J Immunother Cancer. 2024 May 30;12(5):e008599. doi: 10.1136/jitc-2023-008599.

ABSTRACT

BACKGROUND: Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined.

METHODS: We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared.

RESULTS: Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4).

CONCLUSIONS: AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.

PMID:38816231 | DOI:10.1136/jitc-2023-008599

Acta Pharm. 2024 May 30;74(2):249-267. doi: 10.2478/acph-2024-0011. Print 2024 Jun 1.

ABSTRACT

This umbrella review examined systematic reviews of deprescribing studies by characteristics of intervention, population, medicine, and setting. Clinical and humanistic outcomes, barriers and facilitators, and tools for deprescribing are presented. The Medline database was used. The search was limited to systematic reviews and meta-analyses published in English up to April 2022. Reviews reporting deprescribing were included, while those where depre-scribing was not planned and supervised by a healthcare professional were excluded. A total of 94 systematic reviews (23 meta--analyses) were included. Most explored clinical or humanistic outcomes (70/94, 74 %); less explored attitudes, facilitators, or barriers to deprescribing (17/94, 18 %); few focused on tools (8/94, 8.5 %). Reviews assessing clinical or humanistic outcomes were divided into two groups: reviews with deprescribing intervention trials (39/70, 56 %; 16 reviewing specific deprescribing interventions and 23 broad medication optimisation interventions), and reviews with medication cessation trials (31/70, 44 %). Deprescribing was feasible and resulted in a reduction of inappropriate medications in reviews with deprescribing intervention trials. Complex broad medication optimisation interventions were shown to reduce hospitalisation, falls, and mortality rates. In reviews of medication cessation trials, a higher frequency of adverse drug withdrawal events underscores the importance of prioritizing patient safety and exercising caution when stopping medicines, particularly in patients with clear and appropriate indications.

PMID:38815201 | DOI:10.2478/acph-2024-0011

JAMA Otolaryngol Head Neck Surg. 2024 May 30. doi: 10.1001/jamaoto.2024.1177. Online ahead of print.

ABSTRACT

IMPORTANCE: There is no systemic therapy for recurrent or metastatic adenoid cystic carcinoma (ACC) approved by the US Food and Drug Administration.

OBJECTIVE: To examine the efficacy, safety, and tolerability of vascular endothelial growth factor receptor (VEGFR) inhibitors in recurrent or metastatic ACC.

DATA SOURCES: PubMed, Embase, and Cochrane Library were systematically searched for studies of VEGFR inhibitors in recurrent or metastatic ACC from database inception to August 31, 2023.

STUDY SELECTION: Inclusion criteria were prospective clinical trials of recurrent or metastatic ACC treated with VEGFR inhibitors, reporting at least 1 outcome of interest specifically for ACC. Of 1963 identified studies, 17 (0.9%) met inclusion criteria.

DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline was followed to extract data. Data were pooled using a random-effects generalized linear mixed model with 95% CIs.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was best overall response to VEGFR inhibitors, including objective response, stable disease, or progressive disease (PD). Safety and tolerability outcomes included incidence of grade 3 or higher adverse events, rates of exit from trial due to PD or drug-related toxic effects, and dose reduction rate (DRR).

RESULTS: A total of 17 studies comprising 560 patients with recurrent or metastatic ACC treated with 10 VEGFR inhibitors were included. The objective response rate was 6% (95% CI, 3%-12%; I2 = 71%) and stable disease was the most frequent best overall response (82%; 95% CI, 74%-87%; I2 = 67%). The 6-month disease control (defined as objective response and stable disease) rate was 54% (95% CI, 45%-62%; I2 = 52%). The rate of grade 3 or higher adverse events was 53% (95% CI, 42%-64%; I2 = 81%) and of DRR was 59% (95% CI, 40%-76%). Most patients (57%; 95% CI, 44%-70%; I2 = 83%) continued therapy until PD; 21% (95% CI, 15%-28%; I2 = 62%) of patients suspended therapy for toxic effects. In subgroup analysis by specific VEGFR inhibitor, the objective response rate was 14% (95% CI, 7%-25%; I2 = 0%), stable disease rate was 76% (95% CI, 63%-85%; I2 = 0%), proportion treated until PD was 61% (95% CI, 14%-94%; I2 = 94%), and DRR was 78% (95% CI, 66%-87%; I2 = 39%) with lenvatinib. Corresponding axitinib results were objective response rate of 8% (95% CI, 4%-15%; I2 = 0%) and stable disease rate of 85% (95% CI, 72%-92%; I2 = 69%), with 73% (95% CI, 63%-82%; I2 = 0%) of patients treated until PD, and the DRR was 22% (95% CI, 12%-38%; I2 = 77%). Rivoceranib had the highest objective response rate (24%; 95% CI, 7%-57%) but high heterogeneity among studies (I2 = 95%) and the lowest rate of patients who continued therapy until PD (35%; 95% CI, 20%-55%; I2 = 90%).

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that VEGFR inhibitors were associated with high rates of disease stabilization in recurrent or metastatic ACC. Of 10 included VEGFR inhibitors, lenvatinib and axitinib were associated with the best combined and consistent efficacy, safety, and tolerability profiles, substantiating their inclusion in treatment guidelines.

PMID:38814585 | DOI:10.1001/jamaoto.2024.1177

Front Med (Lausanne). 2024 May 15;11:1292406. doi: 10.3389/fmed.2024.1292406. eCollection 2024.

ABSTRACT

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. EDP1815 is an oral, gut-restricted preparation of non-live Prevotella histicola, the first of a new immunomodulatory therapeutic class targeting the small intestine to generate systemic anti-inflammatory responses.

OBJECTIVE: To evaluate safety and efficacy of EDP1815 in mild-to-moderate psoriasis in a proof-of-concept study.

METHODS: A phase 2, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study with a 16-week treatment period and up to 24 weeks of follow-up. Participants were randomized to receive 1, 4, or 10 capsules daily.

RESULTS: EDP1815 was well tolerated with comparable rates of treatment-emergent adverse events to placebo, and no drug-related serious adverse events. Clinically meaningful responses to EDP1815, defined as at least 50% reduction in Psoriasis Area and Severity Index (PASI-50) at week 16, were observed in all 3 cohorts, statistically significant in the 1-capsule (29.7%; P = 0.048) and 4-capsule (31.9%; P = 0.022) groups, compared with placebo (12.1%). Among EDP1815-treated PASI-50 responders at week 16, 60% (18/30) maintained or improved off-treatment responses at week 40.

LIMITATIONS: Continued off-treatment improvement past 16 weeks shows potential for greater therapeutic benefit that was not assessed.

CONCLUSION: EDP1815 was well-tolerated with a placebo-like safety profile, and had meaningful efficacy outcomes in psoriasis, validating this novel immunomodulatory approach.

CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/search?term=NCT04603027, identifier NCT04603027.

PMID:38813388 | PMC:PMC11133679 | DOI:10.3389/fmed.2024.1292406

J Surg Case Rep. 2024 May 28;2024(5):rjae304. doi: 10.1093/jscr/rjae304. eCollection 2024 May.

ABSTRACT

Gingival enlargement is a side effect of several different medication, including immunosuppressants, anticonvulsants, and calcium channel blockers. It is an inflammatory response that starts when plaque and calculus build up on the tooth surface. The most prevalent long-term neurological condition affecting people is epilepsy. In affluent nations, the prevalence of epilepsy is ~ 1%, whereas in less developed countries, it may >2%. The preferred medication for the condition, phenytoin, has major side effects include gingival enlargement. In addition to being visually disfiguring, this enlargement frequently affects speech, chewing and eating. Furthermore, those with poor dental hygiene, causes disabilities with motor coordination and muscular limitations leading to mental disability and physical impairments are more prone to periodontal disease. This article enlightened the mechanism of drug induced gingival enlargement clinically, microbiologically, and surgically.

PMID:38812578 | PMC:PMC11132884 | DOI:10.1093/jscr/rjae304

Front Oncol. 2024 May 14;14:1399574. doi: 10.3389/fonc.2024.1399574. eCollection 2024.

ABSTRACT

INTRODUCTION: Desmoid fibromatosis is an aggressive fibroblastic neoplasm with a high propensity for local recurrence. Targeted therapy for Desmoid fibromatosis represents a novel avenue in systemic treatment. Anlotinib, a novel multitargeted angiogenesis inhibitor, represents a novel approach for targeted therapy. Therefore, this study aims to assess the efficacy and safety of anlotinib in patients with Desmoid fibromatosis.

METHODS: We retrospectively gathered the clinical medical records of Desmoid fibromatosis patients who underwent anlotinib treatment between June 2019 and November 2023 at our center. Anlotinib was initiated at a daily dose of 12 mg and adjusted based on drug-related toxicity. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Progression-free survival served as the primary endpoint and was analyzed utilizing the Kaplan-Meier method.

RESULTS: In total, sixty-six consecutive patients were enrolled. No patients achieved a complete response; however, fourteen patients (21.21%) exhibited a partial response, while forty-six patients (70%) experienced disease stability. Progressive disease was observed in 6 patients (9.10%), and the progression-free survival rates at 12 and 36months were 89.71% and 82.81%, respectively. The disease control rate was 90.91%, while the objective response rate was 21.21%.

CONCLUSION: Anlotinib proves effective in managing recurrent and symptomatic patients with Desmoid fibromatosis. However, the toxicity profile of anlotinib presents a higher risk of Hand-Foot Skin Reaction and hypertension. Therefore, given that 41.67% of patients were subjected to dose adjustments associated with the initial dose of 12 mg, implementing dosage reductions may help balance efficacy with side effects.

PMID:38807768 | PMC:PMC11130419 | DOI:10.3389/fonc.2024.1399574

Sci Rep. 2024 May 28;14(1):12231. doi: 10.1038/s41598-024-62852-z.

ABSTRACT

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019-June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients' health.

PMID:38806549 | DOI:10.1038/s41598-024-62852-z

Curr Comput Aided Drug Des. 2024;20(5):666-672. doi: 10.2174/0115734099265663230926064638.

ABSTRACT

INTRODUCTION: Drug-drug interactions (DDIs) can lead to adverse events and compromised treatment efficacy that emphasize the need for accurate prediction and understanding of these interactions.

METHODS: In this paper, we propose a novel approach for DDI prediction using two separate message-passing neural network (MPNN) models, each focused on one drug in a pair. By capturing the unique characteristics of each drug and their interactions, the proposed method aims to improve the accuracy of DDI prediction. The outputs of the individual MPNN models combine to integrate the information from both drugs and their molecular features. Evaluating the proposed method on a comprehensive dataset, we demonstrate its superior performance with an accuracy of 0.90, an area under the curve (AUC) of 0.99, and an F1-score of 0.80. These results highlight the effectiveness of the proposed approach in accurately identifying potential drugdrug interactions.

RESULTS: The use of two separate MPNN models offers a flexible framework for capturing drug characteristics and interactions, contributing to our understanding of DDIs. The findings of this study have significant implications for patient safety and personalized medicine, with the potential to optimize treatment outcomes by preventing adverse events.

CONCLUSION: Further research and validation on larger datasets and real-world scenarios are necessary to explore the generalizability and practicality of this approach.

PMID:38804324 | DOI:10.2174/0115734099265663230926064638

Int J Chron Obstruct Pulmon Dis. 2024 May 23;19:1105-1121. doi: 10.2147/COPD.S454905. eCollection 2024.

ABSTRACT

PURPOSE: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD).

METHODS: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%.

RESULTS: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%.

CONCLUSION: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

PMID:38803412 | PMC:PMC11129706 | DOI:10.2147/COPD.S454905

BMC Health Serv Res. 2024 May 27;24(1):666. doi: 10.1186/s12913-024-11125-6.

ABSTRACT

BACKGROUND: In 2016, Uganda added Hydroxyurea (HU) to the list of essential drugs to treat sickle cell disease SCD. However, Hydroxyurea utilization has been low for several countries in sub-Saharan Africa. This study examined patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, in Uganda.

METHODS: To understand the patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease, we conducted a parallel convergent mixed methods study at outpatient departments of two national referral hospitals in Uganda from October 2022 to January 2023. The cross-sectional mixed-methods study employed both quantitative and qualitative methods. We collected survey data from a systematic sample of 259 participants and conducted individual interviews with a purposive sample of 40 participants (20 adolescents or their caregivers and 20 adult patients with SCD) and interviewed them individually on their knowledge, perceptions, barriers, and facilitators of HU utilization. Descriptive data were analyzed using Stata 16, whereas qualitative data were analyzed thematically using an inductive approach supported by NVivo 12 software. We triangulated data to determine the concordance of qualitative and quantitative data.

RESULTS: The study enrolled 40 participants for qualitative interviews and 259 patients for quantitative, with an average age of 16, over half being female, 46% having secondary education, and 96% unmarried. The prevalence of HU use was 78%. The study identified three themes as follows: Patient barriers at the individual including Inadequate knowledge about HU, Persistent pain, Poor adherence to HU, Poor communication with health care workers, and Psychosocial and emotional challenges. At the facility level, long queues and poor quality of care, drug-related side effects that affect HU, and drug stock-outs were reported. Myths, rumors, and misconceptions about HU, and gender-related barriers were reported to affect HU utilization at a community level. Facilitators for the use of HU and recommendations for improvement. Facilitators included perceived benefits, long duration on HU, information sharing by healthcare workers, availability of complementary drugs, confirmation of diagnosis, and availability of medication at public health facilities or private pharmacies. Patients suggested continuous adherence support, encouragement from healthcare workers, sensitization about benefits and risks, a peer-to-peer approach, and financial support for adolescents and women to start businesses to resolve financial problems.

CONCLUSION: Implementing the use of HU has been challenging in Uganda and needs improvement. Facilitators to hydroxyurea use have been highlighted, though Patient-identified barriers at individual, facility, and community levels that need to be resolved. The experiences and insights shared by our participants provide invaluable guidance for increasing the uptake of HU. Further studies are needed to establish validated instruments to assess patients' pain communication and adherence to the HU regimen.

PMID:38802815 | DOI:10.1186/s12913-024-11125-6

Cureus. 2024 Apr 23;16(4):e58877. doi: 10.7759/cureus.58877. eCollection 2024 Apr.

ABSTRACT

Drug-induced urticaria and angioedema cases are typically reversible upon discontinuation and can be triggered by antibiotics, angiotensin-converting enzyme inhibitors, or nonsteroidal anti-inflammatory drugs. Piperacillin-tazobactam, a common broad-spectrum antimicrobial, has been linked to severe adverse reactions, such as thrombocytopenia, hemolytic anemia, and Steven Johnson syndrome in some cases. A 35-year-old male presented to the emergency department with fever, cough, and acute breathlessness, complicating his ongoing treatment for pulmonary tuberculosis with bedaquiline and delamanid. He was admitted and received supportive care. On the third day of intravenous piperacillin-tazobactam, he developed drug-induced urticaria and angioedema, which resolved upon discontinuing the drug. Piperacillin/tazobactam-induced hypersensitivity reaction is an immunologic and IgE-mediated immediate reaction. IgE-mediated immediate reactions to three major phenotypes of allergic patients with confirmed to piperacillin/tazobactam are either (1) sensitized to the β-lactam ring or (2) sensitized to the lateral chain of aminopenicillins or (3) selective to piperacillin/tazobactam alone. A skin patch test is advised, or prescribed to avoid hypersensitivity reactions due to piperacillin/tazobactam. This case underscores the challenges of non-adherence to anti-tubercular therapy, leading to drug resistance and prolonged, costly, and sometimes intolerable treatments. Regular patient follow-up, counseling, monitoring, and healthcare provider involvement are essential to enhance treatment adherence. Adverse drug reactions must be promptly reported and managed, and patient-centric approaches are crucial. Digital patient records and standardized data collection are recommended for program evaluation and global policy development. Causality assessment for piperacillin-tazobactam was diagnosed as the probable cause of drug-induced urticaria and angioedema. This case highlights the importance of adherence to tuberculosis treatment to prevent drug resistance. Overall, patient-centered care, monitoring adverse events of drug added, and better data collection are crucial for successful tuberculosis management.

PMID:38800261 | PMC:PMC11116911 | DOI:10.7759/cureus.58877

iScience. 2024 Mar 26;27(6):109571. doi: 10.1016/j.isci.2024.109571. eCollection 2024 Jun 21.

ABSTRACT

Identifying the side effects related to drugs is beneficial for reducing the risk of drug development failure and saving the drug development cost. We proposed a graph reasoning method, RKDSP, to fuse the semantics of multiple connection relationships, the local knowledge within each meta-path, the global knowledge among multiple meta-paths, and the attributes of the drug and side effect node pairs. We constructed drug-side effect heterogeneous graphs consisting of the drugs, side effects, and their similarity and association connections. Multiple relational transformers were established to learn node features from diverse meta-path semantic perspectives. A knowledge distillation module was constructed to learn local and global knowledge of multiple meta-paths. Finally, an adaptive convolutional neural network-based strategy was presented to adaptively encode the attributes of each drug-side effect node pair. The experimental results demonstrated that RKDSP outperforms the compared state-of-the-art prediction approaches.

PMID:38799562 | PMC:PMC11126883 | DOI:10.1016/j.isci.2024.109571

Lancet Infect Dis. 2024 May 23:S1473-3099(24)00236-6. doi: 10.1016/S1473-3099(24)00236-6. Online ahead of print.

ABSTRACT

BACKGROUND: Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population.

METHODS: ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing).

FINDINGS: Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9-18). The median age was 40 years (34-48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12-0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60-1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events.

INTERPRETATION: Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored.

FUNDING: ANRS Maladies Infectieuses Emergentes.

TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

PMID:38797183 | DOI:10.1016/S1473-3099(24)00236-6

J Chem Theory Comput. 2024 Jun 11;20(11):4901-4908. doi: 10.1021/acs.jctc.4c00432. Epub 2024 May 25.

ABSTRACT

Toxicity is a roadblock that prevents an inordinate number of drugs from being used in potentially life-saving applications. Deep learning provides a promising solution to finding ideal drug candidates; however, the vastness of chemical space coupled with the underlying O(n3) matrix multiplication means these efforts quickly become computationally demanding. To remedy this, we present a hybrid quantum-classical neural network for predicting drug toxicity utilizing a quantum circuit design that mimics classical neural behavior by explicitly calculating matrix products with complexity O(n2). Leveraging the Hadamard test for efficient inner product estimation rather than the conventionally used swap test, we reduce the number of qubits by half and remove the need for quantum phase estimation. Directly computing matrix products quantum mechanically allows for learnable weights to be transferred from a quantum to a classical device for further training. We apply our framework to the Tox21 data set and show that it achieves commensurate predictive accuracy to the model's fully classical O(n3) analogue. Additionally, we demonstrate that the model continues to learn, without disruption, once transferred to a fully classical architecture. We believe that combining the quantum advantage of reduced complexity and the classical advantage of noise-free calculation will pave the way for more scalable machine learning models.

PMID:38795030 | DOI:10.1021/acs.jctc.4c00432

Lancet. 2024 May 25;403(10441):2289-2290. doi: 10.1016/S0140-6736(23)02353-X.

NO ABSTRACT

PMID:38796202 | DOI:10.1016/S0140-6736(23)02353-X

Colloids Surf B Biointerfaces. 2024 May 22;240:113984. doi: 10.1016/j.colsurfb.2024.113984. Online ahead of print.

ABSTRACT

Developing the delivery systems with high therapeutic efficacy and low side effects is of great interest and significance for anticancer therapy. Compared to the high cost in synthesizing new chemotherapeutic drugs, exploring the anticancer potentials of existing chemicals is more convenient and efficient. Sodium bicarbonate (BC), a simple inorganic salt, has shown its tumor inhibition capacity via regulating the acidity of tumor microenvironment. However, the effects of intracytoplasmic BC on tumor growth and the potentials of BC to serve as an anticancer agent are still unknown. Herein, we developed a BC-loaded cationic liposome system (BC-CLP) to deliver BC into the cytosol of cancer cells. The in vitro studies showed that the BC-CLP containing 1% BC (w/v) had a size of 112.9 nm and a zeta potential of 19.1 mV, which reduced the viability of the model cancer cells (human oral squamous cell carcinoma HSC-3 cells) to 13.7%. In contrast, the neutral BC-LP caused less than 50% viability reduction. We further found that BC-CLP released BC directly into cytoplasm via membrane fusion pathway rather than endocytosis, leading to the remarkable increase of cytosolic pH, which may contribute to the anticancer effect of BC-CLP. Our findings indicate that BC-CLP is a potential system for high-efficiency cancer therapy without causing drug-related side effects or resistance.

PMID:38795588 | DOI:10.1016/j.colsurfb.2024.113984

Arch Dermatol Res. 2024 May 25;316(6):233. doi: 10.1007/s00403-024-03061-6.

ABSTRACT

Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may clinically mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The aim of this study was to provide a summary of the clinical and histological features of ICI-associated epidermal necrosis, with a special focus on factors associated with fatal outcomes in cases of extensive disease. A total of 98 cases, 2 new cases and 96 reported on PubMed and in the literature, of ICI-associated epidermal necrosis were assessed. Development of epidermal necrosis occurred between 1 day and 3 years after starting ICI therapy, with an average onset of 13.8 weeks for patients with limited (< 30% BSA) and 11.3 weeks for those with extensive (≥ 30% BSA) involvement, and a median onset of 5.8 weeks and 4 weeks respectively. A preceding rash was seen in 52 cases and was more common in extensive cases. Mucosal involvement was only reported in 65% of extensive cases but was significantly associated with fatal reactions. Co-administration of cytotoxic chemotherapy was associated with more extensive disease. Recovery was observed in 96% and 65% of those with limited and extensive involvement respectively and no specific therapy was associated with improved survival. Young age was significantly associated with poor outcomes in extensive disease, the average age of surviving patients was 64.5 years old versus 55.1 years old for deceased patients, p < 0.01. Both superficial perivascular and interface/lichenoid inflammatory infiltrates were commonly seen. These findings suggest that ICI-associated epidermal necrosis should be considered a distinct clinical entity from drug-induced SJS/TEN.

PMID:38795205 | DOI:10.1007/s00403-024-03061-6

Pharmaceutics. 2024 May 9;16(5):636. doi: 10.3390/pharmaceutics16050636.

ABSTRACT

Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)-the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.

PMID:38794298 | DOI:10.3390/pharmaceutics16050636

Pharmaceutics. 2024 Apr 29;16(5):602. doi: 10.3390/pharmaceutics16050602.

ABSTRACT

INTRODUCTION: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel.

METHODS: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay.

RESULTS: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at -60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay.

CONCLUSION: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.

PMID:38794263 | DOI:10.3390/pharmaceutics16050602

Medicina (Kaunas). 2024 May 11;60(5):798. doi: 10.3390/medicina60050798.

ABSTRACT

Backgrounds and Objectives: Using certain medications during an intercurrent illness can increase the risk of drug related problems (DRP) occurring such as acute kidney injury (AKI). Medications that increase this risk include sulfonylureas, angiotensin converting enzyme inhibitors, diuretics, metformin, angiotensin receptor blockers, non-steroidal anti-inflammatories drugs, and sodium glucose co-transporter 2 inhibitors (SADMANS). Sick day medication guidance (SDMG) recommends withholding SADMANS medications during an intercurrent illness where adequate fluid intake cannot be maintained. But uptake of these recommendations is poor, and it is not known whether Australian pharmacists currently provide these recommendations during home medicine reviews (HMR) as per SDMG. We aimed to gain an understanding of the characteristics of DRP identified by pharmacists during HMR, especially those relating to SADMANS medications. Materials and Methods: We conducted a retrospective audit of 201 randomly selected HMR reports, conducted by accredited pharmacists from 2020 to 2022, that were analysed in 2023. All DRP and recommendations were categorised using a modified DOCUMENT system. Results: Overall, over 98% of participants experienced a DRP and a total of 710 DRP were found, where participants experienced an average of 4.0 ± 2.0 DRP each. Non-SADMANS medications accounted for 83.1% of all DRPs, with nervous system medications contributing the most. Common problems seen in non-SADMANS medications were related to toxicity, over/underdosing and undertreating. Diuretics contributed most to DRP in SADMANS medications. Problems with SADMANS were mainly related to toxicity and contraindications. No pharmacists provided SDMG despite 71.1% of participants using at least one SADMANS medication. Conclusions: We conclude that DRP remain prevalent in community pharmacy settings. Sick day recommendations were not provided in the HMRs included in our study, possibly due to lack of pharmacist knowledge and awareness. To ensure best practice, more research should be conducted to determine pharmacists' knowledge of and barriers to provision of sick day recommendations.

PMID:38792982 | DOI:10.3390/medicina60050798