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Cancer Medicine Jun 2024Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL)...
BACKGROUND
Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL.
METHODS
The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable.
RESULTS
In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60).
CONCLUSION
The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.
Topics: Humans; Asparaginase; Child; Male; Female; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Child, Preschool; Retrospective Studies; Adolescent; Infant; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Japan; Antineoplastic Agents
PubMed: 38888368
DOI: 10.1002/cam4.7246 -
United European Gastroenterology Journal Jun 2024With the increasing resistance to antimicrobial agents, susceptibility-guided tailored therapy has been emerging as an ideal strategy for Helicobacter pylori treatment....
BACKGROUND
With the increasing resistance to antimicrobial agents, susceptibility-guided tailored therapy has been emerging as an ideal strategy for Helicobacter pylori treatment. However, susceptibility-guided tailored therapy requires additional cost, time consumption, and invasive procedure (endoscopy) and its superiority over empirical quadruple therapy as the first-line H. pylori treatment remains unclear.
AIMS
To compare the efficacy of culture-based susceptibility-guided tailored versus empirical concomitant therapy as the first-line Helicobacter pylori treatment.
METHODS
This open-label, randomized trial was performed in four Korean institutions. A total of 312 Patients with H. pylori-positive culture test and naïve to treatment were randomly assigned in a 3:1 ratio to either culture-based susceptibility-guided tailored therapy (clarithromycin-based or metronidazole-based triple therapy for susceptible strains or bismuth quadruple therapy for dual-resistant strains, n = 234) or empirical concomitant therapy (n = 78) for 10 days. Eradication success was evaluated by C-urea breath test at least 4 weeks after treatment.
RESULTS
Prevalence of dual resistance to both clarithromycin and metronidazole was 8%. H. pylori eradication rates for tailored and concomitant groups were 84.2% and 83.3% by intention-to-treat analysis (p = 0.859), respectively, and 92.9% and 91.5% by per-protocol analysis, respectively (p = 0.702), which were comparable between the two groups. However, eradication rates for dual-resistant strains were significantly higher in the tailored group than in the concomitant group. All adverse events were grade 1 or 2 based on the Common Terminology Criteria for Adverse Events and the incidence was significantly lower in the tailored group. The proportion of patients discontinuing treatment for adverse events was comparable between the two groups (2.1% vs. 2.6%).
CONCLUSIONS
The culture-based susceptibility-guided tailored therapy failed to show superiority over the empirical concomitant therapy in terms of eradication rate. Based on these findings, the treatment choice in clinical practice would depend on the background rate of antimicrobial resistance, availability of resources and costs associated with culture and susceptibility testing.
PubMed: 38887840
DOI: 10.1002/ueg2.12609 -
Trials Jun 2024Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few...
Financial incentives to motivate treatment for hepatitis C with direct acting antivirals among Australian adults (The Methodical evaluation and Optimisation of Targeted IncentiVes for Accessing Treatment of Early-stage hepatitis C: MOTIVATE-C): protocol for a dose-response randomised controlled...
BACKGROUND
Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care.
METHODS
Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose-response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness.
DISCUSSION
This project seeks to gain an understanding of the dose-response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia.
TRIAL REGISTRATION
ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true ).
Topics: Humans; Antiviral Agents; Motivation; Australia; Randomized Controlled Trials as Topic; Hepatitis C, Chronic; Treatment Outcome; Adult; Drug Costs; Cost-Benefit Analysis; Primary Health Care; Time Factors
PubMed: 38886819
DOI: 10.1186/s13063-024-08212-8 -
Scientific Reports Jun 2024This split-mouth blinded randomized controlled study compared the efficacy of a desensitizing agent with oxalate/resin polymer and a universal adhesive containing... (Randomized Controlled Trial)
Randomized Controlled Trial
Desensitizing efficacy of a universal dentin adhesive containing mesoporous bioactive glass on dentin hypersensitivity: a randomized clinical trial with a split-mouth model.
This split-mouth blinded randomized controlled study compared the efficacy of a desensitizing agent with oxalate/resin polymer and a universal adhesive containing mesoporous bioactive glass (MBG) for dentin hypersensitivity (DH) relief, using Schiff sensitivity score (SSS) and visual analog scale (VAS). Split quadrants containing teeth with DH were treated with either MS Coat ONE or Hi-Bond Universal with MBG as the functional additive. Assessments at baseline, immediately post-application, and at 1- and 2-week follow-ups used standardized stimulus protocols (air, cold, and acid). The SSS difference was the primary outcome, while the VAS difference was the secondary outcome. A mixed linear effect model performed statistical analysis. Immediate DH reduction occurred in response to air stimuli, with a significant decrease in Group HB than in Group MS (p = 0.0178). Cold stimulus reduction exhibited a gradual cumulative effect, with consistently greater reductions in Group HB than in Group MS (p ≤ 0.0377). Both groups effectively managed acidic stimuli, with no significant differences (p > 0.05). The VAS scores decreased gradually over the follow-up period (p < 0.0001). This study highlights the differential efficacy of treatments for various DH triggers and recommends specific approaches based on different stimulus types. The universal adhesive containing MBG demonstrated DH relief potential, promising efficacy identical to or superior to that of a dedicated desensitizing agent. Further research exploring the long-term efficacy and underlying mechanisms is warranted. The universal adhesive containing MBG can be adopted as an in-office desensitizing agent for DH relief. The desensitizing efficacy of universal adhesive matches or surpasses dedicated agents for air and cold stimuli.
Topics: Humans; Dentin Sensitivity; Female; Male; Dentin Desensitizing Agents; Adult; Glass; Treatment Outcome; Ceramics; Dental Cements; Young Adult; Middle Aged; Porosity
PubMed: 38886498
DOI: 10.1038/s41598-024-64404-x -
BMJ Paediatrics Open Jun 2024Neonatal sepsis (NS) is a global health issue, particularly in Sub-Saharan Africa, where it accounts for a substantial portion of neonatal morbimortality. This...
BACKGROUND
Neonatal sepsis (NS) is a global health issue, particularly in Sub-Saharan Africa, where it accounts for a substantial portion of neonatal morbimortality. This multicountry survey aimed to elucidate current practices, challenges and case definitions in managing NS among clinicians in Sub-Saharan Africa.
METHODS
The survey targeted physicians and medical practitioners working in neonatal care who participated in a Self-Administered Web Questionnaire. The main objective was to understand NS and infection case definitions and management from the clinician's point of view and to identify challenges and opportunities in sepsis management. Participants were queried on demographics, definitions and diagnostic criteria, treatment approaches, and infection prevention and control (IPC) measures. A total of 136 participants from 93 healthcare structures responded, providing valuable insights into NS management practices.
RESULTS
From May to July 2022 across 21 Sub-Saharan African countries, 136 neonatal clinicians with an average from 93 structures with on average 10-year experience took the survey. NS ranked highest among prevalent neonatal conditions. Diagnostic case definitions between sepsis and infection were attributed to clinical signs, anamnesis, C reactive protein, white blood cll count and blood cultures with no statistically significant differences. Early-onset sepsis was defined within 72 hours by 48%, while late-onset varied. Antibiotics were likely on admission (86.4%) and during the stay (82.2%). Treatment abandonment was reported unlikely. The preferred antibiotic regimen for early-onset sepsis was intravenous amoxicillin (or ampicillin), gentamycin and cefotaxime. Blood culture availability and IPC protocols were reported as limited, particularly concerning patient environment, pharmacy protocols and clean-dirty circuits.
CONCLUSIONS
This NS survey emphasises clinicians' challenges due to limited access to diagnostic tools and raises concerns about antimicrobial overexposure. IPC also seem limited, according to participants. Addressing these challenges can enhance diagnostic practices, antibiotic stewardship and infection control in the region.
Topics: Humans; Neonatal Sepsis; Infant, Newborn; Africa South of the Sahara; Surveys and Questionnaires; Practice Patterns, Physicians'; Male; Female; Anti-Bacterial Agents
PubMed: 38886111
DOI: 10.1136/bmjpo-2023-002398 -
Journal of Thoracic Disease May 2024There is no established standard 3 line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not...
Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.
BACKGROUND
There is no established standard 3 line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1 or 2 line treatment are administrated as 3 line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3 line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies.
METHODS
This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3 or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years.
DISCUSSION
Currently, there is no standard 3 line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication.
TRIAL REGISTRATION
This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).
PubMed: 38883673
DOI: 10.21037/jtd-23-1858 -
MethodsX Jun 2024This paper provides a complete protocol for studying the effects of inhaled paraquat (PQ), a toxic herbicide that has negative effects systemically and on the lungs. The...
This paper provides a complete protocol for studying the effects of inhaled paraquat (PQ), a toxic herbicide that has negative effects systemically and on the lungs. The protocol aims to evaluate the effects of aerosolized PQ exposure on lung and systemic injury in an animal model, which will provide significant information for therapeutic interventions for PQ-induced pulmonary and systemic damage. The protocol involves the following key components: 1. Study groups: By including control, non-treated aerosolized PQ-exposed, and treated PQ-exposed animals with various agent groups in the experiment, lung and systemic injury in each group could be evaluated, and different measured parameters could be compared among groups. 2. PQ exposure: Animals in the PQ-exposed groups are subjected to PQ aerosol inhalation, simulating occupational or accidental exposure in farmers working with this herbicide. 3. Assessment measures: To determine the degree of lung and systemic injury and its physiological effects, several assessments, such as biochemical markers, histopathological analysis, and functional tests, are used. The protocol offers reliable and accurate results by using standardized methods and data collection. The effect of PQ exposure on lung and systemic injury could be evaluated by statistical analysis of the collected data, which also makes it easier to identify possible protective agents or interventions. This comprehensive evaluation protocol provides an essential basis for studying the mechanisms behind PQ-induced lung and systemic injury and assessing the effectiveness of preventative or therapeutic strategies in minimizing its adverse effects.
PubMed: 38883591
DOI: 10.1016/j.mex.2024.102782 -
MethodsX Jun 2024The coronavirus disease (COVID-19) pandemic affects the healthcare system worldwide and challenges many governments and institutions. Antimicrobial stewardship program...
The coronavirus disease (COVID-19) pandemic affects the healthcare system worldwide and challenges many governments and institutions. Antimicrobial stewardship program advocating the wise use of antimicrobial agents. Its metrics include antimicrobial use measures, process, and outcome performance indications. We will conduct a retrospective observational study with the main hypothesis that the COVID-19 pandemic does not affect the antimicrobial stewardship program and its metrics. We will compare antimicrobial stewardship metrics (process, outcome, utilization) and antibiotic resistance two years before (2018-2019) (Group A) & two years with the COVID-19 pandemic (2020-2021) (Group B). The study will be conducted in Saqr Hospital, a secondary care hospital in the emirate of Ras Al Khaimah in the United Arab Emirates. Data will be analyzed using SPSS version 22. Numerical data will be presented as mean (SD) or median (IQR). Chi-square or Fisher's exact test will be used to analyze categorical data. The -test or Mann-Whitney U test will be used to compare the difference of numerical variables. < 0.05 will be considered statistically significant. Multivariate logistic regression will be used to investigate the relation between different variables with (1) cost and (2) antibiotic resistance.
PubMed: 38883589
DOI: 10.1016/j.mex.2024.102767 -
Journal of Structural Biology: X Jun 2024NMR spectroscopy has played a pivotal role in fragment-based drug discovery by coupling detection of weak ligand-target binding with structural mapping of the binding...
NMR spectroscopy has played a pivotal role in fragment-based drug discovery by coupling detection of weak ligand-target binding with structural mapping of the binding site. Fragment-based screening by NMR has been successfully applied to many soluble protein targets, but only to a limited number of membrane proteins, despite the fact that many drug targets are membrane proteins. This is partly because of difficulties preparing membrane proteins for NMR-especially human membrane proteins-and because of the inherent complexity associated with solution NMR spectroscopy on membrane protein samples, which require the inclusion of membrane-mimetic agents such as micelles, nanodiscs, or bicelles. Here, we developed a generalizable protocol for fragment-based screening of membrane proteins using NMR. We employed two human membrane protein targets, both in fully protonated detergent micelles: the single-pass C-terminal domain of the amyloid precursor protein, C99, and the tetraspan peripheral myelin protein 22 (PMP22). For both we determined the optimal NMR acquisition parameters, protein concentration, protein-to-micelle ratio, and upper limit to the concentration of D-DMSO in screening samples. Furthermore, we conducted preliminary screens of a plate-format molecular fragment mixture library using our optimized conditions and were able to identify hit compounds that selectively bound to the respective target proteins. It is hoped that the approaches presented here will be useful in complementing existing methods for discovering lead compounds that target membrane proteins.
PubMed: 38883400
DOI: 10.1016/j.yjsbx.2024.100100 -
Mediterranean Journal of Hematology and... 2024The nonvitamin K antagonist oral anticoagulants (NOACs) have become the mainstay anticoagulation therapy for patients requiring oral anticoagulants (OACs) in the Gulf... (Review)
Review
BACKGROUND
The nonvitamin K antagonist oral anticoagulants (NOACs) have become the mainstay anticoagulation therapy for patients requiring oral anticoagulants (OACs) in the Gulf Council Cooperation (GCC) countries. The frequency of NOAC-associated major bleeding is expected to increase in the Emergency Department (ED). Nonetheless, we still lack local guidelines and recommendations for bleeding management in the region. The present Delphi-based consensus aims to establish a standardized and evidence-based clinical care pathway for managing NOAC-associated major bleeding in the Kingdom of Saudi Arabia (KSA) and the United Arab Emirates (UAE).
METHODS
We adopted a three-step modified Delphi method to develop evidence-based recommendations through two voting rounds and an advisory meeting between the two rounds. A panel of 11 experts from the KSA and UAE participated in the consensus development.
RESULTS
Twenty-eight statements reached the consensus level. These statements addressed key aspects of managing major bleeding events associated with NOACs, including the increased use of NOAC in clinical practice, clinical care pathways, and treatment options.
CONCLUSION
The present Delphi consensus provides evidence-based recommendations and protocols for the management of NOAC-associated bleeding in the region. Patients with major DOAC-induced bleeding should be referred to a well-equipped ED with standardized management protocols. A multidisciplinary approach is recommended for establishing the association between NOAC use and major bleeding. Treating physicians should have prompt access to specific reversal agents to optimize patient outcomes. Real-world evidence and national guidelines are needed to aid all stakeholders involved in NOAC-induced bleeding management.
PubMed: 38882457
DOI: 10.4084/MJHID.2024.038