A Roadmap for Using Causal Inference and Machine Learning to Personalize Asthma Medication Selection.

Inhaled corticosteroid (ICS) is a mainstay treatment for controlling asthma and preventing exacerbations in patients with persistent asthma. Many types of ICS drugs are used, either alone or in combination with other controller medications. Despite the widespread use of ICSs, asthma control remains suboptimal in many people with asthma. Suboptimal control leads to recurrent exacerbations, causes frequent ER visits and inpatient stays, and is due to multiple factors. One such factor is the inappropriate ICS choice for the patient. While many interventions targeting other factors exist, less attention is given to inappropriate ICS choice. Asthma is a heterogeneous disease with variable underlying inflammations and biomarkers. Up to 50% of people with asthma exhibit some degree of resistance or insensitivity to certain ICSs due to genetic variations in ICS metabolizing enzymes, leading to variable responses to ICSs. Yet, ICS choice, especially in the primary care setting, is often not tailored to the patient's characteristics. Instead, ICS choice is largely by trial and error and often dictated by insurance reimbursement, organizational prescribing policies, or cost, leading to a one-size-fits-all approach with many patients not achieving optimal control. There is a pressing need for a decision support tool that can predict an effective ICS at the point of care and guide providers to select the ICS that will most likely and quickly ease patient symptoms and improve asthma control. To date, no such tool exists. Predicting which patient will respond well to which ICS is the first step toward developing such a tool. However, no study has predicted ICS response, forming a gap. While the biologic heterogeneity of asthma is vast, few, if any, biomarkers and genotypes can be used to systematically profile all patients with asthma and predict ICS response. As endotyping or genotyping all patients is infeasible, readily available electronic health record data collected during clinical care offer a low-cost, reliable, and more holistic way to profile all patients. In this paper, we point out the need for developing a decision support tool to guide ICS selection and the gap in fulfilling the need. Then we outline an approach to close this gap via creating a machine learning model and applying causal inference to predict a patient's ICS response in the next year based on the patient's characteristics. The model uses electronic health record data to characterize all patients and extract patterns that could mirror endotype or genotype. This paper supplies a roadmap for future research, with the eventual goal of shifting asthma care from one-size-fits-all to personalized care, improve outcomes, and save health care resources.

Exploring the Use of Persuasive System Design Principles to Enhance Medication Incident Reporting and Learning Systems: Scoping Reviews and Persuasive Design Assessment.

BACKGROUND: Medication incidents (MIs) causing harm to patients have far-reaching consequences for patients, pharmacists, public health, business practice, and governance policy. Medication Incident Reporting and Learning Systems (MIRLS) have been implemented to mitigate such incidents and promote continuous quality improvement in community pharmacies in Canada. They aim to collect and analyze MIs for the implementation of incident preventive strategies to increase safety in community pharmacy practice. However, this goal remains inhibited owing to the persistent barriers that pharmacies face when using these systems. OBJECTIVE: This study aims to investigate the harms caused by medication incidents and technological barriers to reporting and identify opportunities to incorporate persuasive design strategies in MIRLS to motivate reporting. METHODS: We conducted 2 scoping reviews to provide insights on the relationship between medication errors and patient harm and the information system-based barriers militating against reporting. Seven databases were searched in each scoping review, including PubMed, Public Health Database, ProQuest, Scopus, ACM Library, Global Health, and Google Scholar. Next, we analyzed one of the most widely used MIRLS in Canada using the Persuasive System Design (PSD) taxonomy-a framework for analyzing, designing, and evaluating persuasive systems. This framework applies behavioral theories from social psychology in the design of technology-based systems to motivate behavior change. Independent assessors familiar with MIRLS reported the degree of persuasion built into the system using the 4 categories of PSD strategies: primary task, dialogue, social, and credibility support. RESULTS: Overall, 17 articles were included in the first scoping review, and 1 article was included in the second scoping review. In the first review, significant or serious harm was the most frequent harm (11/17, 65%), followed by death or fatal harm (7/17, 41%). In the second review, the authors found that iterative design could improve the usability of an MIRLS; however, data security and validation of reports remained an issue to be addressed. Regarding the MIRLS that we assessed, participants considered most of the primary task, dialogue, and credibility support strategies in the PSD taxonomy as important and useful; however, they were not comfortable with some of the social strategies such as cooperation. We found that the assessed system supported a number of persuasive strategies from the PSD taxonomy; however, we identified additional strategies such as tunneling, simulation, suggestion, praise, reward, reminder, authority, and verifiability that could further enhance the perceived persuasiveness and value of the system. CONCLUSIONS: MIRLS, equipped with persuasive features, can become powerful motivational tools to promote safer medication practices in community pharmacies. They have the potential to highlight the value of MI reporting and increase the readiness of pharmacists to report incidents. The proposed persuasive design guidelines can help system developers and community pharmacy managers realize more effective MIRLS.

Seasonal Malaria Chemoprevention Therapy in Children Up To 9 Years of Age: Protocol for a Cluster-Randomized Trial Study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended by the World Health Organization for the sub-Sahel region in sub-Saharan Africa for preventing malaria in children 3 months old to younger than 5 years. Since 2016, the Malian National Malaria Control Program has deployed SMC countrywide during its high malaria transmission season at a rate of 4 monthly cycles annually. The standard SMC regimen includes sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ). Resistance against SP is suspected to be rising across West Africa; therefore, assessing the effectiveness of an alternative antimalarial drug for SMC is needed to provide a second-line regimen when it is ultimately needed. It is not well understood whether SMC effectively prevents malaria in children aged 5 years or older. OBJECTIVE: The primary goal of the study is to compare 2 SMC regimens (SP-AQ and dihydroartemisinin-piperaquine [DHA-PQ]) in preventing uncomplicated Plasmodium falciparum malaria in children 3 months to 9 years old. Secondly, we will assess the possible use of DHA-PQ as an alternative SMC drug in areas where resistance to SP or AQ may increase following intensive use. METHODS: The study design is a 3-arm cluster-randomized design comparing the SP-AQ and DHA-PQ arms in 2 age groups (younger than 5 years and 5-9 years) and a control group for children aged 5-9 years. Standard SMC (SP-AQ) for children younger than 5 years was provided to the control arm, while SMC with SP-AQ was delivered to children aged 3 months to 9 years (arm 2), and SMC with DHA-PQ will be implemented in study arm 3 for children up to 9 years of age. The study was performed in Mali's Koulikoro District, a rural area in southwest Mali with historically high malaria transmission rates. The study's primary outcome is P falciparum incidence for 2 SMC regimens in children up to 9 years of age. Should DHA-PQ provide an acceptable alternative to SP-AQ, a plausible second-line prevention option would be available in the event of SP resistance or drug supply shortages. A significant byproduct of this effort included bolstering district health information systems for rapid identification of severe malaria cases. RESULTS: The study began on July 1, 2019. Through November 2022, a total of 4556 children 3 months old to younger than 5 years were enrolled. Data collection ended in spring 2023, and the findings are expected to be published later in early 2024. CONCLUSIONS: Routine evaluation of antimalarial drugs is needed to establish appropriate SMC age targets. The study goals here may impact public health policy and provide alternative therapies in the event of drug shortages or resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT04149106, https://clinicaltrials.gov/ct2/show/NCT04149106. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51660.

In Vivo Real-Time Pharmaceutical Evaluations of Near-Infrared II Fluorescent Nanomedicine Bound Polyethylene Glycol Ligands for Tumor Photothermal Ablation.

Pharmaceutical evaluations of nanomedicines are of great significance for their further launch into industry and clinic. Near-infrared (NIR) fluorescence imaging plays essential roles in preclinical drug development by providing important insights into the biodistributions of drugs in vivo with deep tissue penetration and high spatiotemporal resolution. However, NIR-II fluorescence imaging has rarely been exploited for in vivo real-time pharmaceutical evaluations of nanomedicine. Herein, we developed a highly emissive NIR-II luminophore to establish a versatile nanoplatform to noninvasively monitor the in vivo metabolism of nanomedicines bound various polyethylene glycol (PEG) ligands in a real-time manner. An alternative D-A-D conjugated oligomer (DTTB) was synthesized to achieve NIR-II emission peaked at ∼1050 nm with high fluorescence QYs of 13.4% and a large absorption coefficient. By anchoring with the DTTB molecule, intrinsically fluorescent micelles were fabricated and bound with PEG ligands at various chain lengths. In vivo NIR-II fluorescence and photoacoustic imaging results revealed that an appropriate PEG chain length could effectively contribute to the longer blood circulation and better tumor targeting. In vivo therapeutic experiments also confirmed the optimized nanomedicines have efficient photothermal elimination of tumors and good biosafety. This work offered an alternative highly fluorescent NIR-II material and demonstrated a promising approach for real-time pharmaceutical evaluation of nanomedicine in vivo.

Incomplete Freund's adjuvant reduces arginase and enhances Th1 dominance, TLR signaling and CD40 ligand expression in the vaccine site microenvironment.

BACKGROUND: Immunogenicity of cancer vaccines is impacted by adjuvants and schedule, but systematic assessments of their effects have not been performed. Montanide ISA-51, an incomplete Freund's adjuvant (IFA), is used in many vaccine trials, but concerns have been raised about negative effects in murine studies. We found in humans that IFA enhances systemic immune responses and that repeat vaccination at one site (same site vaccination (SSV)) creates tertiary lymphoid structures (TLS) in the vaccine site microenvironment (VSME). We hypothesized that vaccination with peptides+IFA+pICLC or SSV×3 with peptides in IFA would create an immunogenic milieu locally at the VSME, with activated dendritic cells (DC), TLS-associated chemokines and a Th1-dominant VSME. METHODS: Biopsies of the VSME were obtained from participants on two clinical trials who were immunized with multiple melanoma peptides (MELITAC 12.1) in adjuvants comprising IFA and/or the TLR3-agonist pICLC. Biopsies were obtained either a week after one vaccine or a week after SSV×3. Controls included normal skin and skin injected with IFA without peptides. Gene expression analysis was performed by RNAseq. RESULTS: VSME samples were evaluated from 27 patients. One vaccine with peptides in pICLC+IFA enhanced expression of CD80, CD83, CD86 (p<0.01), CD40 and CD40L (p<0.0001) over normal skin; these effects were significantly enhanced for SSV with peptides+IFA. Vaccines containing pICLC increased expression of TBX21 (T-bet) but did not decrease GATA3 over normal skin, whereas SSV with peptides in IFA dramatically enhanced TBX21 and decreased GATA3, with high expression of IFNγ and STAT1. SSV with peptides in IFA also reduced arginase-1 (ARG1) expression and enhanced expression of TLR adapter molecules TICAM-1 (TRIF) and MYD88. Furthermore, SSV with IFA and peptides also enhanced expression of chemokines associated with TLS formation. CONCLUSIONS: These findings suggest that SSV with peptides in IFA enhances CD40L expression by CD4 T cells, supports a Th1 microenvironment, with accumulation of activated and mature DC. Increased expression of TLR adaptor proteins after SSV with peptides in IFA might implicate effects of the skin microbiome. Reduced ARG1 may reflect diminished suppressive myeloid activity in the VSME. TRIAL REGISTRATION NUMBER: (NCT00705640, NCT01585350).

Understanding of guidance for acupuncture and moxibustion interventions on COVID-19 (Second edition) issued by CAAM.

At present, the situation of global fight against COVID-19 is serious. WHO (World Health Organization)-China Joint Mission fully confirms the success of "China's model" against COVID-19 in the report. In fact, one particular power in "China's model" is acupuncture and moxibustion of traditional Chinese medicine. To better apply "non-pharmaceutic measures"-the external technique of traditional Chinese medicine, in the article, the main content of Guidance for acupuncture and moxibustion interventions on COVID-19 (Second edition) issued by China Association of Acupuncture-Moxibution is introduced and the discussion is stressed on the selection of moxibustion device and the duration of its exertion.

Analysis and Suggestions for Parts of the Problem of"General Principles for Processing"in Chinese Phar-macopoeia / 中国药房

OBJECTIVE:To provide reference for standardizing the names and definitions for the processing methods of"gener-al principles for processing"in reprinted Chinese Pharmacopoeia. METHODS:Comparing with the Processing of Chinese Mate-ria,Beijing Processing Specification for TCM Decoction Pieces,Shennong Bencaojing and National Processing Specification for Chinese Herbal Medicine,parts of the name and definition problems for processing methods of"general principles for processing"in Chinese Pharmacopoeia (2015 edition,Vol Ⅳ) were analyzed,and suggestions were put forward. RESULTS:The definitions of partial items in the"general principles for processing"in Chinese Pharmacopoeia remained to be normalized and operability re-mained to be improved. For example,the definitions of stir-frying,stir-frying with wine,stir-frying with vinegar,stir-frying with salt and stir-frying with honey were not accurate,so as the steaming. The name of the processing method under the term of decoc-tion pieces was not identified,there was deviation in the scope of crystallizing definition,and amount of pharmaceutic adjuvant was not worthy to be generalized. CONCLUSIONS:When generalizing and defining the processing methods for all TCM decoction pieces,Chinese Pharmacopoeia should give consideration to the popularity,accuracy and universality.

Evaluation of a possible predictor for Federal Joint Committee decisions on early benefit assessments according to the German act on the reform of the market for medicinal products.

OBJECTIVES: As of 1st January 2011 the German drug market is regulated by the act on the reform of the market for medicinal products (AMNOG). Since then the normal procedure for reimbursement of a new pharmaceutical is a benefit assessment by the joint federal committee (G-BA) which determines one of six additional benefit levels. METHODS: In order to evaluate a possible predictor of G-BA decisions, the 'evaluation of pharmaceutical innovations (EVITA)' score was calculated for 40 out of 63 dossiers and compared with published G-BA appraisals. RESULTS: Univariate ordinary least squares (p<0.001) and ordered logit regression (p=0.008) analyses show statistically significant correlations between EVITA scores and the G-BA additional benefit levels. Moreover, for the prediction of an additional benefit level of at least 'minor', an EVITA score cutpoint of ≥3 is associated with a sensitivity of 100% and a specificity of 80%. For the prediction of an additional benefit level of at least 'considerable', an EVITA score cutpoint of ≥7.5 is associated with a sensitivity of 100% and a specificity of 93.1%. CONCLUSION: The present investigation indicates that the EVITA score may have some potential to act as a possible predictor of G-BA decisions related to AMNOG early benefit assessments.