Stud Health Technol Inform. 2024 Aug 22;316:781-785. doi: 10.3233/SHTI240528.

ABSTRACT

The ability to fine-tune pre-trained deep learning models to learn how to process a downstream task using a large training set allow to significantly improve performances of named entity recognition. Large language models are recent models based on the Transformers architecture that may be conditioned on a new task with in-context learning, by providing a series of instructions or prompt. These models only require few examples and such approach is defined as few shot learning. Our objective was to compare performances of named entity recognition of adverse drug events between state of the art deep learning models fine-tuned on Pubmed abstracts and a large language model using few-shot learning. Hussain et al's state of the art model (PMID: 34422092) significantly outperformed the ChatGPT-3.5 model (F1-Score: 97.6% vs 86.0%). Few-shot learning is a convenient way to perform named entity recognition when training examples are rare, but performances are still inferior to those of a deep learning model fine-tuned with several training examples. Perspectives are to evaluate few-shot prompting with GPT-4 and perform fine-tuning on GPT-3.5.

PMID:39176909 | DOI:10.3233/SHTI240528

Stud Health Technol Inform. 2024 Aug 22;316:1226-1230. doi: 10.3233/SHTI240632.

ABSTRACT

Adverse drug reaction are defined as "harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product". In France, adverse effects due to medicines are reported to the French National Agency of Medicines (ANSM) by the healthcare professionals or consumers. The objective of this study was to implement a tool that facilitates the utilization of ANSM reports by synthesizing information to effectively inform prescribers and users. We focused on 3 psychotropic classes: antidepressants, antipsychotics and anxiolytics. We extracted relevant data from the ANSM website through a webscraping process, based on the names of molecules in these 3 classes: antidepressants, antipsychotics, and anxiolytics. We implemented a web interface with R Shiny that provides three panels: (i) a presentation of the active ingredient with the fewest reports for a selected adverse effect category, (ii) the adverse reactions for a selected active ingredient ranked in descending order, and (iii) a comparison of two active ingredients where, for each adverse effect, the active ingredient with the fewest reported adverse drug events (ADEs) is displayed. Our application allows for synthesizing information to effectively inform prescribers and users. In the ANSM existing interface, molecules can only be viewed one by one, and the ratio needs to be calculated manually, making it difficult to compare molecules. It is important to note that this is not a prescription assistance device but rather for informational purposes. In the future, the application may be expanded to include other categories of molecules. Finally, the indicators provided by our tool could be compared to those from other pharmacovigilance databases.

PMID:39176602 | DOI:10.3233/SHTI240632

Cureus. 2024 Jul 23;16(7):e65207. doi: 10.7759/cureus.65207. eCollection 2024 Jul.

ABSTRACT

Androgen deprivation therapy (ADT) is one of the effective treatment methods for prostate cancer, often used with radiation therapy. Among the key ADT agents is leuprolide, a synthetic gonadotropin-releasing hormone agonist, which effectively suppresses testosterone production which is a requisite for the growth and division of prostate cancer cells. However, leuprolide is associated with several well-known side effects and less common dermatological reactions. In this case, we present an 80-year-old male patient with stage IIB prostate cancer who developed diffuse maculopapular dermatitis following leuprolide acetate ADT. The patient first experienced mild dermatitis following the fifth monthly 7.5 mg leuprolide injection before it developed into a general body rash after six injections. The dermatitis manifested on the patient's arms, thighs, calves, dorsum, and back of hands but sparing the abdomen, face, and neck. The pruritic dermatitis was managed successfully with a three-week course of prednisone which led to complete resolution without long-term sequelae. This case highlights the importance of recognizing and managing dermatological side effects associated with ADT. Clinicians should maintain an index of suspicion and act promptly when these side effects manifest. Systematic reporting and further research are essential to enhance patient safety and understanding of drug-related dermatological manifestations.

PMID:39176344 | PMC:PMC11340855 | DOI:10.7759/cureus.65207

Clin Transl Sci. 2024 Aug;17(8):e13891. doi: 10.1111/cts.13891.

ABSTRACT

Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

PMID:39175217 | DOI:10.1111/cts.13891

Eur J Hosp Pharm. 2024 Aug 22:ejhpharm-2024-004184. doi: 10.1136/ejhpharm-2024-004184. Online ahead of print.

ABSTRACT

A 53-year-old male with recovering alcohol dependency, diagnosed with bipolar disorder and recurrent episodes of diverticulitis, came to the emergency department with disorientation and confusion after 3 days of treatment with metronidazole 250 mg/12 hours and ciprofloxacin 500 mg/12 hours for acute diverticulitis. In the hospital emergency department, he presented moments of agitation, fluctuations of attitude, increased basal tremor, with rhythmic movement of the left arm and leg, as well as generalised rigidity with an episode of tonic-clonic seizure of 1.5-2 min duration. After performing different diagnostic tests, significant brain findings were ruled out. The pharmacy department recommended the discontinuation of one of the two drugs. As a result, the on-call doctor adjusted the patient's treatment: disulfiram and previous antibiotic therapy (metronidazole and ciprofloxacin) were discontinued, and amoxicillin/clavulanic acid 2 g/8 hour was prescribed instead. The patient progressed well and fully recovered.

PMID:39174292 | DOI:10.1136/ejhpharm-2024-004184

Cureus. 2024 Jul 22;16(7):e65081. doi: 10.7759/cureus.65081. eCollection 2024 Jul.

ABSTRACT

Metformin is a first-line medication used in the treatment of type 2 diabetes mellitus along with other conditions such as insulin resistance and polycystic ovarian syndrome. Overall, metformin appears to be well tolerated with a low incidence of side effects; however, in certain high-risk populations, it can trigger a hemolytic crisis. This case report describes a middle-aged man who was initiated on metformin for new-onset diabetes, following which he had an acute hemoglobin drop and was diagnosed to be having a hemolytic crisis requiring hospitalization. He was diagnosed with a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) on admission. Extensive workup was done to rule out other causes of hemolysis, all of which came back to be negative. The offending agent was stopped and the patient received supportive care after which he improved. This case highlights a rare, yet important, side effect of metformin that needs to be observed in certain individuals, especially patients with G6PD deficiency. Routine testing of high-risk populations known to be G6PD deficient should be considered before initiating metformin.

PMID:39170996 | PMC:PMC11337140 | DOI:10.7759/cureus.65081

J Clin Pharmacol. 2024 Aug 22. doi: 10.1002/jcph.6117. Online ahead of print.

ABSTRACT

Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and Tmax upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.

PMID:39169827 | DOI:10.1002/jcph.6117

J Pharmacol Exp Ther. 2024 Aug 21:JPET-MR-2024-002184. doi: 10.1124/jpet.124.002184. Online ahead of print.

ABSTRACT

ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including IKr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-Tpeak, Tpeak-Tend and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo and in vivo models for proarrhythmic risk prediction, such as CiPA in silico model, iPS cell-derived cardiomyocyte sheet, Langendorff perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on post-marketing clinical use. Significance Statement Since ICH S7B/E14 guidelines unfortunately hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, Comprehensive In Vitro Proarrhythmia Assay and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, ICH released Q&As (Stage 1) emphasizing "double negative" nonclinical scenario for low-risk compounds, and new Q&As (Stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers, and explores various models for proarrhythmic risk prediction.

PMID:39168651 | DOI:10.1124/jpet.124.002184

Thromb Haemost. 2024 Aug 21. doi: 10.1055/a-2398-9344. Online ahead of print.

ABSTRACT

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT.

METHODS: This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a positive platelets in an antigen challenge model of a 30 mL fetal-maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 10^9 HPA-1a positive platelets on day 8.

RESULTS: Four subjects received 0.09 mg SC RLYB212, 5 received 0.29 mg SC RLYB212, and 2 received placebo. RLYB212 achieved rapid elimination of HPA-1a positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life vs placebo. Following HPA-1a positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ~10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events.

CONCLUSION: The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.

PMID:39168139 | DOI:10.1055/a-2398-9344

Ren Fail. 2024 Dec;46(2):2392883. doi: 10.1080/0886022X.2024.2392883. Epub 2024 Aug 21.

ABSTRACT

INTRODUCTION: Patients with chronic kidney disease (CKD) are at increased risk of developing tuberculosis (TB). These patients may also be at higher risk of developing antitubercular treatment (ATT)-associated adverse drug reactions (ADRs). Although dose modification has been recommended, data regarding the impact of impaired kidney function on ATT-associated ADRs is sparse. We studied the incidence and profile of ATT-associated ADRs in patients with CKD and compared them with those with normal kidney function.

METHODOLOGY: This retrospective study analyzed all patients initiated on ATT from January 2016 to August 2019. Patients were grouped into CKD and normal kidney function based on their eGFR. Data on ATT-associated ADRs were collected from medical records. Predictors of ADRs were assessed using univariable and multivariable logistic regression. Additionally, Propensity score matching and analysis were done for CKD and normal kidney function in 1:3 ratio.

RESULTS: Of 1815 patients on ATT, 75 (4.1%) had CKD. ADRs were more frequent [36/75 (48.0%) vs. 239/1740 (13.7%), p ≤ 0.0001] and more severe [15/46 (32.6%) vs. 43/283 (15.1%), p = 0.010] in CKD than those with normal kidney function. The most common ADRs were hepatobiliary [23/75 (30.6%) vs. 156/1740 (8.9%), p ≤ 0.0001], neuropsychiatric [8/75(10.6%) vs. 21/1740(1.2%), p ≤ 0.0001], renal [4/75(5.3%) vs. 8/1740(0.4%), p = 0.001], and gastrointestinal [5/75(6.6%) vs. 34/1740 (1.9%), p = 0.020]. CKD was an independent predictor for ADRs (OR -4.96, 95% CI: 2.79-8.82; p ≤ 0.0001). The matched cohort showed similar results.

CONCLUSION: ATT-associated ADRs were more common and severe in patients with CKD, despite drug dose modifications. Optimal dosing of ATT in CKD needs to be further evaluated.

PMID:39165235 | DOI:10.1080/0886022X.2024.2392883

JMIR Res Protoc. 2024 Aug 20;13:e60828. doi: 10.2196/60828.

ABSTRACT

BACKGROUND: One strategy to prevent adverse effects resulting from chemotherapy treatment is to perform physical exercises during treatment. However, there is still no consensus on the best type and intensity of exercise, nor when it should be started. Most studies have been carried out in patients with breast cancer, usually a few weeks after starting chemotherapy, on an outpatient basis 2 to 3 times a week. The main differences in our study are that we carried out physical training in hospitalized patients undergoing a cycle of chemotherapy for cancer treatment and that this training was carried out 5 times a week and was not restricted to a specific type of cancer.

OBJECTIVE: We aimed to evaluate the effects of aerobic training on symptoms related to chemotherapy (nausea, vomiting, asthenia, and sensation of weakness), fatigue, mobility, clinical complications, and length of hospital stay of patients during the drug treatment cycle. We also evaluated patient satisfaction with the proposed intervention, the adverse effects of aerobics training, and the cost-effectiveness of this intervention.

METHODS: This is a controlled and randomized trial with blinded evaluation that will include 94 hospitalized patients with cancer for 1 or more cycles of chemotherapy. The intervention group will perform aerobic training during a cycle of chemotherapy. The control group will receive a booklet with guidelines for staying active during the hospitalization period. The groups will be compared using a linear mixed model for fatigue, mobility, and chemotherapy-related symptoms before and after the intervention. The length of hospital stay will also be compared between groups using Kaplan-Meier survival analysis. The incidence of complications will be compared using the χ2 test. Cost-effectiveness and cost-utility analyses will be performed for the impact of exercise and quality-adjusted life years with the EQ-5D-3L-21 quality of life trials. The implementation variables (acceptability, suitability, and feasibility) will be evaluated by frequencies.

RESULTS: The clinical trial registration was approved in March 2023. Recruitment and data collection for the trial are ongoing, and the results of this study are likely to be published in late 2025.

CONCLUSIONS: Chemotherapy has side effects that negatively impact the quality of life of patients with cancer. Aerobic exercise can reduce these side effects in a simple and inexpensive way. The field of work of physical therapists could be expanded to oncology if the intervention works.

TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clínicos RBR-6b4zwx3; https://tinyurl.com/39c4c7wz.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/60828.

PMID:39163116 | DOI:10.2196/60828

Clin Case Rep. 2024 Aug 19;12(8):e9310. doi: 10.1002/ccr3.9310. eCollection 2024 Aug.

ABSTRACT

Acyclovir can cause neurotoxicity and nephrotoxicity, especially in diabetic patients with renal impairment. Consider acyclovir dose adjustment, close monitoring of kidney function, and hemodialysis as a potential therapeutic option in such cases.

PMID:39161675 | PMC:PMC11331032 | DOI:10.1002/ccr3.9310

Mil Med. 2024 Aug 19;189(Supplement_3):546-550. doi: 10.1093/milmed/usae182.

ABSTRACT

INTRODUCTION: The World Health Organization identified vaccine hesitancy as one of the top 10 threats to global health. Vaccine hesitancy is defined as a delay in acceptance or refusal of vaccination despite the availability of vaccination services. Because vaccine safety concerns are important contributors to hesitancy, people who have experienced adverse events following immunization (AEFI) may be at especially high risk for subsequent vaccine hesitancy. The Defense Health Agency Immunization Healthcare Division (DHA IHD) provides specialized vaccine care to persons who have experienced AEFI. The impact of this specialized vaccine care on subsequent vaccine hesitancy has not been fully explored.

MATERIALS AND METHODS: A cohort of patients (n= 146) was identified among those who received consultative care from DHA IHD clinicians for AEFI concerns between April 2017 and September 2022. Analyses were restricted to non-uniformed beneficiaries of the Military Health System (MHS). Uniformed beneficiaries of the MHS were excluded from this analysis since vaccination mandates preclude the use of vaccine uptake as a measure of vaccine hesitancy. Outcomes were evaluated by reviewing MHS vaccination records after initial AEFI consultation through January 2023. Vaccine acceptance was considered the inverse of hesitancy, and was defined by: (a) receipt of any subsequent vaccination, (b) receipt of seasonal influenza vaccine, (c) receipt of subsequent doses of the AEFI-associated vaccine, if clinically recommended, and (d) receipt of COVID-19 vaccine.

RESULTS: A diverse group of patients with a wide range of AEFI concerns received specialized vaccine care from DHA IHD clinicians during this period. Among the cohort, 78% of patients received any subsequent vaccination, 55.2% received seasonal influenza vaccine, 57.8% received a subsequent dose of their AEFI-associated vaccine when the vaccine was clinically recommended, and 48.9% received COVID-19 vaccine. The proportion of patients who received influenza vaccine exceeded the reported rate of influenza vaccine uptake by the general population during this time period.

CONCLUSION: Specialized vaccine care after AEFI concerns was associated with relatively high acceptance of subsequent vaccinations. The experiences of DHA IHD clinicians, in providing specialized vaccine care to AEFI patients, may serve as a model for other organizations that are working to reduce vaccine hesitancy, even beyond the MHS.

PMID:39160803 | DOI:10.1093/milmed/usae182

Drug Des Devel Ther. 2024 Aug 13;18:3617-3628. doi: 10.2147/DDDT.S475706. eCollection 2024.

ABSTRACT

OBJECTIVE: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients.

MATERIALS AND METHODS: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry.

RESULTS: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 μg/mL, or the VCZ CN was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased.

CONCLUSION: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.

PMID:39156484 | PMC:PMC11330242 | DOI:10.2147/DDDT.S475706

Cureus. 2024 Jul 16;16(7):e64703. doi: 10.7759/cureus.64703. eCollection 2024 Jul.

ABSTRACT

The immune checkpoint inhibitor pembrolizumab is now considered a first-line treatment for recurrent or metastatic head and neck squamous cell cancer. Pembrolizumab is less toxic than conventional chemotherapy but may result in immune-related adverse events. We report a case in which liver injury occurred just two days after the administration of pembrolizumab plus chemotherapy. A 48-year-old woman achieved a complete response after chemoradiotherapy for cT2N3bM0 squamous cell carcinoma of the oropharynx with multiple lymph node metastases. However, the tumor recurred one year later, and she was started on pembrolizumab plus chemotherapy. On day 3, her alanine aminotransferase and aspartate transaminase concentrations markedly increased. She was initially diagnosed with drug-induced liver injury and all medications were withdrawn. Her liver function recovered within two weeks without intervention. The lymphocyte transformation test was only positive for pembrolizumab. Clinicians should consider pembrolizumab-induced allergic hepatitis as a possible cause of liver injury after excluding liver metastasis and immune-related adverse events.

PMID:39156358 | PMC:PMC11327630 | DOI:10.7759/cureus.64703

Vaccine. 2024 Sep 17;42(22):126197. doi: 10.1016/j.vaccine.2024.126197. Epub 2024 Aug 15.

ABSTRACT

BACKGROUND: In 2016, the World Health Organization recommended that a fractional dose of yellow fever (YF) vaccine could be used in persons 2 years of age or older in response to an emergency that resulted in a global shortage of available YF vaccine. However, this recommendation did not extend to the youngest age group licensed for YF vaccine because there were no published data on the use or safety of fractional dose YF vaccination in children aged 9-23 months. We conducted a single-blind randomized controlled trial, comparing the immunogenicity and safety of fractional one-fifth and one-half doses of Bio-Manguinhos 17DD YF vaccine with full dose in children aged 9-23 months old in Uganda. In this paper, we present the interim analysis on safety.

METHODS: Children aged 9-23 months presenting for routine well-child services were recruited for inclusion at one of three study sites. We collected data during March 26, 2019-August 31, 2020, on all adverse events following immunization (AEFI) during active surveillance for 28 days post-vaccination using multiple collection tools including a diary card with an objective measurement of fever. An independent team from the Uganda national AEFI Committee investigated and classified serious AEFI (SAE) according to Brighton Collaboration Criteria.

RESULTS: Among 1053 enrolled children, 672 (64%) were reported to have a non-serious AEFI (NSAE) and 17 (2%) were reported to have a SAE. The most common AEFI were diarrhoea, fever, and rash, each reported by 355 (34%), 338 (33%), and 188 (18%) participants, respectively. Among 17 participants with SAE, eight were reported to have had seizures and five were hospitalised for seizures or other causes (respiratory symptoms, gastrointestinal illness, malaria). Four SAEs (deaths) occurred >28 days after vaccination. There were no reported cases of pre-specified or vaccine-related SAEs. We observed no significant difference in frequency or severity of adverse events among the study groups.

CONCLUSIONS: Using comprehensive active surveillance monitoring, we did not identify any unexpected safety concerns among children aged <2 years receiving YF vaccination, including with the fractional doses. Although we identified a high number of both serious and non-serious AEFI, none were determined to be causally related to YF vaccination. These results provide evidence for the safety of fractional dose YF vaccination among children aged 9-23 months.

PMID:39153293 | DOI:10.1016/j.vaccine.2024.126197

Pharmazie. 2024 Aug 1;79(7):163-168. doi: 10.1691/ph.2024.4548.

ABSTRACT

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

PMID:39152557 | DOI:10.1691/ph.2024.4548

Int J Antimicrob Agents. 2024 Aug 14:107301. doi: 10.1016/j.ijantimicag.2024.107301. Online ahead of print.

ABSTRACT

BACKGROUND: Tenofovir containing antiretroviral therapy regimens may bring long-term toxicity-related side effects. We aimed to assess the virological efficacy of co-formulated darunavir-ritonavir plus lamivudine compared to darunavir-ritonavir plus tenofovir and emtricitabine or lamivudine.

METHODS: The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in naïve adults living with HIV. Patients were randomized 1:1 to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir-ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir-ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of less than 50 copies/mL at week 48 in the intention-to-treat population. We used the FDA snapshot algorithm and a non-inferiority margin of -12%. Secondary objectives included safety analysis in the per-protocol population. This study is registered at ClinicalTrials.gov, NCT02770508.

RESULTS: Between November 2015 to October 31, 2020, 336 participants were randomly assigned either to the triple therapy arm (165) or the dual therapy arm (171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the double therapy group (91%) achieved virological suppression (difference -2·1%, 95%CI -7·0 to 2·9). Drug-related adverse events were more common in the triple therapy group (p=0·04). Two toxicity-related events led to discontinuation in each group.

INTERPRETATION: Co -formulated darunavir/ ritonavir plus lamivudine has shown non-inferiority and a safer toxicity profile compared to a standard-of-care triple regimen including tenofovir in treatment-naïve patients.

PMID:39151647 | DOI:10.1016/j.ijantimicag.2024.107301

Am J Manag Care. 2024 Aug 1;30(8):e233-e239. doi: 10.37765/ajmc.2024.89592.

ABSTRACT

OBJECTIVES: To evaluate the FeelBetter machine learning system's ability to accurately identify older patients with multimorbidity at Brigham and Women's Hospital at highest risk of medication-associated emergency department (ED) visits and hospitalizations, and to assess the system's ability to provide accurate medication recommendations for these patients.

STUDY DESIGN: Retrospective cohort study.

METHODS: The system uses medications, demographics, diagnoses, laboratory results, health care utilization patterns, and costs to stratify patients' risk of ED visits and hospitalizations. Patients were assigned 1 of 22 risk levels based on their system-generated risk percentile of either ED visits or hospitalizations. Logistic regression models were used to estimate the odds of ED visits and hospitalizations associated with each successive risk level compared with the 45th to 50th percentiles. After stratification, 100 high-risk (95th-100th percentiles) and 100 medium-risk (45th-55th percentiles) patients were randomly selected for generation of medication recommendations. Two clinical pharmacists reviewed the system-generated medication recommendations for these patients.

RESULTS: Logistic regression models predicting 3-month utilization showed that compared with the 45th to 50th percentiles, patients in the top 1% risk percentile had ORs of 7.9 and 17.3 for ED visits and hospitalizations, respectively. The first 5 high-priority medications on each patient's medication list were associated with a mean (SD) of 6.65 (4.09) warnings. Of 1290 warnings reviewed, 1151 (89.2%) were assessed as correct.

CONCLUSIONS: The FeelBetter system effectively stratifies older patients with multimorbidity at risk of ED use and hospitalizations. Medication recommendations provided by the system are largely accurate and can potentially be beneficial for patient care.

PMID:39146480 | DOI:10.37765/ajmc.2024.89592

J Thorac Dis. 2024 Jul 30;16(7):4702-4710. doi: 10.21037/jtd-23-1851. Epub 2024 Jul 11.

ABSTRACT

BACKGROUND: The prognosis and first-line treatment response of patients with borderline resectable esophageal squamous cell carcinoma (ESCC) are unsatisfactory. We are conducting the borderline resectable esophageal squamous (BRES-1) study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy in patients with borderline resectable ESCC.

METHODS: A total of 30 patients with borderline resectable ESCC will be enrolled in the BRES-1 study. These patients will undergo three stages of treatment: neoadjuvant therapy, surgery, and adjuvant therapy. Preoperative therapies will include camrelizumab, cisplatin, and nab-paclitaxel. Preoperative therapies will include camrelizumab, which will be given every 3 weeks for 6 weeks at a dose of 200 mg (baseline weight <50 kg, 3 mg/kg), nab-paclitaxel (130 mg/m2 on days 1 and 8 of one period with 21 days, a total of two cycles), and cisplatin (75 mg/m2 on day 1 of one period with 21 days, a total of two cycles). Patients will undergo esophagectomy 3-6 weeks after completing the neoadjuvant treatment. Three weeks after surgery, camrelizumab combined with chemotherapy will continue to be used for two cycles of maintenance therapy. Then, only camrelizumab will be administered for an entire year. The primary endpoint of this study will be pathological complete response (pCR).

DISCUSSION: The BRES-1 trial will evaluate the efficacy and safety of camrelizumab combined with chemotherapy for patients with borderline resectable ESCC. Translational research will explore perioperative complications and drug-related adverse events (AEs).

TRIAL REGISTRATION: ChiCTR, ChiCTR2200056728. Registered 11 February 2022. https://www.chictr.org.cn/index.aspx.

PMID:39144354 | PMC:PMC11320267 | DOI:10.21037/jtd-23-1851