Do probiotic interventions improve female unexplained infertility? A critical commentary.

Disruption of women's gut and cervicovaginal microbiota has been associated with multiple gynaecological diseases such as endometriosis, polycystic ovary syndrome, non-cyclic pelvic pain and infertility. Female infertility affects 12.6% of women worldwide; its aetiology is complex and multifactorial and can be underpinned by uterine pathologies, systemic diseases and age. In addition, a new perspective has emerged on the role of the gut and vaginal microbiomes in reproductive health. Research shows that the administration of precisely selected probiotics, often in combination with prior antibiotic treatment, may facilitate the restoration of symbiotic microbiota to increase successful conception and assisted reproductive technology outcomes. However, clarity on this issue from fuller research is currently hampered by a lack of consistency and harmonization in clinical studies: various lactobacilli and bifidobacteria species have been delivered through both the oral and vaginal routes, in different dosages, for different treatment durations. This commentary explores the intricate relationship between the microbiota in the cervicovaginal area and gut of women, exploring their potential contribution to infertility. It highlights ongoing research on the use of probiotic formulations in improving pregnancy outcomes, critically examining the divergent findings in these studies, which complicate a conclusive assessment of the efficacy of these interventions.

The role of artificial intelligence in generating original scientific research.

Artificial intelligence (AI) is a revolutionary technology that is finding wide application across numerous sectors. Large language models (LLMs) are an emerging subset technology of AI and have been developed to communicate using human languages. At their core, LLMs are trained with vast amounts of information extracted from the internet, including text and images. Their ability to create human-like, expert text in almost any subject means they are increasingly being used as an aid to presentation, particularly in scientific writing. However, we wondered whether LLMs could go further, generating original scientific research and preparing the results for publication. We taskedGPT-4, an LLM, to write an original pharmaceutics manuscript, on a topic that is itself novel. It was able to conceive a research hypothesis, define an experimental protocol, produce photo-realistic images of 3D printed tablets, generate believable analytical data from a range of instruments and write a convincing publication-ready manuscript with evidence of critical interpretation. The model achieved all this is less than 1 h. Moreover, the generated data were multi-modal in nature, including thermal analyses, vibrational spectroscopy and dissolution testing, demonstrating multi-disciplinary expertise in the LLM. One area in which the model failed, however, was in referencing to the literature. Since the generated experimental results appeared believable though, we suggest that LLMs could certainly play a role in scientific research but with human input, interpretation and data validation. We discuss the potential benefits and current bottlenecks for realising this ambition here.

Electroactive Polymers for On-Demand Drug Release.

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.

Virtually Possible: Enhancing Quality Control of 3D-Printed Medicines with Machine Vision Trained on Photorealistic Images.

Three-dimensional (3D) printing is an advanced pharmaceutical manufacturing technology, and concerted efforts are underway to establish its applicability to various industries. However, for any technology to achieve widespread adoption, robustness and reliability are critical factors. Machine vision (MV), a subset of artificial intelligence (AI), has emerged as a powerful tool to replace human inspection with unprecedented speed and accuracy. Previous studies have demonstrated the potential of MV in pharmaceutical processes. However, training models using real images proves to be both costly and time consuming. In this study, we present an alternative approach, where synthetic images were used to train models to classify the quality of dosage forms. We generated 200 photorealistic virtual images that replicated 3D-printed dosage forms, where seven machine learning techniques (MLTs) were used to perform image classification. By exploring various MV pipelines, including image resizing and transformation, we achieved remarkable classification accuracies of 80.8%, 74.3%, and 75.5% for capsules, tablets, and films, respectively, for classifying stereolithography (SLA)-printed dosage forms. Additionally, we subjected the MLTs to rigorous stress tests, evaluating their scalability to classify over 3000 images and their ability to handle irrelevant images, where accuracies of 66.5% (capsules), 72.0% (tablets), and 70.9% (films) were obtained. Moreover, model confidence was also measured, and Brier scores ranged from 0.20 to 0.40. Our results demonstrate promising proof of concept that virtual images exhibit great potential for image classification of SLA-printed dosage forms. By using photorealistic virtual images, which are faster and cheaper to generate, we pave the way for accelerated, reliable, and sustainable AI model development to enhance the quality control of 3D-printed medicines.

Energy consumption and carbon footprint of 3D printing in pharmaceutical manufacture.

Achieving carbon neutrality is seen as an important goal in order to mitigate the effects of climate change, as carbon dioxide is a major greenhouse gas that contributes to global warming. Many countries, cities and organizations have set targets to become carbon neutral. The pharmaceutical sector is no exception, being a major contributor of carbon emissions (emitting approximately 55% more than the automotive sector for instance) and hence is in need of strategies to reduce its environmental impact. Three-dimensional (3D) printing is an advanced pharmaceutical fabrication technology that has the potential to replace traditional manufacturing tools. Being a new technology, the environmental impact of 3D printed medicines has not been investigated, which is a barrier to its uptake by the pharmaceutical industry. Here, the energy consumption (and carbon emission) of 3D printers is considered, focusing on technologies that have successfully been demonstrated to produce solid dosage forms. The energy consumption of 6 benchtop 3D printers was measured during standby mode and printing. On standby, energy consumption ranged from 0.03 to 0.17 kWh. The energy required for producing 10 printlets ranged from 0.06 to 3.08 kWh, with printers using high temperatures consuming more energy. Carbon emissions ranged between 11.60 and 112.16 g CO2 (eq) per 10 printlets, comparable with traditional tableting. Further analyses revealed that decreasing printing temperature was found to reduce the energy demand considerably, suggesting that developing formulations that are printable at lower temperatures can reduce CO2 emissions. The study delivers key initial insights into the environmental impact of a potentially transformative manufacturing technology and provides encouraging results in demonstrating that 3D printing can deliver quality medicines without being environmentally detrimental.

Advancing oral delivery of biologics: Machine learning predicts peptide stability in the gastrointestinal tract.

The oral delivery of peptide therapeutics could facilitate precision treatment of numerous gastrointestinal (GI) and systemic diseases with simple administration for patients. However, the vast majority of licensed peptide drugs are currently administered parenterally due to prohibitive peptide instability in the GI tract. As such, the development of GI-stable peptides is receiving considerable investment. This study provides researchers with the first tool to predict the GI stability of peptide therapeutics based solely on the amino acid sequence. Both unsupervised and supervised machine learning techniques were trained on literature-extracted data describing peptide stability in simulated gastric and small intestinal fluid (SGF and SIF). Based on 109 peptide incubations, classification models for SGF and SIF were developed. The best models utilized k-Nearest Neighbor (for SGF) and XGBoost (for SIF) algorithms, with accuracies of 75.1% (SGF) and 69.3% (SIF), and f1 scores of 84.5% (SGF) and 73.4% (SIF) under 5-fold cross-validation. Feature importance analysis demonstrated that peptides' lipophilicity, rigidity, and size were key determinants of stability. These models are now available to those working on the development of oral peptide therapeutics.

Machine learning using multi-modal data predicts the production of selective laser sintered 3D printed drug products.

Three-dimensional (3D) printing is drastically redefining medicine production, offering digital precision and personalized design opportunities. One emerging 3D printing technology is selective laser sintering (SLS), which is garnering attention for its high precision, and compatibility with a wide range of pharmaceutical materials, including low-solubility compounds. However, the full potential of SLS for medicines is yet to be realized, requiring expertise and considerable time-consuming and resource-intensive trial-and-error research. Machine learning (ML), a subset of artificial intelligence, is an in silico tool that is accomplishing remarkable breakthroughs in several sectors for its ability to make highly accurate predictions. Therefore, the present study harnessed ML to predict the printability of SLS formulations. Using a dataset of 170 formulations from 78 materials, ML models were developed from inputs that included the formulation composition and characterization data retrieved from Fourier-transformed infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Multiple ML models were explored, including supervised and unsupervised approaches. The results revealed that ML can achieve high accuracies, by using the formulation composition leading to a maximum F1 score of 81.9%. Using the FT-IR, XRPD and DSC data as inputs resulted in an F1 score of 84.2%, 81.3%, and 80.1%, respectively. A subsequent ML pipeline was built to combine the predictions from FT-IR, XRPD and DSC into one consensus model, where the F1 score was found to further increase to 88.9%. Therefore, it was determined for the first time that ML predictions of 3D printability benefit from multi-modal data, combining numeric, spectral, thermogram and diffraction data. The study lays the groundwork for leveraging existing characterization data for developing high-performing computational models to accelerate formulation development.

Multimodal Diagnosis for Pulmonary Embolism from EHR Data and CT Images.

Pulmonary Embolism (PE) is a severe medical condition that can pose a significant risk to life. Traditional deep learning methods for PE diagnosis are based on Computed Tomography (CT) images and do not consider the patient's clinical context. To make full use of patient's clinical information, this article presents a multimodal fusion model ingesting Electronic Health Record (EHR) data and CT images for PE diagnosis. The proposed model is based on multilayer perception and convolutional neural networks. To remove the invalid information in the EHR data, the multidimensional scaling algorithm is performed for feature dimension reduction. The EHR data and CT images of 600 patients are used for experiments. The experiment results show that the proposed models outperform existing methods and the multimodal fusion model shows better performance than the single-input model.

Current clinical translation of microbiome medicines.

The microbiome is experiencing increasing scrutiny for its role in disease, and the number of new research reports describing microbiome-disease relationships is growing exponentially. Researchers are increasingly working to translate the emerging fundamental science into microbiome medicines that will address important unmet needs in the clinic. We summarise the types of microbiome medicines that have the most translational potential, and provide a detailed analysis of the current global microbiome medicines pipeline and the challenges facing clinical translation. The regulatory pipeline is currently dominated by probiotics intended for oral delivery to the gastrointestinal (GI) tract; however, several non-living biologics and small molecules provide notable exceptions. With the first microbiome medicine set to begin the regulatory submission process in 2022, it is an exciting time for the field.

Machine learning to empower electrohydrodynamic processing.

Electrohydrodynamic (EHD) processes are promising healthcare fabrication technologies, as evidenced by the number of commercialised and food-and-drug administration (FDA)-approved products produced by these processes. Their ability to produce both rapidly and precisely nano-sized products provides them with a unique set of qualities that cannot be matched by other fabrication technologies. Consequently, this has stimulated the development of EHD processing to tackle other healthcare challenges. However, as with most technologies, time and resources will be needed to realise fully the potential EHD processes can offer. To address this bottleneck, researchers are adopting machine learning (ML), a subset of artificial intelligence, into their workflow. ML has already made ground-breaking advancements in the healthcare sector, and it is anticipated to do the same in the materials domain. Presently, the application of ML in fabrication technologies lags behind other sectors. To that end, this review showcases the progress made by ML for EHD workflows, demonstrating how the latter can benefit greatly from the former. In addition, we provide an introduction to the ML pipeline, to help encourage the use of ML for other EHD researchers. As discussed, the merger of ML with EHD has the potential to expedite novel discoveries and to automate the EHD workflow.

Active Machine learning for formulation of precision probiotics.

It is becoming clear that the human gut microbiome is critical to health and well-being, with increasing evidence demonstrating that dysbiosis can promote disease. Increasingly, precision probiotics are being investigated as investigational drug products for restoration of healthy microbiome balance. To reach the distal gut alive where the density of microbiota is highest, oral probiotics should be protected from harsh conditions during transit through the stomach and small intestines. At present, few probiotic formulations are designed with this delivery strategy in mind. This study employs an emerging machine learning (ML) technique, known as active ML, to predict how excipients at pharmaceutically relevant concentrations affect the intestinal proliferation of a common probiotic, Lactobacillus paracasei. Starting with a labelled dataset of just 6 bacteria-excipient interactions, active ML was able to predict the effects of a further 111 excipients using uncertainty sampling. The average certainty of the final model was 67.70% and experimental validation demonstrated that 3/4 excipient-probiotic interactions could be correctly predicted. The model can be used to enable superior probiotic delivery to maximise proliferation in vivo and marks the first use of active ML in microbiome science.

Advancing pharmacy and healthcare with virtual digital technologies.

Digitalisation of the healthcare sector promises to revolutionise patient healthcare globally. From the different technologies, virtual tools including artificial intelligence, blockchain, virtual, and augmented reality, to name but a few, are providing significant benefits to patients and the pharmaceutical sector alike, ranging from improving access to clinicians and medicines, as well as improving real-time diagnoses and treatments. Indeed, it is envisioned that such technologies will communicate together in real-time, as well as with their physical counterparts, to create a large-scale, cyber healthcare system. Despite the significant benefits that virtual-based digital health technologies can bring to patient care, a number of challenges still remain, ranging from data security to acceptance within the healthcare sector. This review provides a timely account of the benefits and challenges of virtual health interventions, as well an outlook on how such technologies can be transitioned from research-focused towards real-world healthcare and pharmaceutical applications to transform treatment pathways for patients worldwide.

Machine learning predicts the effect of food on orally administered medicines.

Food-mediated changes to drug absorption, termed the food effect, are hard to predict and can have significant implications for the safety and efficacy of oral drug products in patients. Mimicking the prandial states of the human gastrointestinal tract in preclinical studies is challenging, poorly predictive and can produce difficult to interpret datasets. Machine learning (ML) has emerged from the computer science field and shows promise in interpreting complex datasets present in the pharmaceutical field. A ML-based approach aimed to predict the food effect based on an extensive dataset of over 311 drugs with more than 20 drug physicochemical properties, referred to as features. Machine learning techniques were tested; including logistic regression, support vector machine, k-Nearest neighbours and random forest. First a standard ML pipeline using a 80:20 split for training and testing was tried to predict no food effect, negative food effect and positive food effect, however this lead to specificities of less than 40%. To overcome this, a strategic ML pipeline was devised and three tasks were developed. Random forest achieved the strongest performance overall. High accuracies and sensitivities of 70%, 80% and 70% and specificities of 71%, 76% and 71% were achieved for classifying; (i) no food effect vs food effect, (ii) negative food vs positive food effect and (iii) no food effect vs negative food effect vs positive food effect, respectively. Feature importance using random forest ranked the features by importance for building the predictive tasks. The calculated dose number was the most important feature. Here, ML has provided an effective screening tool for predicting the food effect, with the potential to select lead compounds with no food effect, reduce the number of animal studies, and accelerate oral drug development studies.

Machine Learning Predicts Drug Metabolism and Bioaccumulation by Intestinal Microbiota.

Over 150 drugs are currently recognised as being susceptible to metabolism or bioaccumulation (together described as depletion) by gastrointestinal microorganisms; however, the true number is likely higher. Microbial drug depletion is often variable between and within individuals, depending on their unique composition of gut microbiota. Such variability can lead to significant differences in pharmacokinetics, which may be associated with dosing difficulties and lack of medication response. In this study, literature mining and unsupervised learning were used to curate a dataset of 455 drug-microbiota interactions. From this, 11 supervised learning models were developed that could predict drugs' susceptibility to depletion by gut microbiota. The best model, a tuned extremely randomised trees classifier, achieved performance metrics of AUROC: 75.1% ± 6.8; weighted recall: 79.2% ± 3.9; balanced accuracy: 69.0% ± 4.6; and weighted precision: 80.2% ± 3.7 when validated on 91 drugs. This machine learning model is the first of its kind and provides a rapid, reliable, and resource-friendly tool for researchers and industry professionals to screen drugs for susceptibility to depletion by gut microbiota. The recognition of drug-microbiome interactions can support successful drug development and promote better formulations and dosage regimens for patients.

Machine Learning and Machine Vision Accelerate 3D Printed Orodispersible Film Development.

Orodispersible films (ODFs) are an attractive delivery system for a myriad of clinical applications and possess both large economical and clinical rewards. However, the manufacturing of ODFs does not adhere to contemporary paradigms of personalised, on-demand medicine, nor sustainable manufacturing. To address these shortcomings, both three-dimensional (3D) printing and machine learning (ML) were employed to provide on-demand manufacturing and quality control checks of ODFs. Direct ink writing (DIW) was able to fabricate complex ODF shapes, with thicknesses of less than 100 µm. ML algorithms were explored to classify the ODFs according to their active ingredient, by using their near-infrared (NIR) spectrums. A supervised model of linear discriminant analysis was found to provide 100% accuracy in classifying ODFs. A subsequent partial least square algorithm was applied to verify the dose, where a coefficient of determination of 0.96, 0.99 and 0.98 was obtained for ODFs of paracetamol, caffeine, and theophylline, respectively. Therefore, it was concluded that the combination of 3D printing, NIR and ML can result in a rapid production and verification of ODFs. Additionally, a machine vision tool was used to automate the in vitro testing. These collective digital technologies demonstrate the potential to automate the ODF workflow.

Connected healthcare: Improving patient care using digital health technologies.

Now more than ever, traditional healthcare models are being overhauled with digital technologies of Healthcare 4.0 increasingly adopted. Worldwide, digital devices are improving every stage of the patient care pathway. For one, sensors are being used to monitor patient metrics 24/7, permitting swift diagnosis and interventions. At the treatment stage, 3D printers are under investigation for the concept of personalised medicine by allowing patients access to on-demand, customisable therapeutics. Robots are also being explored for treatment, by empowering precision surgery, rehabilitation, or targeted drug delivery. Within medical logistics, drones are being leveraged to deliver critical treatments to remote areas, collect samples, and even provide emergency aid. To enable seamless integration within healthcare, the Internet of Things technology is being exploited to form closed-loop systems that remotely communicate with one another. This review outlines the most promising healthcare technologies and devices, their strengths, drawbacks, and opportunities for clinical adoption.

Machine learning predicts 3D printing performance of over 900 drug delivery systems.

Three-dimensional printing (3DP) is a transformative technology that is advancing pharmaceutical research by producing personalized drug products. However, advances made via 3DP have been slow due to the lengthy trial-and-error approach in optimization. Artificial intelligence (AI) is a technology that could revolutionize pharmaceutical 3DP through analyzing large datasets. Herein, literature-mined data for developing AI machine learning (ML) models was used to predict key aspects of the 3DP formulation pipeline and in vitro dissolution properties. A total of 968 formulations were mined and assessed from 114 articles. The ML techniques explored were able to learn and provide accuracies as high as 93% for values in the filament hot melt extrusion process. In addition, ML algorithms were able to use data from the composition of the formulations with additional input features to predict the drug release of 3D printed medicines. The best prediction was obtained by an artificial neural network that was able to predict drug release times of a formulation with a mean error of ±24.29 min. In addition, the most important variables were revealed, which could be leveraged in formulation development. Thus, it was concluded that ML proved to be a suitable approach to modelling the 3D printing workflow.

Machine Learning Uncovers Adverse Drug Effects on Intestinal Bacteria.

The human gut microbiome, composed of trillions of microorganisms, plays an essential role in human health. Many factors shape gut microbiome composition over the life span, including changes to diet, lifestyle, and medication use. Though not routinely tested during drug development, drugs can exert profound effects on the gut microbiome, potentially altering its functions and promoting disease. This study develops a machine learning (ML) model to predict whether drugs will impair the growth of 40 gut bacterial strains. Trained on over 18,600 drug-bacteria interactions, 13 distinct ML models are built and compared, including tree-based, ensemble, and artificial neural network techniques. Following hyperparameter tuning and multi-metric evaluation, a lead ML model is selected: a tuned extra trees algorithm with performances of AUROC: 0.857 (±0.014), recall: 0.587 (±0.063), precision: 0.800 (±0.053), and f1: 0.666 (±0.042). This model can be used by the pharmaceutical industry during drug development and could even be adapted for use in clinical settings.

Disrupting 3D printing of medicines with machine learning.

3D printing (3DP) is a progressive technology capable of transforming pharmaceutical development. However, despite its promising advantages, its transition into clinical settings remains slow. To make the vital leap to mainstream clinical practice and improve patient care, 3DP must harness modern technologies. Machine learning (ML), an influential branch of artificial intelligence, may be a key partner for 3DP. Together, 3DP and ML can utilise intelligence based on human learning to accelerate drug product development, ensure stringent quality control (QC), and inspire innovative dosage-form design. With ML's capabilities, streamlined 3DP drug delivery could mark the next era of personalised medicine. This review details how ML can be applied to elevate the 3DP of pharmaceuticals and importantly, how it can expedite 3DP's integration into mainstream healthcare.

Harnessing artificial intelligence for the next generation of 3D printed medicines.

Artificial intelligence (AI) is redefining how we exist in the world. In almost every sector of society, AI is performing tasks with super-human speed and intellect; from the prediction of stock market trends to driverless vehicles, diagnosis of disease, and robotic surgery. Despite this growing success, the pharmaceutical field is yet to truly harness AI. Development and manufacture of medicines remains largely in a 'one size fits all' paradigm, in which mass-produced, identical formulations are expected to meet individual patient needs. Recently, 3D printing (3DP) has illuminated a path for on-demand production of fully customisable medicines. Due to its flexibility, pharmaceutical 3DP presents innumerable options during formulation development that generally require expert navigation. Leveraging AI within pharmaceutical 3DP removes the need for human expertise, as optimal process parameters can be accurately predicted by machine learning. AI can also be incorporated into a pharmaceutical 3DP 'Internet of Things', moving the personalised production of medicines into an intelligent, streamlined, and autonomous pipeline. Supportive infrastructure, such as The Cloud and blockchain, will also play a vital role. Crucially, these technologies will expedite the use of pharmaceutical 3DP in clinical settings and drive the global movement towards personalised medicine and Industry 4.0.