3D Laser Writing of Low-Loss Cross-Section-Variable Type-I Optical Waveguide Passive/Active Integrated Devices in Single Crystals.

Optical waveguides fabricated in single crystals offer crucial passive/active optical components for photonic integrated circuits. Single crystals possess inherent advantages over their amorphous counterpart, such as lower optical losses in visible-to-mid-infrared band, larger peak emission cross-section, higher doping concentration. However, the writing of Type-I positive refractive index modified waveguides in single crystals using femtosecond laser technology presents significant challenges. Herein, this work introduces a novel femtosecond laser direct writing technique that combines slit-shaping with an immersion oil objective to fabricate low-loss Type-I waveguides in single crystals. This approach allows for precise control of waveguide shape, size, mode-field, and refractive index distribution, with a spatial resolution as high as 700 nm and a high positive refractive index variation on the order of 10-2, introducing new degrees of freedom to design and fabricate passive/active optical waveguide devices. As a proof-of-concept, this work successfully produces a 7 mm-long circular-shaped gain waveguide (≈10 µm in diameter) in an Er3+-doped YAG single crystal, exhibiting a propagation loss as low as 0.23 dB cm-1, a net gain of ≈3 dB and a polarization-insensitive character. The newly-developed technique is theoretically applicable to arbitrary single crystals, holding promising potential for various applications in integrated optics, optical communication, and photonic quantum circuits.

Localized Temperature Engineering Enables Writing of Heterostructures in Glass for Polarized Photoluminescence of Perovskites.

Metal halide perovskite (MHP) structures that exhibit polarized photoluminescence (PL) have attracted significant interest in fabricating light field regulation elements for display, imaging, and information storage applications. We report a three-dimensional direct lithography of heterostructures for controllable polarized PL inside glass by laser-induced localized temperature engineering. The heterostructures consisted of oriented periodic structures (OPSs) and MHP nanocrystals, and the mechanism for hierarchical distribution of heterostructures was illustrated. The patterning of heterostructures for manipulable polarized PL can be used for information encryption, wave-plate, and polarized micro-LEDs.

Inhaled delivery of cetuximab-conjugated immunoliposomes loaded with afatinib: A promising strategy for enhanced non-small cell lung cancer treatment.

Afatinib (AT), an FDA-approved aniline-quinazoline derivative, is a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Combining it with cetuximab (CX), a chimeric human-murine derivative immunoglobulin-G1 monoclonal antibody (mAb) targeting the extracellular domain of epidermal growth factor receptor (EGFR), has shown significant improvements in median progression-free survival. Previously, we developed cetuximab-conjugated immunoliposomes loaded with afatinib (AT-MLP) and demonstrated their efficacy against NSCLC cells (A549 and H1975). In this study, we aimed to explore the potential of pulmonary delivery to mitigate adverse effects associated with oral administration and intravenous injection. We formulated AT-MLP dry powders (AT-MLP-DPI) via freeze drying using tert-butanol and mannitol as cryoprotectants in the hydration medium. The physicochemical and aerodynamic properties of dry powders were well analyzed firstly. In vitro cellular uptake and cytotoxicity study revealed concentration- and time-dependent cellular uptake behavior and antitumor efficacy of AT-MLP-DPI, while Transwell assay demonstrated the superior inhibitory effects on NSCLC cell invasion and migration. Furthermore, in vivo pharmacokinetic study showed that pulmonary delivery of AT-MLP-DPI significantly increased bioavailability, prolonged blood circulation time, and exhibited higher lung concentrations compared to alternative administration routes and formulations. The in vivo antitumor efficacy study carried on tumor-bearing nude mice indicated that inhaled AT-MLP-DPI effectively suppressed lung tumor growth.

Toward a10†dB net-gain waveguide amplifier in an Er3+-Yb3+ co-doped phosphate glass.

High-gain materials and high-quality structures are the two main conditions that determine the amplification performance of optical waveguides. However, it has been hard to balance each other, to date. In this work, we demonstrate breakthroughs in both glass optical gain and optical waveguide structures. We propose a secondary melting dehydration technique that prepares high-quality Er3+-Yb3+ co-doped phosphate glass with low absorption loss. Additionally, we propose a femtosecond laser direct-writing technique that allows controlling the cross section, size, and mode field of waveguides written in glass with high accuracy, leveraging submicron-resolution multi-scan direct-writing optical waveguide technology, which is beneficial for reducing insertion loss. As a proof of concept demonstration, we designed and fabricated two kinds of waveguides, namely, LP01- and LP11-mode waveguides in the Er3+-Yb3+ co-doped phosphate glass, enabling insertion loss as low as 0.9 dB for a waveguide length of 2 mm. Remarkably, we successfully achieved an optical amplification for both the waveguides with a net gain of >7 dB and a net-gain coefficient of >3.5 dB/mm, which is approximately one order of magnitude larger than that in the Er3+-Yb3+ co-doped phosphate glass fabricated by the traditional melt-quenching method. This will open new avenues toward the development of integrated photonic chips.

Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation.

Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS. The specificity and potency of one optimal lead XQ2B were characterized in cellular assays. Concordantly, XQ2B inhibited herpes simplex virus-1 (HSV-1)-induced antiviral immune responses and enhanced HSV-1 infection in vitro and in vivo. Furthermore, XQ2B significantly suppressed the elevated levels of type I interferon and proinflammatory cytokines in primary macrophages from Trex1-/- mice and systemic inflammation in Trex1-/- mice. XQ2B represents the specific cGAS inhibitor targeting protein-DNA interaction and phase separation and serves as a scaffold for the development of therapies in the treatment of cGAS-dependent inflammatory diseases.

Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease.

Human glutaminyl cyclase (hQC) is drawing considerable attention and emerging as a potential druggable target for Alzheimer's disease (AD) due to its close involvement in the pathology of AD via the post-translational pyroglutamate modification of amyloid-ß. A recent phase 2a study has shown promising early evidence of efficacy for AD with a competitive benzimidazole-based QC inhibitor, PQ912, which also demonstrated favorable safety profiles. This finding has sparked new hope for the treatment of AD. In this review, we briefly summarize the discovery and evolution of hQC inhibitors, with a particular interest in classic Zinc binding group (ZBG)-containing chemicals reported in recent years. Additionally, we highlight several high-potency inhibitors and discuss new trends and challenges in the development of QC inhibitors as an alternative and promising disease-modifying therapy for AD.

Triptorelin nanoparticle-loaded microneedles for use in assisted reproductive technology.

Triptorelin is a first-line drug for assisted reproductive technology (ART), but the low bioavailability and frequent subcutaneous injection of triptorelin impair the quality of life of women preparing to become pregnant. We report silk fibroin (SF)-based microneedles (MNs) for transdermal delivery of triptorelin-loaded nanoparticles (NPs) to improve bioavailability and achieve safe and efficacious self-administration of triptorelin. Triptorelin was mixed into an aqueous solution of SF with shear force to prepare NPs to control the release and avoid the degradation of triptorelin by enzymes in the skin. Two-step pouring and centrifugation were employed to prepare nanoparticles-encapsulated polymeric microneedles (NPs-MNs). An increased ß-sheet content in the conformation ensured that NPs-MNs had good mechanical properties to pierce the stratum corneum. Transdermal release of triptorelin from NPs-MNs was increased to ∼65%. The NPs-MNs exhibited a prolonged drug half-life and increased relative bioavailability after administration to rats. Surging levels of luteinizing hormone and estradiol in plasma and their subsequent prolonged downregulation indicate the potential therapeutic role of NPs-MNs in ART regimens. The triptorelin-loaded NPs-MNs developed in this study may reduce the physical and psychological burden of pregnant women using ART regimens.

A rapid-crosslinking antimicrobial hydrogel with enhanced antibacterial capabilities for improving wound healing.

One of the main reasons impeding wound healing is wound infection caused by bacterial colonization with a continuous stage of inflammation. Traditional wound treatments like gauze are being replaced by tissue adhesives with strong wet tissue adhesion and biocompatibility. Herein, a fast-crosslinking hydrogel is developed to achieve both strong antimicrobial properties and excellent biocompatibility. In this study, a simple and non-toxic composite hydrogel was prepared by the Schiff base reaction between the aldehyde group of 2,3,4-trihydroxybenzaldehyde (TBA) and the amino group of ε-Poly-L-lysine (EPL). Subsequently, a succession of experiments toward this new hydrogel including structure characterization, antimicrobial properties, cell experiment and wound healing were applied. The results of the experiments show that the EPL-TBA hydrogel not only exhibited excellent contact-active antimicrobial activities against Gram-negative bacteria Escherichia coli (E. coil) and Gram-positive Bacteria Staphylococcus aureus (S. aureus), but also inhibited the biofilm formation. More importantly, the EPL-TBA hydrogel promoted the wound healing with low cytotoxicity in vivo. These findings indicate that the EPL-TBA hydrogel has a promising use as a wound dressing in the bacterial infection prevention and wounds healing acceleration.

Nanoparticle drug delivery systems for synergistic delivery of tumor therapy.

Nanoparticle drug delivery systems have proved anti-tumor effects; however, they are not widely used in tumor therapy due to insufficient ability to target specific sites, multidrug resistance to anti-tumor drugs, and the high toxicity of the drugs. With the development of RNAi technology, nucleic acids have been delivered to target sites to replace or correct defective genes or knock down specific genes. Also, synergistic therapeutic effects can be achieved for combined drug delivery, which is more effective for overcoming multidrug resistance of cancer cells. These combination therapies achieve better therapeutic effects than delivering nucleic acids or chemotherapeutic drugs alone, so the scope of combined drug delivery has also been expanded to three aspects: drug-drug, drug-gene, and gene-gene. This review summarizes the recent advances of nanocarriers to co-delivery agents, including i) the characterization and preparation of nanocarriers, such as lipid-based nanocarriers, polymer nanocarriers, and inorganic delivery carriers; ii) the advantages and disadvantages of synergistic delivery approaches; iii) the effectual delivery cases that are applied in the synergistic delivery systems; and iv) future perspectives in the design of nanoparticle drug delivery systems to co-deliver therapeutic agents.

High-order mode waveguide amplifier with high mode extinction ratio written in an Er3+-doped phosphate glass.

Inscription of fiber-compatible active waveguides in high-gain glass, followed by direct interconnection with few-mode fibers, is one of the most promising solutions for all-optical mode-division multiplexing. In this work, based on the femtosecond laser writing technique, we propose a general fabrication scheme for inscribing high-order mode waveguides in glass, by carefully tailoring the cross-section of the waveguides to match the mode intensity distribution via an improved multi-scan approach. Specifically, we design and fabricate two kinds of waveguides, namely, LP01-mode waveguide and LP11-mode waveguide in a highly Er3+-doped phosphate glass, enabling the insertion loss of the waveguides to be as low as 1.88 dB, and the mode extraction factor of the LP11-mode waveguide up to ∼24 dB. Importantly, we have successfully achieved optical amplification of the waveguides, with an on-off gain as high as 3.52 dB. This novel high-order mode waveguide amplifier has broad application prospects in monolithic on-chip integrated photonic light sources and optical interconnection with few-mode fiber and/or silicon-based waveguide.

Knowledge-Based Reasoning Network for Relation Detection.

With the rapid growth of large-scale knowledge bases (KBs), knowledge base question answering (KBQA) has attracted increasing attention recently. Relation detection plays an important role in the KBQA system, which finds a compatible answer by analyzing the semantics of questions and querying and reasoning with multiple KB triples. Significant progress has been made by deep neural networks. However, existing methods often concern on detecting single-hop relation without path reasoning, and a few of these methods exploit the multihop relation reasoning, which involves the answer reasoning from the noisy and abundant relational paths in the KB. Meanwhile, the relatedness between question and answer candidates has received little attention and remains unsolved. This article proposes a novel knowledge-based reasoning network (KRN) for relation detection, including both single-hop relation and multihop relation. To address the semantic gap problem in question-answer interaction, we first learn attentive question representations according to the influence of answer aspects. Then, we learn the single-hop relation sequence through different levels of abstraction and adopt the KB entity and structure information to denoise the multihop relation detection task. Finally, we adopt a Siamese network to measure the similarity between question representation and relation representation for both single-hop and multihop relation KBQA tasks. We conduct experiments on two well-known benchmarks, SimpleQuestions and WebQSP, and the results show the superiority of our approach over the state-of-the-art models for both single-hop and multihop relation detection. Our model also achieves a significant improvement over existing methods on KBQA end task. Further analysis demonstrates the robustness and the applicability of the proposed approach.

Hyaluronic acid-modified redox-sensitive hybrid nanocomplex loading with siRNA for non-small-cell lung carcinoma therapy.

A novel hyaluronic acid (HA)-modified hybrid nanocomplex HA-SeSe-COOH/siR-93C@PAMAM, which could efficiently deliver siRNA into tumor cells via a redox-mediated intracellular disassembly, was constructed for enhanced antitumor efficacy. Thereinto, siR-93C (siRNA) and positive PAMAM were firstly mixed into the electrostatic nano-intermediate, and then diselenide bond (-SeSe-)-modified HA was coved to shield excessive positive charges. This hybrid nanocomplex displayed uniform dynamic sizes, high stability, controlled zeta potential and narrow PDI distribution. Moreover, the -SeSe- linkage displayed GSH/ROS dual responsive properties, improving intracellular trafficking of siRNA. In vitro assays in A549 cell line presented that HA-SeSe-COOH/siR-93C@PAMAM has low cytotoxicity, rapid lysosomal escape and significant transfection efficiency; besides, an efficient proliferation inhibition ability and enhanced apoptosis. Furthermore, in animal studies, this negative-surfaced hybrid nanocomplex showed a prolonged circulation in blood and improved inhibition of tumor growth. All these results verified our hypothesis in this study that diselenide bonds-modified HA could promote not only stability and safety of nanoparticles in vivo but also intracellular behavior of siRNA via redox-dual sensitive properties; furthermore, this hybrid nanocomplex provided a visible potential approach for siRNA delivery in the antitumor field.

Charge reversal nano-systems for tumor therapy.

Surface charge of biological and medical nanocarriers has been demonstrated to play an important role in cellular uptake. Owing to the unique physicochemical properties, charge-reversal delivery strategy has rapidly developed as a promising approach for drug delivery application, especially for cancer treatment. Charge-reversal nanocarriers are neutral/negatively charged at physiological conditions while could be triggered to positively charged by specific stimuli (i.e., pH, redox, ROS, enzyme, light or temperature) to achieve the prolonged blood circulation and enhanced tumor cellular uptake, thus to potentiate the antitumor effects of delivered therapeutic agents. In this review, we comprehensively summarized the recent advances of charge-reversal nanocarriers, including: (i) the effect of surface charge on cellular uptake; (ii) charge-conversion mechanisms responding to several specific stimuli; (iii) relation between the chemical structure and charge reversal activity; and (iv) polymeric materials that are commonly applied in the charge-reversal delivery systems.

Silk fibroin double-layer microneedles for the encapsulation and controlled release of triptorelin.

A double-layer silk fibroin microneedles (SF-MNs) was proposed for the transdermal delivery of triptorelin. Two-step pouring and centrifugation were employed to prepare SF-MNs. Triptorelin was wrapped in MNs in the form of microcrystals with a size of ∼1 µm. ß-sheet nanocrystals (the secondary structure of silk fibroin) were adjusted in content by methanol-vapor treatment to manipulate the characteristics of SF-MNs prepared with two concentrations of silk fibroin. The mechanical strength of MNs was measured and analyzed in proportion to the ß-sheet content. The triptorelin in MNs could be released sustainedly in phosphate-buffered saline for 168 h, and the release amount decreased with increasing ß-sheet content. The Ritger-Peppas equation was employed to fit the release data. A linear decreasing relationship was observed between the diffusion coefficient and increased ß-sheet content. After administration to rats, SF-MNs exhibited long-term testosterone inhibition and maintained castration levels for ≥7 d. Manipulable mechanical properties and release behavior combined with biocompatibility and biodegradability render SF-MNs as viable long-term transdermal delivery devices for triptorelin.

Styrene-Acrylic Emulsion with "Transition Layer" for Damping Coating: Synthesis and Characterization.

In order to study the dynamic mechanical properties of styrene-acrylic latex with a core/shell structure, a variety of latexes were synthesized by semi-continuous seeded emulsion polymerization based on "particle design" with the same material. The latexes were characterized by rotary viscosimeter, dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), transmission electron microscope (TEM), dynamic mechanical analysis (DMA), and universal testing machine. The effects of difference at the glass transition temperature (Tg) of core and shell and the introduction of the "transition layer" on the damping and mechanical properties of latex film were studied. The results indicate that as the Tg of core and shell gets closer, the better the compatibility of core and shell, from phase separation to phase continuity. Furthermore, the introduction of the "transition layer" can effectively improve the tensile strength and tan δ (max) of the latex film. The tensile strength and maximum loss factor (f = 1 Hz) of latex with the "transition layer" increased by 36.73% and 29.11% respectively compared with the latex without the "transition layer". This work provides a reference for the design of emulsion for damping coating.

Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy.

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.

Raloxifene alleviates amyloid-ß-induced cytotoxicity in HT22 neuronal cells via inhibiting oligomeric and fibrillar species formation.

Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-ß (Aß) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aß42 aggregation and destabilizes preformed Aß42 fibrils through directly interacting with the N-terminus and middle domains of Aß42 peptides. Consequently, raloxifene not only reduces direct toxicity of Aß42 in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-ß induced by Aß42 peptides, and then alleviates microglia-mediated indirect toxicity of Aß42 to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.

Manipulating Polymer Donors Toward a High-Performance Polymer Acceptor Based On a Fused Perylenediimide Building Block With a Built-In Twisting Configuration.

A novel fused perylene diimide (PDI)-based polymer electron acceptor (PFPDI-BDF) with a built-in twisting configuration was constructed for application in all-polymer solar cells (all-PSCs). To shed light on the compatibility of the FPDI polymer acceptor and to identify a suitable polymer donor for device applications, we considered herein to investigate three polymer donors (PBDB-T, PTB7-Th, and PCPDTFBT) with different optical and electronic properties as well as polymer chain packing behavior for comparing the device performance. After being fabricated with PFPDI-BDF, polymer donor PBDB-T with a wide band gap showed a decent power conversion efficiency (PCE) of 4.86% with an open-circuit voltage (Voc) of 0.82 V, a short-circuit current density (Jsc) of 8.94 mA cm-2, and a recorded fill factor (FF) of 66.3%, which is one of the best FF reported for PDI-based all-polymer solar cells (all-PSCs). The enhanced efficiency of 6.05% was found in the medium band gap polymer PTB7-Th devices due to the more complementary absorption region that makes the photoactive blends absorb more photons, giving rise to an increased Jsc of 12.97 mA cm-2. On the other hand, due to the inferior exciton dissociation/extraction efficiency and unfavorable morphology compatibility, the narrow band gap polymer donor PCPDTFBT/PFPDI-BDF devices exhibited the worst PCE of only 0.71% with a low Jsc of 2.2 mA cm-2 and a FF of 42.4%.

EAPB: entropy-aware path-based metric for ontology quality.

BACKGROUND: Entropy has become increasingly popular in computer science and information theory because it can be used to measure the predictability and redundancy of knowledge bases, especially ontologies. However, current entropy applications that evaluate ontologies consider only single-point connectivity rather than path connectivity, and they assign equal weights to each entity and path. RESULTS: We propose an Entropy-Aware Path-Based (EAPB) metric for ontology quality by considering the path information between different vertices and textual information included in the path to calculate the connectivity path of the whole network and dynamic weights between different nodes. The information obtained from structure-based embedding and text-based embedding is multiplied by the connectivity matrix of the entropy computation. EAPB is analytically evaluated against the state-of-the-art criteria. We have performed empirical analysis on real-world medical ontologies and a synthetic ontology based on the following three aspects: ontology statistical information (data quantity), entropy evaluation (data quality), and a case study (ontology structure and text visualization). These aspects mutually demonstrate the reliability of the proposed metric. The experimental results show that the proposed EAPB can effectively evaluate ontologies, especially those in the medical informatics field. CONCLUSIONS: We leverage path information and textual information to enrich the network representational learning and aid in entropy computation. The analytics and assessments of semantic web can benefit from the structure information but also the text information. We believe that EAPB is helpful for managing ontology development and evaluation projects. Our results are reproducible and we will release the source code and ontology of this work after publication. (Source code and ontology: https://github.com/AnonymousResearcher1/ontologyEvaluate ).

An ontology-driven clinical decision support system (IDDAP) for infectious disease diagnosis and antibiotic prescription.

BACKGROUND: The available antibiotic decision-making systems were developed from a physician's perspective. However, because infectious diseases are common, many patients desire access to knowledge via a search engine. Although the use of antibiotics should, in principle, be subject to a doctor's advice, many patients take them without authorization, and some people cannot easily or rapidly consult a doctor. In such cases, a reliable antibiotic prescription support system is needed. METHODS AND RESULTS: This study describes the construction and optimization of the sensitivity and specificity of a decision support system named IDDAP, which is based on ontologies for infectious disease diagnosis and antibiotic therapy. The ontology for this system was constructed by collecting existing ontologies associated with infectious diseases, syndromes, bacteria and drugs into the ontology's hierarchical conceptual schema. First, IDDAP identifies a potential infectious disease based on a patient's self-described disease state. Then, the system searches for and proposes an appropriate antibiotic therapy specifically adapted to the patient based on factors such as the patient's body temperature, infection sites, symptoms/signs, complications, antibacterial spectrum, contraindications, drug-drug interactions between the proposed therapy and previously prescribed medication, and the route of therapy administration. The constructed domain ontology contains 1,267,004 classes, 7,608,725 axioms, and 1,266,993 members of "SubClassOf" that pertain to infectious diseases, bacteria, syndromes, anti-bacterial drugs and other relevant components. The system includes 507 infectious diseases and their therapy methods in combination with 332 different infection sites, 936 relevant symptoms of the digestive, reproductive, neurological and other systems, 371 types of complications, 838,407 types of bacteria, 341 types of antibiotics, 1504 pairs of reaction rates (antibacterial spectrum) between antibiotics and bacteria, 431 pairs of drug interaction relationships and 86 pairs of antibiotic-specific population contraindicated relationships. Compared with the existing infectious disease-relevant ontologies in the field of knowledge comprehension, this ontology is more complete. Analysis of IDDAP's performance in terms of classifiers based on receiver operating characteristic (ROC) curve results (89.91%) revealed IDDAP's advantages when combined with our ontology. CONCLUSIONS AND SIGNIFICANCE: This study attempted to bridge the patient/caregiver gap by building a sophisticated application that uses artificial intelligence and machine learning computational techniques to perform data-driven decision-making at the point of primary care. The first level of decision-making is conducted by the IDDAP and provides the patient with a first-line therapy. Patients can then make a subjective judgment, and if any questions arise, should consult a physician for subsequent decisions, particularly in complicated cases or in cases in which the necessary information is not yet available in the knowledge base.