and 52 RT-PCR negative samples were collected at POC. Fifty Pre-Covid serum specimens were used as controls. Clinical data including symptom onset date was collected from patient history and the medical record. Results:The overall sensitivity for the kit was 74% (95% CI: 59.7%-85.4%). The sensitivity for IgM and IgG detection >14 days after date of onset was 88% (95% CI: 68.8%-97.5%) and 84% (95% CI: 63.9%-95.5%), with a Negative Predictive Value (NPV) of 94% for IgM (95% CI: 83.5%-98.8%) and 93% for IgG (95% CI: 81.8%-97.9%). The overall specificity was 94% (95% CI: 83.5%-98.8%). The Immunoglobulin specific specificity was 94% for IgM (95% CI: 83.5%-98.8%) and 98% for IgG (95% CI: 89.4%-100.0%). Discussion and Conclusion:Humasis® COVID-19 IgG/IgM LFA demonstrates greater than 90% NPV for samples collected 14 days after the onset of symptoms using samples collected at POC.
Mutations on Epidermal Growth Factor Receptor (EGFR) cause a variety of cancers including breast and lung cancers. The single mutation T790M on the tyrosine kinase domain of EGFR signifies the response to the cancer drugs gefitinib, which leads to the development of resistance to such a drug. Detecting the mutation thus provides effective therapeutic options for patients who are in need of cancer drug treatments. We sought to develop a facile, rapid detection method for the T790M mutation using Bridged Nucleic Acids (BNA), which has been known to enhance the hybridization affinity of oligonucleotides. Oligonucleotides containing BNA bases, called BNA-clamp and designed to block PCR reaction against wild-type genes were used to discriminate the presence of mutant genes mixed with a large number of wild-type genes. Real-time PCR in conjugation with BNA-clamping allows us to observe different degrees of PCR amplification depending on the ratio of wild-type and mutant genes. In an effort to explore the possibility, several 13-mer oligonucleotide clamps were prepared with various numbers of BNA bases. Tm value analysis suggests that the clamps containing 9 BNA bases (BNA-clamp-9) would be most effective in distinguishing the mutant from wild-type genes, and sensitivity tests using BNA-clamp-9 revealed that the clamp had the ability to detect 0.1% or lower levels of the T790M mutation among wild-type genes. Furthermore, binding structures were analyzed via Molecular Dynamics (MD) simulations, revealing that BNA-clamp-9 distorts the originally constructed BDNA structure. Additionally through umbrella sampling, binding free energies with -60 kJ/mol for the wild-type and -40 kJ/mol for the mutant gene were obtained. This BNA-clamping and real time PCR technology may offer a promising avenue to detect clinically important mutations in the future
Summary Worldwide morbidity and mortality associated with Covid-19 are severe and ongoing. The Pfizer-BioNTech vaccine is said to be up to 95% effective against severe disease or death. We were able to demonstrate that an additional 9.8% of COVID-19 vaccine doses could theoretically be given if the residual vaccine within the reconstituted Pfizer vials after six doses are extracted were used. This could be achieved by aseptically combining this excess vaccine from multiple vials to achieve full 0.3ml doses. Methods An observational study was conducted in April, 2021, at a mass vaccine site run by a community volunteer organization on Bainbridge Island, Washington. We measured the amount of Pfizer-BioNTech COVID-19 vaccine that was left in 172 vials after six doses had been withdrawn per Centers for Disease Control (CDC) protocol. Results A total of 30.68 ml of leftover vaccine was measured and discarded as medical waste. 1,036 doses were given from these vials. An extra 102 doses theoretically could have been given using the residual vaccine in the vials. This would have resulted in 9.8% additional doses of COVID-19 vaccine without requiring new vials. Conclusion The ability to combine solution from reconstituted Pfizer vaccine vials to minimize waste and obtain additional doses of vaccine could result in an increase in the number of individuals that could be vaccinated worldwide without additional cost. Further studies to validate our findings are warranted. Clinical trials to study the feasibility, safety and efficacy of protocols using this excess vaccine should be considered.
Malignant Pleural Mesothelioma (MPM) is a highly aggressive and almost universally fatal neoplasm with limited treatment options. The role of the programmed cell death protein 1 (PD-1) pathway has garnered attention due to its role in eliciting the immune checkpoint response of T cells, resulting in evasion of tumor cells from immune surveillance and chemotherapy resistance. Although, PD-1 checkpoint inhibitors have achieved success in various malignancies, resistance is common. Recently, the role of the gut microbiome in immunomodulation and response to cancer treatment has been recognized. We report a 70-year old female with stage 4 MPM who experienced restoration of therapeutic efficacy and prolonged survival with FMT and pembrolizumab despite prior antibiotic treatment, which is known to attenuate response.
AbstractWe propose a simple method to determine the infection rate from the time dependence of the daily confirmed new cases, in which the logarithm of the rate is fitted by piece-wise quadratic functions. Exploiting this method, we analyze the time dependence of the outbreak of COVID-19 in 190 countries around the world and determine the status of the outbreak in each country by the dependence of the infection rate on the number of new cases. We show that the infection status of each country can be completely classified into nine different states and that the infection status of countries succeeded in controlling COVID-19 implies the importance of the quarantine and/or self-isolation measure.
Background: Several reports have raised safety concerns regarding the use of probiotics. To address these concerns, this study examined the relative abundance (proportion of the microbiome made up of a particular taxa) and normalized read counts (number of times a particular microbe was identified) of Bifidobacteria in the gut microbiome of healthy subjects participating in an ongoing study on the microbiome. Bifidobacteria is a critically important constituent of the human microbiome and plays roles in digestion, gut immunity, and cancer prevention. Methods: Fecal samples were analyzed using next-generation sequencing to evaluate composition and relative abundance of bacterial phyla through species level in each subject`s microbiome. The primary outcomes of this subgroup analysis were relative abundance and normalized read count of genus Bifidobacteria in subjects who took unregulated probiotics, regulated probiotics, or no probiotics. Results: The relative abundance and normalized read count of Bifidobacteria were significantly lower in the microbiome of subjects who took unregulated probiotics (n=15) than in the microbiomes of both those who took regulated probiotics (n=12, P=0.0002) and no probiotics (n=13, P=0.0483) (0.18 vs. 9.59 vs. 5.66 relative abundance). Discussion: Subjects taking unregulated probiotics had a significantly lower relative abundance of Bifidobacteria, which could potentially have a detrimental impact on health. Next-generation sequencing could be a useful tool to guide decisions on the appropriate use of probiotics based on dysbiosis.
Background: This study aims to examine the influence of BCG status and TB prevalence on variances among countries regarding the new Multisystem Inflammatory Syndrome in Children (MIS-C). Material and methods: We chose all countries which report MIS-C till 23/6/2020. The number of MIS-C cases for each 10 million inhabitants has been examined among 3 categories of countries classified according to BCG program status. TB prevalence, MIS-C no./10 million (M) population and COVID-19 deaths/M are taken as markers. Receiver Operation Characteristic-(ROC) curve, with some relative indicators such as (sensitivity and specificity rates), estimation area of the trade-off between sensitivity and specificity, and cutoff points were used with different studied markers for discriminating different three pairs of countries (which have different BCG practices). Results: BCG vaccination and high TB prevalence were found significantly associated with decreased MIS-C no. and COVID-19 deaths. Conclusion: Findings might explain variances of MIS-C incidence and COVID-19 mortality among countries worldwide. Further studies to confirm this relationship and to confirm possible similar relations in Kawasaki Disease (KD) in previous epidemics are recommended. Ovarian Cancer (EOC) in early stage is difficult to diagnose. Serum indicators for stage I-II of epithelial ovarian cancer which confined to pelvic cavity were found through retrospective analysis, possible early detection methods might be found. Methods: 165 patients were diagnosed as epithelial ovarian cancer at stage I-II from January 1st, 2015 to December 31st, 2019. Data was collected including age, pathological type, serum D-dimer (D-D), Neutrophil to Lymphocyte ratio (N/L), the platelet to Lymphocyte ratio (P/L), Cancer Antigen 125 (CA125), Human Epididymis Protein 4 (HE4) and diameter of the ovarian mass by ultrasound. Results: D-D, CA125, HE4, ROMA, diameter, pathological type and age were significantly different in the different stage, age showed independent effect after logistical regression (P<0.05). D-D, CA125, HE4, ROMA, diameter, age and stage were significantly different in the different pathological type, and diameter showed significant independent influence on different pathological type after binary logistic regression (P<0.05). Conclusion: CA125, HE4, ROMA, diameter of tumor, D-dimer and age were found significantly different between stage I and stage II, with age shows good effect on the diagnosis for stage II and diameter of tumor shows diagnostic value for non-serous ovarian cancer. Combined diagnosis may improve the diagnosis rate of early ovarian cancer.
The emergence of a novel SARS-CoV-2 coronavirus at the end of 2019 and its accelerated spread worldwide to become a pandemic has had, from the medical biotechnology point of view, an unprecedented global response, to the point that there are currently 176 vaccine candidates in the preclinical stage and 66 in clinical stage. The purpose of the present work is to elaborate a hierarchical landscape of the current status of 12 phase 3 vaccines, taking into account their attributes of technological platform, safety, and efficacy. The methodology used was that of conceptual knowledge representation, resulting in, firstly, appropriate classification of stage 3 vaccines, in four categories, the first made up of the BBIBP-CorV, BBV152, CoronoVac and Wuhan Institute vaccines; the second Medicago's CoVLP vaccine; the third, conformed by NVX-CoV2373, BNT162, AstraZeneca (AZD1222); and the fourth, conformed by Ad26.COV2. S and Ad5-nCoV. This hierarchy of COVID-19 vaccines enables the development of adaptable strategies to implement cost-effective clinical trials aimed at controlling the pandemic.
A total of 6,628 PUBMED-registered publications on the relationships between the effects of vaccination and the provision of micronutrients have been studied by methods of topological analysis of text data. In case of insufficient intake of certain micronutrients, the functioning of the acquired immunity is disrupted resulting in an imbalance of populations of T-cells CD4+/CD8+ and of B-lymphocytes. Nutritional supplements of folate, vitamins A, D and B12, which are recognized regulators of cell division, support a wide range of lymphocyte populations. Trace elements zinc, iron, selenium, manganese and omega-3 polyunsaturated fatty acids are also important for supporting the mechanisms of acquired immunity. The data presented show that a course intake of these micronutrients by patients planning vaccination can significantly improve its effectiveness. In particular, these micronutrients can increase the titers of antibodies to pathogens, and to reduce the percentage of patients who still contract infection after vaccination. Supplements of these micronutrients can also contribute to the safety of vaccination: to prevent malaise and, in the unfortunate case of contracting infection despite the vaccine, to reduce the severity of the course and the mortality from the corresponding infection.
