This article reports a case study of a middle-aged patient diagnosed with Ketosis-Prone Diabetes (KPD) and diabetic ketoacidosis who had a mobile thrombus in the distal aortic arch with catastrophic complications from thrombus embolization. The pathogenesis of the mobile aortic thrombus is currently under investigation, with many risk factors having been found. Based on the patient's limited manifestation of atherosclerosis and the absence of any indications of thrombophilia, KPD and inflammation from uncontrolled hyperglycemia likely played a significant role in the formation of the thrombus. KPD is a subtype of diabetes characterized by the abrupt onset of severe hyperglycemia and ketoacidosis. The inflammation caused by uncontrolled hyperglycemia in KPD patients can lead to endothelial dysfunction and the activation of prothrombotic pathways. There is a lack of consensus regarding the optimal approach for managing a mobile aortic thrombus. The main strategies under consideration are conservative care, including anticoagulation alone, invasive removal of the thrombus, or endovascular intervention. A mobile aortic thrombus is an uncommon clinical phenomenon. Mobile thrombi are more frequently detected in the thoracic aorta and less commonly in the aortic arch. Increased use of imaging studies has led to better detection of this source of systemic embolization. The exact etiology and pathophysiology are unclear, but risk factors can be broadly categorized into vascular endothelial injury states, abnormal coagulation function disorders, malignancy, steroids, estrogen, and trauma . How to 2 presented to an outside hospital complaining of chest pain, acute onset severe abdominal pain, vomiting, and numbness of the left lower extremity. The patient's medical history was unremarkable except for dyslipidemia. Prior to admission, he was not taking any medications. He was transferred to our institution for emergent treatment of bilateral lower extremity acute limb ischemia, rhabdomyolysis, and acute renal failure. He was immediately taken to the operating room for a right popliteal and tibial artery embolectomy, right lower extremity four-compartment fasciotomies, left lower extremity iliac, femoral, and popliteal artery embolectomies and left lower extremity above the knee amputation under general anesthesia. An intraoperative transesophageal echocardiogram (TEE) showed a large, partially mobile echo density distal to the left subclavian artery. The echodensity measured approximately 2 cm x 1 cm  angiography, which showed a low-density filling defect in the aortic arch at the level of the ligamentum arteriosum consistent with a non-occlusive aortic arch thrombus and multiple distal emboli occluding the left and right internal iliac arteries Figure . The ascOn postoperative day 2, he was noted to have absent Doppler signals in his right lower extremity; an arterial duplex ultrasound showed evidence of outflow obstruction and no flow to the distal posterior and anterior tibial arteries. He was taken to the operating room for repeat embolectomy of the right lower extremity. The remainder of his hospital course required completing the left above-the-knee amputation and right lower extremity wound care. The metabolic derangements continued to improve, and his insulin requirements greatly decreased.An extensive thrombophilia workup was unremarkable, including antithrombin III levels, protein C and S, factor V Leiden mutation, prothrombin mutation, lupus anticoagulant, and antiphospholipid. In addition, the paroxysmal nocturnal hemoglobinuria assay, antineutrophilic cytoplasmic antibody (ANCA), JAK2 mutation analysis, and RPR (Rapid Plasma Reagin) for syphilis were also all negative. The patient's first episode of diabetic ketoacidosis was attributed to ketosis-prone diabetes, given his normal C-peptide levels and negative Beta-cell autoantibodies.A subsequent magnetic resonance imaging (MRI) two weeks after presentation showed no evidence of thrombus. He continued anticoagulation with heparin and transitioned to Aspirin and Apixaban before being discharged to a rehabilitation facility.The current case describes a middle-aged patient with a new diagnosis of KPD and diabetic ketoacidosis, who presented with a mobile thrombus of the distal aortic arch, manifested by aortoiliac thrombosis, needing above-the-knee amputation and revascularization. The cascade of prothrombotic events that ensued with uncontrolled hyperglycemia may have precipitated local thrombus formation in an aorta devoid of primary aortic disease, that is, without signs of aortic atherosclerosis, aneurysm, aortic dissection, or aortitis. The floating aortic thrombus was treated conservatively with systemic anticoagulation, and a full resolution was evidenced with appropriate imaging studies two weeks later.A floating aortic arch thrombus in a nonaneurysmal, minimally atherosclerotic, or normal aorta is currently regarded as a distinct clinical entity . It has KPD or Flatbush diabetes is a form of diabetes that usually presents with new-onset diabetes with provoked or unprovoked diabetic ketoacidosis (DKA). The classification of KPD is determined by the presence or absence of β-cell autoantibodies (A+ or A-) and β-cell functional reserve (β+ or β-), resulting in four distinct types. KPD is prevalent in African, African American, Asian, and Hispanic populations . A subseA floating aortic thrombus may be identified in individuals who exhibit symptoms following a serious embolic event. The patient's aortic thrombus was found after a computed tomography angiogram (CTA) and visualized again during the intraoperative transesophageal echocardiogram (TEE). TEE is the preferred ultrasound method for examining the thoracic aorta. It provides high-resolution images of the aortic arch, with one notable exception of a small segment of the distal ascending aorta near the innominate artery . Since tNo guidelines or consensus are reported in the literature on managing a mobile aortic thrombus. Available case series describe success with systemic anticoagulation therapy alone, thrombolytic treatment, minimally invasive endovascular stent graft, or surgical thrombus removal with or without graft replacement . Open thThe clinical presentation of KPD and diabetic ketoacidosis with a mobile aortic thrombus is rare. The association of these two distinct pathologies and their causes remains unclear. CTA and TEE play essential roles in diagnosing and evaluating primary aortic diseases. Combining the information from both imaging modalities allows for a more accurate diagnosis and treatment plan. Conservative management with anticoagulation is an acceptable initial approach. This allows for treating the underlying cause and stabilizing the thrombus, reducing the risks and morbidities associated with interventional procedures. However, no guidelines or consensus exist on managing mobile aortic thrombus. Further research is needed to fully understand these two conditions' complex pathogenesis and identify effective preventive measures.


We explored the use of needle-free injection (NFI) technology to deliver oncolytic viruses (OVs) for treating solid tumours. The study assesses the infectivity of OVs following NFI and compares the effectiveness of intratumoural administration of Vesicular Stomatitis Virus (VSV) to that of traditional needle injection (NI) in subcutaneous tumours in mice. NFI improves viral tissue distribution and preserves therapeutic activity of this virotherapy. The study establishes NFI as an efficient delivery method for OVs and underscores the need for further optimization to enhance therapeutic efficacy.Intratumoural delivery of oncolytic viruses (OVs) to solid tumours is currently performed via multiple percutaneous methods of needle injections (NI). In this study, we investigated the potential use of a novel delivery approach, needle-free injection (NFI), to administer OVs to subcutaneous tumours. The stability and genetic integrity of several RNA and DNA viruses exposed to high-pressure jet injectors were first evaluated in vitro. We demonstrate that replication competence and infectivity of the viruses remained unchanged after NFI, as compared to traditional NI. Using the oncolytic Vesicular Stomatitis Virus expressing luciferase (VSVΔ51-Luc) in the syngeneic CT26 subcutaneous tumour model, we show that NFI administration not only successfully delivers infectious particles but also increases the dissemination of the virus within the tumour tissues when compared to NI. Furthermore, mice treated with VSVΔ51-Luc by NFI delivery showed similar reduction in tumour growth and survival compared to those with needle-administered virus. These results indicate that NFI represents a novel approach to administer and potentially increase the spread of OVs within accessible solid tumours, highlighting its usefulness in virotherapy. Oncolytic viruses (OVs) represent a promising immunotherapeutic approach to cancer treatment. OVs selectively replicate in cancer cells while sparing normal cells . This seThe initial hurdles in achieving sufficient infection lie in the physical barriers and elevated interstitial pressure of solid tumours. These factors restrict the distribution of oncolytic viruses (OVs) and contribute to suboptimal deliveries, diminishing the spread of OVs within the tumour tissue. Consequently, this limitation hampers the overall therapeutic efficacy of the treatment . IntratuNeedle-free injection (NFI) technology is a method to deliver medications without the need of a needle or syringe. In NFI, the therapeutic agent is delivered via a high-pressure, narrow jet stream of liquid that penetrates the skin and reaches into subcutaneous or intramuscular layers. The original purpose of NFI technology was to provide a more user-friendly and pain-free alternative to needle injection systems. This technology is currently being used to deliver effectively a variety of therapeutic agents, including insulin, other hormones, antibiotics, and vaccines; it has been shown to induce potent immunogenicity in the case of the vaccines ,20,21,22In this study, we assessed the efficacy of first-generation NFI technology in delivering OVs to subcutaneous tumours. We first examined in vitro the replication competence of the oncolytic RNA viruses Vesicular Stomatitis Virus (VSVΔ51-GFP), Measles Virus (MeV-GFP) and Reovirus (ReoV), as well as the oncolytic DNA viruses Herpes Simplex Virus-1 (HSV1-GFP) and Vaccinia virus (VACV-GFP), when exposed to the high-pressure jet stream of needle-free injector system. All viruses subjected to NFI were found to infect and replicate to similar levels as compared to viruses delivered via traditional needle injection. We then investigated the intratumoural spread, as well as the effect on tumour growth and survival rate in vivo using a CT26 subcutaneous tumour- bearing mice administered VSVΔ51-Luc delivered either by NFI or NI. Improved luciferase expression, suggesting increased spread of virus, was detected in tumour tissues administered via NFI compared to that by NI. In addition, reduction in tumour growth and survival rate in mice treated with VSVΔ51-Luc delivered by NFI was found to be similar to those treated by NI. Overall, this study provides the first proof-of-principle for the use of NFI in delivering OVs, and our results demonstrate the potential of developing this delivery method for the treatment of solid tumours with OVs.2.Murine colorectal carcinoma cell line CT26, human HEK293T, murine L929 and African green monkey Vero cells were obtained from the American Type Culture Collection . These cells were cultured in Dulbecco’s Modified Eagle Medium   supplemented with 10% fetal bovine serum  and 0.1% penicillin and streptomycin  at 37 °C in 5% COg for 10 min, and the supernatants were collected. Viral supernatants were subjected to ultracentrifugation at 28,000× g for 90 min on a sucrose cushion layer , with the exception of VSVΔ51-Luc. VSVΔ51-Luc for use in animal studies was purified using a 10–40% opti-prep gradient as previously described /2 (ref). Animals were sacrificed either when an individual tumour reached 1500 mm3 or at an alternative humane endpoint. All animal procedures were conducted with approval from the University of Ottawa Animal Care Committee.When tumours reached palpable size, approximately 5 × 5 mm, they were injected intratumourally twice on day 1 and day 3 with VSV-Luc at 1 × 10We first conducted in vitro experiments to assess whether several clinically relevant OVs would be affected when subjected to high-pressure liquid jet injections as compared to needle injections A,B. MeV 8 PFU of VSVΔ51-Luc was administered intratumourally using a traditional needle or the needle-free jet injector system, and luciferase activity was measured 24 h post administration using IVIS (p < 0.0001) (p = 0.9375)  D,E. Nota 0.9375) F, sugges3, two intratumoural injections of 1 × 108 PFU of VSVΔ51-Luc were administered on day one and three to maximize the antitumour effect of this OV  . While in this model there was no significant difference in tumour volume and survival between the NI and NFI groups , these results confirm that NFI of OVs can provide a similar performance in terms of therapeutic outcome for the treatment of subcutaneous solid tumours.Given the promising effect of NFI on intratumoural spread of OV, we next tested whether this could translate into a better outcome in tumour volume reduction and survival. We repeated the subcutaneous CT26 tumour implantation model. When tumours reached 50–60 mm this OV A. As expctively) B,C. HoweThe usage of needle-free injection technology is gaining attention as a promising technique for the delivery of small therapeutic molecules like insulin . The useIntratumoural distribution and replication of different types of OVs plays a crucial role in stimulating effective antitumour immune responses . OV infeThis study was performed using a first-generation needle-free jet injector device designed for human administration of insulin into skin tissues. An important limitation of this study was that the injector’s pressure and size were not ideal for administration to mouse models of cancer, requiring careful handling for successful injections. Even though the device was not optimized for mouse cancer models, we observed improved viral distribution into the tumour tissues by NFI as compared to NI. Improved initial viral infection could ultimately promote better tumour growth control; however, in this model, two doses of VSVΔ51-Luc already provided strong cancer regression, rendering the observed increased viral spread less impactful on tumour reduction compared to NI. Nonetheless, our results suggest that optimization of the technology could achieve useful outcomes for intratumoural delivery of OVs. Other oncolytic viruses with limited therapeutic efficacy due to poor viral spread, and additional hard-to-treat cancer models, could ultimately exhibit elevated benefits from administration by NFI. One potential improvement could be achieved via altering the nozzle geometry to optimize diffusion of OV-containing liquid inside solid tumour . In addiNeedle-Free Injection technology represents an effective alternative delivery method for OVs to target accessible solid tumours. Overcoming the physical barriers of tumour microenvironments is a critical challenge for virotherapy, and this initial investigation demonstrates that NFI maintains the infectivity and therapeutic potential of OVs. In a subcutaneous mouse tumour model, NFI could even enhance the intratumoural distribution of virus, showcasing its promise as an efficient and convenient delivery method compared to traditional needle injections. While the study was performed using a first-generation device not originally designed for animal experiments, future optimization of this technology has the potential to improve the effectiveness and therapeutic distribution of OVs within tumour tissues, making it a promising route for the intratumoural administration of oncolytic virotherapies.


Polymer-based semiconductors and organic electronicsencapsulatea significant research thrust for informatics-driven materials development.However, device measurements are described by a complex array of designand parameter choices, many of which are sparsely reported. For example,the mobility of a polymer-based organic field-effect transistor (OFET)may vary by several orders of magnitude for a given polymer as a plethoraof parameters related to solution processing, interface design/surfacetreatment, thin-film deposition, postprocessing, and measurement settingshave a profound effect on the value of the final measurement. Incompletecontextual, experimental details hamper the availability of reusabledata applicable for data-driven optimization, modeling , and analysis of new organic devices. To curate organicdevice databases that contain reproducible and findable, accessible,interoperable, and reusable (FAIR) experimental data records, dataontologies that fully describe sample provenance and process historyare required. However, standards for generating such process ontologiesare not widely adopted for experimental materials domains. In thiswork, we design and implement an object–relational databasefor storing experimental records of OFETs. A data structure is generatedby drawing on an international standard for batch process control(ISA-88) to facilitate the design. We then mobilize these representativedata records, curated from the literature and laboratory experiments,to enable data-driven learning of process–structure–propertyrelationships. The work presented herein opens the door for the broaderadoption of data management practices and design standards for boththe organic electronics and the wider materials community. For example, data-driven techniques haverecently been leveraged to pursue targeted advances for thin-filmdevice applications including organic field-effect transistors (OFETs),8 organic light-emitting diodes (OLEDs),12 and organic photovoltaics (OPVs).17 Early successes include the application of self-driven laboratoryworkflows to screen quaternary OPV formulations at the full devicelevel.18 Indeed, these endeavors have positionedorganic electronics as a significant research thrust within the materialsinformatics community.The domain of conjugatedpolymer semiconductors is of keen interestto both the materials informatics and the organic electronics communitiesdue to the promising opportunities this class of materials offersfor large-area, printable, deformable electronic devices and energyapplications.19 and OCELOT,20 they mostly include computational data on smallmolecules. A recent effort in Deep4Chem mined over 1000 peer-reviewedarticles to build an experimental database of chromophores,21 but similar to prior efforts it largely targetselectronic structure–property measurements and is not inclusiveof process history. In extending database management effectively topolymer-based devices, providing data models that are inclusive ofexperimental processing information are priorities for storing accurateand reproducible records.Despite recent accomplishments, rationaldesign of organic electronicdevices, particularly those that are polymer based, still largelymaterializes through one-parameter-at-a-time, hypothesis-driven studiesdue to the limited availability of representative experimental data.The conjugated polymer materials domain is a research area with acompelling need for experimental data management solutions. Whilea few examples of shared data sets or databases that target organicelectronics research have been reported, such as the Harvard CleanEnergy Project–6–100 cm2/V·s)22 and polythiophene)] (DPP-DTT) (∼10–5–101 cm2/V·s).8 Thisperformance variation is attributed to not only batch-to-batch characteristicsof the polymer but also a plethora of parameters related to the polymer’sprocess history, starting with the solution state through the thin-filmdeposition process.24 Another source of variation isthat mobility values are derived from device measurements via modelfitting, and employing different methods/parameters  may affect the extracted mobilityvalue. Recording processing and measurement parameters provides indispensablecontextual value to organic device data, but nonetheless, recordingall of them efficiently is not straightforward. Additionally, sincethe design space is inherently dynamic due to the evolving natureof research, data models must be designed with flexibility in mindwithout sacrificing consistent vocabulary. Thus, generating a representativedata ontology describing the experimental device realm is a challengethat must be addressed to enable reliable database designs.25Experimental database design and managementfor polymer electronicshowever is nontrivial, especially when a plurality of the relevantattributes related to the provenance of the sample must be includedaccurately to form a robust, “reusable” data record.Data ontologies are not standardized in the organic electronics space:fully capturing all relevant experimental information is challenging,and organic device performance is highly sensitive to the many parametersassociated with the active layer deposition process. For example,the charge-carrier mobility (μ), a key figure of merit for OFETs,has been shown to vary significantly for poly(3-hexylthiophene) (P3HT)(∼1028 while the Community Resource for Innovation in Polymer Technology(CRIPT) proposes a framework to comprehensively describe polymer data,seeking to unify all aspects of sample provenance from synthesis,processing, characterization, properties, and instrumentation/citationmetadata.29 These active endeavors openthe door for a broader adoption of polymer-based data management solutions,but it is up to various communities to enable tailored data modelsfor their specific subdomains.30Though process representations are notnew problems for the sakeof curating materials databases, navigating these challenges for experimentalpolymer domains has only been explored recently by a minority of materialsdata researchers. The experimental database effort in MaterialsMinepromotes the inclusion of processing terms for polymer nanocomposites,31 Building a data repository that can handle the many nuancesof this complex design space is expected to provide a platform toenhance hypothesis design, scientific decision making, and model developmentwithin the traditionally “small data” space of the organicelectronics community.In this work, we used OFETs as a model system to propose an experimentaldata ontology associated with semiconducting polymer processing. Wethen produced a data structure that focuses on the deposition of theactive semiconducting polymer layer and leveraged it to implementan experimental repository relating the semiconducting polymer processhistory to device performance. To guide a robust representation ofthat process history, this work draws upon ISA-88, an internationalstandard for automation in batch process control, to construct generalizablerelationships across process transformations within the fabricationprocedure to create the semiconducting thin film.22.134 An overview of the majormaterials and process stages involved in depositing the semiconductingpolymer layer and a nonexhaustive set of their related parameters/attributesis presented in Defining the requiredinformation to capture is facilitated by published reporting standardsfor experimental OFET device data.35 Choices in the material characteristicsof the polymer  yield a range of structural and morphological motifsthat in turn significantly impact device performance.36 The identity of the solvent(s) used affects not only thepolymer–solvent interactions in the solution state but alsothe dynamics of the thin-film deposition process, thereby influencingthe structure and performance of the final active layer.37The primary material parameters describe the componentsof theactive semiconducting layer as well as any other materials  included in the processing procedure.The polymer and any other components are dissolved into a solutionthat is ultimately deposited onto the device substrate. As the behaviorof the polymer in the solution state is a key determinant of its thin-filmbehavior, all information associated with the solution makeup andits processing is especially crucial to capture for data provenancepurposes.7 and materialchoices  may influencedevice measurements,38 this design informationis important to include in a data entry to promote experimental reproducibility.32The OFET device substrate is a layereddevice structure, comprisingsubstrate, gate electrode, dielectric, and source/drain electrodes.The most common electrode configurations used in the organic electronicscommunity include (a) bottom-gate bottom-contact (BGBC), (b) bottom-gatetop-contact (BGTC), (c) top-gate bottom-contact (TGBC), and (d) top-gatetop-contact (TGTC). The electrode configuration is a necessary contextualdetail for reporting a device measurement, as substrate designs oftentake advantage of charge-carrier behavior at different interfaces.Additionally, as substrate design parameters 39 in a prescribed sequence to promote solution-stateaggregation,42 while the surface pretreatment procedure may include,for example, a cleaning process followed by a surface modification step via self-assembled monolayer(SAM).43 As an example, differences insolution aging times  can leadto noticeable structural changes that affect the final value of thedevice measurement in P3HT.45An emphasis of the work herein is thatprocessing information isindispensable for the purpose of storing reproducible device data.Seemingly minor differences in processing can lead to significantchanges in the recorded charge-carrier mobility of an OFET sample.Omitting information related to this process history will thereforelead to errors or inaccuracies when comparing device data across experiments.Even prior to deposition, the solution and device substrate undergoprocess transformations that can affect the deposited thin-film anddevice characteristics. Solution-based processes may include operationssuch as sonication, aging, poor solvent addition, cooling, etc.47 Meniscus-guided coating techniques, for example, yield a set ofdeposition regimes governed by a complex parameter space that includesflow conditions, coating speeds, stage temperatures, drying times,contact angles, etc.48 In combination withthe solution properties and surface interactions, coating conditionsare often chosen carefully to tune the morphology of the depositedthin film. Postprocessing operations may also be performed after thecoating stage, such as annealing49 or selectiveetching,50 to further control the thin-filmmorphology. Throughout all processing steps, the ambient environment may also playa role in the final properties.51The coating processcould be performed through a plethora of solution-castingmethods including drop casting, spin coating, blade coating, inkjetprinting, slot die coating, etc., that all have different physicalimpacts on thin-film morphology and therefore device performance,especially when coupled with solution pretreatment.52 orwhen different voltage ranges are chosen to obtain the fitted mobilityvalue.53 Guidelines on robust mobilityextraction protocols and measurement metadata reporting are relevanthere and are elaborated on in the literature.54Instrument settings are classified as attributes of the measurementrather than the fabrication process, but this metadata is importantas it contextualizes the reported value. Particularly, OFET performancemetrics can be nontrivial to represent because a charge-carrier mobilityvalue is not a measurement per se; it is a parameter value derivedfrom curve fitting of the actual measurement, a transfer curve sweep.Therefore, the measurement and fitting protocol used to extract thecharge-carrier mobility benchmark from the actual transfer curve isan important consideration. Unreported details about measurement regimes,voltage sweep range/direction, the measurement environment, etc.,can lead to misinterpretations about the provenance of device metricssuch as the mobility. In some cases, mobilities extracted from thesame device data can differ significantly when different extractionmethods are used , time-of-flight (ToF), etc.)2.255 At a high level, the entity–relationship diagram in The translationof the real-world parameter space and its relationship to a robustdata model requires definition and elaboration of an ontology. Wedirect the reader to introductory SQL and database literature to facilitateconceptual understanding of the database model enumerated below.N) relationshipwith measurement, since a single OFET could be measured a number oftimes by a variety of characterization methods not limited to deviceperformance. A measurement has a type  and the heterogeneous data  and metadata  associated with it. An experiment refers to thesource information associated with the reporting of the sample andtherefore has a citation type  and metadata associated with that source , date published, author information, etc.).Experiment and sample have a one-to-many relationship as a singleexperiment may report multiple samples. A process recipe refers tothe unique material ingredients and process sequence through whichthe sample was generated. The process recipe contains foreign keys that link information about thedevice substrate and the solution (the latter contains polymer andsolvent information) and to process stage nodes that subdivide theprocess history (vide infra). Metadata fields linked to the materialentities contain information such as polymer batch or lot information,supplier information, etc. These material nodes also serve as placeholdersto expand the data model to include more details on synthetic routes(for polymer) and/or device fabrication routes (for device substrate)in future database development. Sample and process recipe have a many-to-one(N–1) relationship as a given sample devicecan only be associated with one process recipe but the same processrecipe could be used for multiple samples.A sample refers to a single organic device in theform in whichall of its characterization data (a set of measurement objects) werecollected and contain explicit information associating it with itsreporting origin (experiment) and its physical origin/process history(process) 2. Sample2.344 The example above exemplifies a broader challengein robustly handling information in both dynamic and nuanced waysin sample recipes.Comparingdevice data reported from multiple sources requires that the variousnuances of the experimental design space are accurately representedin a robust data format. Particularly, understanding the sensitivityof the process space is non-negotiable for the sake of reproducibilityand accurate data representation. However, in contrast to the otherentities in 29 However, there is noestablished standard for defining the boundaries of a “process”for the sake of knowledge representation in materials data structures.We propose that incorporating a universal standard to help composeand arrange individual process stages would foster the adoption ofgeneralized data models that can be used to model a broad set of applicationdomains that are sensitive to complex processing histories.One avenue to formulate a data structureis to subdivide the sample generation process into a series of subprocessesthat appear in a consistent ordering for any given polymer activelayer in an OFET, model the relationships among a standard domainof entities within those subprocesses, and use the resulting graphto sort data. Recently, Walsh et al. proposed a generalized polymerdata structure in CRIPT, introducing a data format for process entitiesthat can be sequentially arranged to represent successive materialtransformations.31 ISA-88 is a standard that is used in batch process controlto organize the various pieces of data associated with a complex networkof instrumentation and process stages, wherein a batch process inputmaterial is fed to a defined order of processing actions  in series or in parallel to obtain some output material.Section 4.1 of ISA-88 defines a series of hierarchical subdivisionsthat are increasingly descriptive of an overall batch process. Ifthe first level of the hierarchy is the overall process, the processis subdivided at the second level as an ordered set of process stageswhich operate independently from each other, usually in a plannedsequence of physical changes in the material being processed. Processstages can be broken up into individual process operations, whichare defined as major activities that result in a chemical or physicalchange in the material inputs. At the lowest level of the processmodel, process actions represent the minor activities that make upa process operation. Within each level of complexity, entities area directed set of process subnodes organized in serial, parallel,or both.31Therefore, herein we adopt an international automation standardin ISA-88 to facilitate the conceptual modeling of the conjugatedpolymer deposition in a logical way 3a.31 ISAfixed stages and represent logical subdivisions that broadly describe the activelayer transformation of the input materials. The conjugated polymer process recipe is expandedto process stagesof substrate pretreatment, solution processing, film deposition, andpostprocessing at the second level of ISA-88 3b. TheseFurther expanding the process operations into individualprocessactions is possible but provides a level of complexity that may notbe required for sufficient database design, as the main purpose ofthe process model is to identify the most appropriate object classificationto store attributes. For example, a “sonication” nodemight be expanded to process actions such as “set sonicationtime” or “set sonication intensity”, but thisinformation can be just as easily represented by storing the attributes“sonication time” and “sonication intensity”in the parent process operation node 3c. Howev3Supporting Information) and unpublished laboratory data. The following section discussesthe initial construction and continued curation of experimental devicerecords into the database and provides a brief demonstration of utilizingthe database for meaningful searching and data visualization.The prior section proposes a general data structure and ontologyfor storing information related to the formation of the conjugatedpolymer active layer in a device such as an OFET. ISA-88’ssequenced process model also allows for process history to be effectivelycaptured in a data model as the conjugated polymer is transformedinto the final active layer of the measured device through a batchprocess. The process representation provides a high-level fixed structure to promote aspects of a consistent relational schema while providingflexibility for storing dynamic information within each of the stages.Using the data model described above, an experimental repository ofOFET device measurements was curated from a set of published, peer-reviewedliterature data naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5′-) (N2200). TheP3HT, DPP-DTT, and N2200 data were curated from a body of literaturecombining over 50 peer-reviewed journal articles reporting OFET deviceperformance containing a heterogeneous set of information includingprocess-related parameters and some structural characterization data.A subset of the database was also curated using unpublished recordsfrom laboratory experiments.The database was seededusing a set of experimental data sets for a set of three model polymersystems for electronic devices: P3HT, DPP-DTT, and poly and flexible storagefor unstructured information or data fields that may evolve with researchthrusts over time . A complete description of the DBMS table schema,based on the data model described earlier, is available in the Supporting Information.The database was constructed using PostgreSQL, an open-source, relationaldatabase management system primarily based on the structured querylanguage (SQL) that has strong support for NoSQL features. This allowedthe database to have the preferred functionalities of the relationalmodel  while allowing for storage flexibility where attributes maybe dynamic.3.326 process and material keywords from CRIPT,56 etc.) but largely uses custom keywords thatprovide more specificity to descriptors relevant to the organic devicefabrication domain . A fulllist of terms is available in the Supporting Information for the database implementation version described herein. Futuredesign efforts will employ updated terminologies from shared communityresources when available, as shared vocabularies promote consistentdescriptions and interoperability. An experimental data entry templatethat incorporates this controlled vocabulary has also been adaptedfrom a similar template shared by MaterialsMine.27 This template not only is intended to reduce the timeand inconvenience that is inevitable for an experimentalist or domainexpert to fill out a data record for database entry but provides atool to reduce the error checking and validation workload on the backend. Future template versions could be implemented as user-friendlywebforms, a web application, or directly coupled to electronic laboratorynotebooks or integrated laboratory instrumentation to facilitate theprocess of database inserts for newly curated experimental records.Thediversity of categorical or text descriptors in the OFET parameterspace requires the use of a consistent vocabulary of keywords to guidethe naming of attributes and free-text fields. Naming errors can inpart be mitigated through built-in DBMS functionalities but may persist,especially in JSON formats, due to flexible key-value naming. At thetime of writing, the implementation of OFET-db uses some keywordsborrowed from other large-scale materials database efforts , where devices made from a higher PDIpolymer are more likely to have mobilities in the upper range of thedata set.r = 0.79) but remain uncorrelated for DPP-DTT (0.03) andN2200 (0.23)  1. PDI maThe data model implemented herein also provides theflexibilityto index information from structural measurements , which enhances the ability tointerrogate process–structure–property relations. Thepopulation of structural measurements is much smaller than the numberof device measurements, but here, we show that structural informationis available and representative.d spacing extracted from available GIWAXS data.Most notably, d spacing, indicating that the lamellarspacing tends to decrease with an increasing conjugated backbone lengthfor DPP-DTT. A corresponding negative correlation between d spacing and mobility suggests that this change in lamellarspacing is a potential indicator for improved charge transport characteristicsin the thin film, as decreased lamellar spacing could facilitate chargehopping.59 Though this distance is merelyone factor characterizing the crystalline domain, this observationdraws interest in considering further parameters  to study the impacton device performance. As the data reported here is relatively sparse,with only 31 of the DPP-DTT device samples registering associatedGIWAXS data, more meaningful structure–property observationscould potentially be extracted when a richer set of structural datais recorded. Nonetheless, we demonstrate the utility of using ourpreliminary body of populated data to inform future work toward aricher experimental repository and greater physical understanding.Such observations can suggest new hypotheses that can then be testedwith additional experiments.For example, Supporting Information) to show the subset of data extractedfrom the database in 38 that compares the OFET mobility of devices depositedonto substrates sequentially pretreated with either of three pairsof silanes: methyltrichlorosilane (MTS) and octadecyltrichlorosilane(OTS-18), OTS-18 and phenyltrichlorosilane (PTS), and octyltrichlorosilane(OTS-8) and OTS-18. For all three of the pairings, noticeable differencesin performance were observed depending on whether OTS-18 treatmentwas performed before or after the other silane agent.We expect that future data-driven studies thatuse OFET-db as aresource will benefit from representative storage of process history,as materials characteristics alone often provide insufficient informationfor fully understanding the experimental sensitivity of device performance.To that end, with our proposed process ontology we aim to enable thecuration of experimental data with the associated process historyof samples with the future intention of providing advanced analysesbased on process recipes. A preliminary demonstration of the abilityto curate, select, and plot process sequenced data is presented brieflyherein. We used a query that searched for devices deposited on substratestreated by more than one surface modification agent  in fully describing deviceperformance as such processes will affect the relationship betweensolution-state and thin-film assembly and therefore the final deviceproperties. A major challenge, however, is that drawing device comparisonsacross different authors based on a standard recipe  would require more data since the processspace is very large.4Herein, we demonstratethe design and implementation of a datamodel for the experimental domain of OFETs as a foundation for broadlyenabling database curation and management for organic thin-film electronics.Specifically, capturing process history in a manner that conformsto standard data protocols was a key challenge that was addressedby employing ISA-88, a batch process data model. Then, a databasewas constructed based on the model using PostgreSQL, enabling storagecapabilities for both SQL (structured data) and NoSQL (document-baseddata) to provide flexibility without sacrificing the advantages ofdata redundancy/normalization in the relational model. While the workand discussion presented provides an experimental database that appliesto the OFET active layer, it also serves as a model for adaptationto other aspects of organic device experiments by designing the datastructure around an accepted process standard. Moving forward, enhancingmaterials ontologies to comprehensively capture classifications ofprocess steps would facilitate the future design of data models inother domains that accurately manifest the real-world experimentalprocesses. This is a necessary pursuit in elucidating the format inwhich a sample’s provenance is recorded within a database inFAIR data structures. Additionally, future work will build upon thepreliminary body of curated experimental data to mobilize data-drivenexperimentation for polymer-based organic electronics.


The quality and yield of pork are significantly affected by the development and growth of porcine skeletal muscle. To identify the genetic factors that underlie this biological process, we initiated a study focusing on transposable elements (TEs). Due to their capacity of self-replication and relocation within the host genome, TEs play an important role in shaping the genome regulatory landscape. By utilizing extensive transcriptomic data spanning 27 developmental stages of porcine skeletal muscle, we created a comprehensive atlas of TE expression, revealing the intricate relationship between active TEs and epigenetic modifications. Through gene co-expression network analysis and the integration of multi-omics data, we uncovered a TE-mediated genetic regulatory network governing the development and growth of skeletal muscle. This research not only identifies valuable candidate genes for the genetic improvement of the economic traits of pork but also introduces an innovative TE-centric approach for dissecting the genetic factors contributing to complex traits.The development and growth of porcine skeletal muscle determine pork quality and yield. While genetic regulation of porcine skeletal muscle development has been extensively studied using various omics data, the role of transposable elements (TEs) in this context has been less explored. To bridge this gap, we constructed a comprehensive atlas of TE expression throughout the developmental stages of porcine skeletal muscle. This was achieved by integrating porcine TE genomic coordinates with whole-transcriptome RNA-Seq data from 27 developmental stages. We discovered that in pig skeletal muscle, active Tes are closely associated with active epigenomic marks, including low levels of DNA methylation, high levels of chromatin accessibility, and active histone modifications. Moreover, these TEs include 6074 self-expressed TEs that are significantly enriched in terms of muscle cell development and myofibril assembly. Using the TE expression data, we conducted a weighted gene co-expression network analysis (WGCNA) and identified a module that is significantly associated with muscle tissue development as well as genome-wide association studies (GWAS) of the signals of pig meat and carcass traits. Within this module, we constructed a TE-mediated gene regulatory network by adopting a unique multi-omics integration approach. This network highlighted several established candidate genes associated with muscle-relevant traits, including HES6, CHRNG, ACTC1, CHRND, MAMSTR, and PER2, as well as novel genes like ENSSSCG00000005518, ENSSSCG00000033601, and PIEZO2. These novel genes hold promise for regulating muscle-related traits in pigs. In summary, our research not only enhances the TE-centered dissection of the genetic basis underlying pork production traits, but also offers a general approach for constructing TE-mediated regulatory networks to study complex traits or diseases. The pig holds a crucial place in agriculture, serving as a primary protein source for humans. Over a long period of geographical isolation and differences in domestication selection, Eastern and Western pig populations have developed significant variations in various economically important traits. For example, Western pigs typically exhibit higher growth rates and superior meat production performance, while Eastern pigs show a stronger tolerance to roughage, slower growth rates, and a higher fat content ,2. PriorIt is well established that the development and growth of skeletal muscle, which comprises a significant portion of a pig’s body, are closely linked to economic traits that are relevant to meat production. Therefore, since the advent of genetic breeding, deciphering the genetic regulatory mechanisms governing porcine skeletal muscle development and growth has been of significant importance in accelerating the improvement of pork production traits. In the past decade, the application of GWAS analysis has led to the identification of numerous single nucleotide polymorphisms (SNPs) that are associated with pig meat production traits. For instance, Zhou and colleagues conducted a meta-analysis of GWAS in Duroc pig populations, pinpointing SNPs that are associated with average daily gain (ADG) and lean meat percentage (LMP) . Gao andSkeletal muscle development and growth consist of two sequential phases: myofiber formation before birth and myofiber hypertrophy after birth ,13. The TEs are repetitive DNA sequences that are capable of replicating and relocating within a host genome. With the advancements in sequencing technologies, research on TEs has broadened, revealing that their distribution in the genome is far from random ,26. It iIn this study, we employed a widely utilized TE quantification tool, SQuIRE , to accuThe RNA-seq data for Landrace skeletal muscle (longissimus dorsi) used in this study were sourced from our prior publication (SRP158448) , with thWe downloaded the reference genome sequence for pigs (susScr11.fa) from the UCSC database  for TE aA dynamic heatmap of expressed TEs across the 27 examined developmental stages was generated using the R package Complexheatmap (v2.6.2) . The priWe performed weighted gene co-expression analysis on the expression matrix of 6074 self-expressed TEs across the 27 examined stages of skeletal muscle development using the R package WGCNA (v1.69) to uncover their key modules in muscle development. The analysis comprised the following main steps: Firstly, we used the pickSoftThreshold function to determine the best soft threshold  for constructing the gene co-expression network. Next, we divided genes into different co-expression modules using the topological overlap matrix (TOM) dissimilarity as the clustering distance measure to capture co-expression relationships between genes. To better understand the organizational structure of the modules, we utilized the plotDendroAndColors function to generate a module clustering dendrogram and assigned different color labels to different modules to visually display their distribution and composition. Finally, we determined the final modules using the blockwiseModules function with the parameters minModuleSize = 30, TOMType = “unsigned”, pamRespectsDendro = FALSE, and mergeCutHeight = 0.25. To explore the correlation between the modules and the regulation of muscle development growth stages, following previous research, we divided muscle development into four states based on the physiological characteristics of skeletal muscle at different stages: primary myofiber formation, second myofiber formation, myofiber type transition, and the fattening phase. We calculated the correlation between different modules and these states using the cor function.A functional enrichment analysis of the modules was conducted by extracting nearby genes of TEs within the modules using the clusterProfiler package. The GWAS data for the pig were analyzed—related traits used in this study were collected from the animal QTLdb database . Within p-value (p.adj) of <0.05 and a correlation coefficient (Rs) of ≥0.3 were defined as being positively regulated by TE, while genes with p.adj < 0.05 and Rs < −0.3 were defined as being negatively regulated by TE. Through this coordinated change in correlation, we identified TE–gene pairs. Furthermore, we employed the exportNetworkToCytoscape function from the WGCNA package, combined with a threshold of 0.2, to filter reliable TE–TE interaction pairs within modules, thereby creating an initial TE–TE–gene regulatory network. Finally, by overlapping Meat and Carcass GWAS-associated loci extended by 20 kb with TEs, we filtered out regulatory relationships between TE and GWAS loci, resulting in the formation of the ultimate hub TE–TE–gene regulatory network governing muscle development. Visualization of the hub TE–TE–gene regulatory network was performed using Cytoscape software (v3.10.1) [The identification of TE target genes was conducted by utilizing the bedtools’ closest plugin to extract genes located upstream and downstream of TEs. Subsequently, we analyzed the correlation between TE and adjacent gene expression levels across 27 developmental stages using the psych package’s corr.test function (v2.2.5) with the parameter method = “spearman” and adjust = “fdr”. Genes with an adjusted v3.10.1) , and nodv3.10.1) .In our study, we examined the expression profiles of TEs in porcine skeletal muscles across 27 distinct developmental phases, spanning from embryonic to adult stages, by using SQuIRE software (v0.9.9.9a-beta). To our knowledge, this marks the creation of the first-ever dynamic expression atlas illustrating the behavior of TEs during porcine muscle development. Notably, this atlas is the most comprehensive TE expression atlas, offering a more thorough coverage of developmental timepoints than any other TE expression atlas across all known species.Across these 27 different developmental stages, we successfully identified a total of 39,640 expressed TEs. Notably, the number of expressed TEs in porcine muscle tissue during the embryonic stage was higher than that observed after birth a. Among To investigate the similarity of TE and gene expression patterns across different developmental stages of skeletal muscle, we conducted sample PCA clustering analyses across the 27 time points. Two PCA plots were generated, one based on the expressed genes and the other on TEs b. We fouTo gain a deeper understanding of the molecular characteristics of TE expression in porcine skeletal muscle, we carried out a comprehensive analysis of the expressed TEs. Firstly, within these expressed TEs, we identified the presence of four primary TE classes: LINE, SINE, LTR, and DNA. Notably, in comparison to the nonexpressed TEs, the expressed TEs exhibited an enrichment of SINE and DNA classes a. SubseqEpigenetic modifications play a pivotal role in regulating TE transcriptional activity. Hence, we investigated the relationship between various epigenetic signals and TE transcription in porcine skeletal muscle. First, we explored the relationship between TE expression levels and methylation modifications. We categorized TEs into levels of high, middle, and low based on their expression at each stage. During the majority of the developmental stages, our analysis unveiled a distinct inverse correlation between TE transcriptional activity and methylation levels. Notably, this trend became more prominent following birth c.In addition, we collected ATAC, H3K27ac, and H3K4me3 peak signal data from porcine skeletal muscle and compared the enrichment patterns of expressed and nonexpressed TEs in these three epigenetic signals. To our surprise, we observed a significant enrichment of expressed TEs in regions with active epigenetic signals d. This sThe identification of a substantial number of expressed TEs located within genes poses a challenge: discerning whether a TE-mapping RNA-Seq read originates from a gene promoter or a TE promoter . FollowiAn impressive discovery was that at each developmental stage, the expression levels of self-expressed TEs were consistently higher than those of gene-dependent TEs b. SubseqTo study the interactions of self-expressed TEs in regulating skeletal muscle development, we employed a weighted gene co-expression strategy on the expression matrix (FPKM) of these TEs across the 27 examined developmental stages. As illustrated in Furthermore, we investigated the genetic contributions of these modules to muscle-related traits. Specifically, we conducted an enrichment analysis of self-expressed TEs within the five modules in GWAS signals of meat and carcass traits in pigs. As expected, the results demonstrated that only TEs within the turquoise module exhibited significant enrichment in meat and carcass traits e, suggesTo identify critical transcription factors acting on the turquoise module, we performed motif enrichment analysis on the self-expressed TEs within the module. As a control, we randomly selected an equivalent number of TEs from other self-expressed TEs to serve as a reference for the transcription factor enrichment analysis. Our results showed that the TEs within the turquoise module displayed significant and specific enrichment for well-known regulators of skeletal muscle development, including MYOD  and TCF1The genetic regulatory mechanisms underlying complex traits or diseases often involve multilevel molecular regulations ,57. We aHere, we further refined TE target genes by evaluating the expression between TEs and their neighboring genes across 27 developmental stages. In the end, we identified 2194 TE–gene pairs with a positive regulatory relationship and 427 TE–gene pairs with a negative regulatory relationship a. ImportWGCNA analysis is frequently used in studying gene–gene interactions. Using this approach, we also identified TE–TE pairs within the turquoise module that possess strong and robust interactive capabilities. Subsequently, by incorporating TE–gene pairs, we established an initial TE–TE–gene regulatory network that elucidates interactions among TEs and reveals the mechanisms through which TEs exert their influence on phenotypes via gene regulation. By comparing it with the GWAS signals of five major economical traits in pigs, we found that the TE–TE–gene regulatory network exhibited specific enrichment in meat and carcass traits c, therebLastly, we refined the hub TE–TE-gene network by incorporating meat and carcass GWAS signals. Briefly, a TE was considered as a hub if it had SNPs that were within ±20 kb of meat- and carcass-associated SNPs d. The raIn summary, our work not only included the construction of a TE–TE–gene network that sheds light on the cis- and trans-regulatory factors implicated in skeletal muscle, but also presents a novel approach to prioritizing critical TEs and genes underlying the formation of complex economic traits.The pig, a significant domesticated animal, represents a rich source of protein for human consumption through pork. To enhance the quality and yield of pork through genetic improvement, previous research has leveraged diverse multi-omics strategies to deepen our understanding of the genetic regulatory mechanisms underlying skeletal muscle development ,20,22. NThe quality of our TE expression atlas is supported by several observations and by previous research. For example, within the expressed TEs that we identified, the proportion of gene-dependent TEs was significantly higher than that of self-expressed TEs. However, self-expressed TEs demonstrated a stronger potential for regulating muscle tissue development. These findings align with Chang’s discoveries in zebrafish, where it was found that approximately two-thirds of TE transcripts might be driven by nearby gene promoters, and self-expressed TEs exhibited tightly regulated expression patterns during zebrafish embryonic development .Additionally, we uncovered a negative correlation between TE methylation levels and their expression, aligning with prior research indicating that DNA methylation can inhibit transposon expression and mobility ,66,67. MA noteworthy highlight of this study is our innovative approach to constructing gene regulatory networks. We chose a TE-centric approach due to the significantly higher transcription signals of self-expressed TEs observed in muscle tissue and the notable enrichment of these TEs in functions that are relevant to muscle biology. As the genetic regulation of complex traits involves a multilevel molecular process, we extended the network by first applying WGCNA to construct an initial TE–TE–gene regulatory network. This network encompasses regulatory modules that are highly relevant to skeletal muscle development and enriched in GWAS signals of meat and carcass traits. Subsequently, the hub components of the network were identified by overlapping TEs containing SNPs that are highly linked to the GWAS signals. The rationale for this approach is to utilize naturally occurring DNA variants as a form of perturbation experiment, establishing the connection between cis-regulatory elements and phenotypes. Taken together, this integration of population genetics data and functional genomics data greatly enhances our ability to leverage TEs in unraveling the genetic mechanisms that underlie muscle-related traits.In the TE–TE–gene network, we pinpointed numerous genes that have previously demonstrated close associations with muscle-related traits. Notable examples include HES6, a known regulator of myogenic differentiation ,69; CHRNOne limitation of our study is the reliance on expression correlations to construct targeted regulatory relationships within the regulatory network. Previous studies have reported that the neighboring genes of TEs are their potential target genes ,70, and To our knowledge, this is the first ever establishment of a dynamic expression landscape of TEs during the development of pig skeletal muscles. It unveiled the distribution of transcriptionally active TEs within the genome and their associations with epigenetic modifications. Furthermore, we pioneered the innovative construction of a gene regulatory network centered on TEs, identifying potential genes that are closely implicated in the regulation of skeletal muscle development. In summary, our research not only provides vital candidate targets for enhancing pork production traits but also offers a general method for dissecting the genetic basis of complex traits.


Non-invasive ventilation application in neurocritical care with risk of pneumocephalus is controversial. Non-invasive ventilation-related increased intrathoracic pressure increases intracranial pressure via direct transmission of intrathoracic pressure to the intracranial cavity. In addition, increased thoracic pressure decreases venous return to the heart and increases vena jugularis interna pressure, thereby increasing cerebral blood volume. 2 as manifested by a larger increase in PaO2/FiO2 ratio and provide the theoretical basis in pneumocephalus because augmenting the PaO2 more effectively would accelerate nitrogen (N2) washout.Pneumocephalus is one of the major concerns after non-invasive ventilation application in head/brain trauma patients. Non-invasive mechanical ventilation may be performed in limited conditions in head trauma/brain surgery with appropriate and close monitoring. High-flow nasal cannula oxygen therapy can provide higher FiOAs a result, non-invasive mechanical ventilation may be performed in limited manner in head trauma/ brain surgery with appropriate and close monitoring. Non-invasive mechanical ventilation may be used in head trauma/brain surgery with dural injury in limited conditions with appropriate and close monitoring. Patients under treatment with continue positive airway pressure and bi-level positive airway pressure may develop pneumocephalus. High-flow nasal oxygen therapy may be a choice in head trauma/brain surgery patients.1 Non-invasive ventilation (NIV) may provide optimum respiratory support to patients thus avoiding the complications of invasive mechanical ventilation including barotrauma (pneumothorax), volutrauma, biotrauma, ventilator-associated pneumonia and sinusitis, delirium, decreased cardiac output, fluid retention, pulmonary emboli and deep venous thrombosis.3 Recently, NIV has been suggested as a treatment option in patients with trauma, acute respiratory insufficiency and in the early stage of “Acute Respiratory Distress Syndrome” (ARDS).4 However, the NIV application in these conditions is still a matter of discussion in the scientific literature.5Mechanical ventilation is an artificial positive pressure support for respiration to assist breathing in case of respiratory failure (either hypercapnic or hypoxemic). It reduces the patient’s work of breathing by overcoming excessive imposed loads  with subsequent improvements of oxygenation and carbon dioxide elimination.6 Air moves into the cranium via a fistula which acts as a 1-way valve. A decreased cerebrospinal fluid-related decreased intracranial pressure supports air bubbles wiggling through the cranium. Also, increased thoracic pressure decreases venous return to the heart and increases vena jugularis interna pressure, thereby increasing cerebral blood volume.7After an initial cranial defect, air can move into the brain through a paranasal sinüs or the mastoid cells, which can be aggravated by swallowing, coughing or sneezing under a pressure greater than that within the cranium.8 The main goal in managing head trauma/brain surgery patients must be to protect the patient from secondary damage, primarily cerebral ischaemia of the primary injury. Secondary damage occurs due to hypoxia, hypercapnia, hypotension, hypoglycaemia and hyperpyrexia, especially in head/brain trauma patients. Therefore, management of head trauma/brain surgery patients is targeted at optimising cerebral perfusion, oxygenation, and avoiding hypoxia and hypercapnia.9It is important to consider the mechanism and extension of injury when deciding to administer NIV in trauma patients. For example, head, neck and middle face traumas are unsuitable for administration of NIV. Furthermore, high consciousness levels and integrity of the upper airways should be ensured in such cases.The aim of this narrative review is to emphasise the aspects of NIV treatment which may not be reviewed in the literature in this controversial use of NIV in head injury. 2 above 11 kPa) and hypercapnia  and to avoid intubation.11 Before considering NIV on such patients, it is necessary to determine whether the patient’s upper airway is compromised or not. It must be kept in mind that NIV [continue positive airway pressure (CPAP) and bi-level positive airway pressure (BIPAP)] application to prevent respiratory failure may cause pneumocephalus (PNC) which indicates the presence of air in the intracranial cavity.12In patients with head trauma/brain surgery who are conscious in the perioperative period, NIV can be applied to prevent hypoxia  who underwent trans-sphenoidal resection. At the end of 2 weeks, PNC developed in the patient. Chee BNH et al14 performed CPAP in the post-operative period because of OSA in patients with ventriculo-peritoneal shunting after trauma and surgery. Continue positive airway pressure application was discontinued due to developing rhinorrhoea in these patients, and the defect was surgically closed afterwards.Kopelovich et al14If there is a pathology in the area close to the air inlet during NIV application or if the operation is performed in these areas , post-operative NIV applications should be carefully monitored. Non-invasive ventilation applications can be performed more safely after 6 weeks of dural repair.15 reported their findings on the use of CPAP in a morbidly obese patient with OSA who underwent an awake craniotomy. They stated that the patient who was under sedation with dexmedetomidine remained comfortable and cooperative during the operation. Lee et al16 applied CPAP during the perioperative period with a mask under deep sedation to patients with severe chronic obstructive pulmonary disease (COPD) undergoing frontal craniotomy. This procedure is called “awake operation” which does not require a deep sedation. They reported that this application was very effective and that intraoperative NIV administration prevented the development of hypoxemia and hypercarbia. They did not observe any post-operative complications. In another study, patients with OSA under CPAP treatment were divided into 2 groups after trans-sphenoidal pituitary resection.17 One group received CPAP in the post-operative period, while the other group did not, and there were no differences between the 2 groups in terms of post-operative complications.In 2008, Huncke et al18 The Canadian Critical Care Trials Group and the Canadian Critical Care Society Non-invasive Ventilation guidelines do not recommend NIV application in similar cases due to insufficient findings and controversies.19In the British Thoracic Society guidelines, NIV application in multi-trauma patients with hypoxemic respiratory failure is recommended and rated as C-level and had low-grade evidence.13A pressure of around 15 cmH2O applied to the upper airways by a NIV treatment which is close to the intracranial pressure makes no difference. In the absence of a previous injury, this level of pressure is unlikely to have any effect on air intake into the CNS. However, air can enter the intracranial compartments directly through the fractures of the cranial bones and sinuses as a result of trauma and the defect created by a penetrating body. In such a case, the positive pressure effect of NIV will facilitate air entry through the existing defect. It has been shown that positive pressure applied to the upper airways, even for a short time, can cause pneumocephalus in patients with previous sphenoid sinus bone rupture.Continue positive airway pressure can increase intrathoracic pressure resulting in a decrease in venous return and cardiac output. A decreased venous return may result in an increase in intracranial pressure and together with a decreased cardiac output following an undesirable negative effect on cerebral blood flow that may arise. Non-invasive ventilation treatment in patients with head trauma/brain surgery who require mechanical respiratory support should exclude patients with a reported or suspected fractures of the skull of cranial bones and sinuses, dural defects or fistulas. 20 The administration of nasal high-flow oxygen therapy, another form of non-invasive ventilatory support, may help respiratory mechanics by improving ventilation and increasing oxygenation. It provides nasal respiratory support with optimally heated and humidified oxygen at high-flow rates (up to 60 L per minute).21 In high-flow applications, tidal volume is increased and end-tidal expiratory lung volumes have been shown to improve oxygenation. Moreover, it decreases respiratory rate proportionally to the delivered flow rate.22 High-flow nasal cannula (HFNC) oxygen therapy can provide higher FiO2 as manifested by a larger increase in PaO2/FiO2 ratio and provide the theoretical basis for using HFNC oxygen therapy in PNC because augmenting the PaO2 more effectively would accelerate N2 washout. Based on a previous mathematical model of the rate of PNC absorption, HFNC oxygen therapy can theoretically outperform other conventional oxygen therapy devices such as non-rebreather mask (NRB).26 However, it has also been reported that it does not affect atelectasis compared to standard oxygenation. However, it prevents the closure of airways and prevents dead space ventilation. This delivers high mean airway pressure. Thus, the work of breathing during HFNC therapy is reduced.27 There may be improved intracranial compliance. Pneumocephalus has not been reported in any head trauma/brain surgery patient who has applied for HFNC oxygen therapy.When compensatory mechanisms such as hypoxic pulmonary vasoconstriction become insufficient, pulmonary and extra-pulmonary damage can potentially lead to increased morbidity and mortality.28 applied high-flow intranasal oxygen to a patient with OSA who underwent awake craniotomy. Oxygen and carbon dioxide partial pressure levels remained normal under deep sedation. The patient and the surgeon were highly satisfied. No complications were observed in the post-operative period.Wong et al29 presented 3 cases of post-operative PNC who were symptomatic. All patients improved both clinically and radiographically within a few hours with the administration of HFNC oxygen therapy, faster than in both anecdotal experience and published trials due to its steady FiO2 administration, positive pressure, comfort and low side-effect profile. Additionally, HFNC oxygen therapy may be the ideal mode of oxygen delivery in cases of post-operative PNC. Siegel et al30 there are no reports of oxygen toxicity with the use of HFNC. Otherwise, there are no guidelines regarding contra-indications of HFNC oxygen therapy, but considerations should be taken as with other modes of positive pressure NIV .31Though the concept of pulmonary oxygen toxicity has been well described,35 Nevertheless, it needs to be considered, as early diagnosis and appropriate treatment can modify prognosis. There is no sufficient data about HFNC safety of use in head trauma/brain surgery and further research is needed to evaluate its safety and effectiveness and the frequency of serious adverse events. The resulting knowledge should be used to develop clear guidelines and protocols for the use of HFNC oxygen therapy in such situations.On the other hand, tension PNC with severe neurological sequelae was a rare complication in HFNC in paediatric population receiving respiratory support with HFNC oxygen therapy.As a result, NIV can be applied in conscious and cooperative patients without head and neck trauma, deformed bone and soft tissue damage in the face. In these patients, NIV administration is not recommended in the guidelines as reflected by a “low-grade recommendation” for the use of NIV in trauma patients by the British Thoracic Society guidelines and “no recommendation” by Canadian Critical Care Trials Group/Canadian Critical Care Society NIV Guidelines Group because there is still much disagreement on this issue. Patients undergoing NIV should be monitored strictly because PNC may develop. In recent years, nasal high-flow oxygen application is encouraged in head trauma/brain surgery patients with no complications observed in the post-operative period. Further prospective, randomised, clinical studies are needed on this topic.Non-invasive mechanical ventilation may be performed in limited conditions in head trauma/brain surgery with dural injury with appropriate and close monitoring. During NIV application in patients with head trauma/brain surgery, a close serial neurologic examination based on consciousness and changes in exam should be done in addition to haemodynamic, and respiratory monitoring should be performed. There are many reported cases of PNC developing in patients with CPAP and BIPAP treatment. High-flow nasal oxygen therapy may be a choice in head trauma/brain surgery patients. Further prospective, clinical, randomised controlled trials are needed in this subject.


Staphylococcus aureus (MSSA) bacteremia with mitral and aortic endocarditis. Progressive PR prolongation prompted re-evaluation, ultimately finding the progression of a new aortic abscess, changing the patient’s care pathway. With a standardized approach of obtaining regular ECGs in patients with aortic endocarditis, it is possible to identify the progression of aortic valve endocarditis, thereby lowering the risk of morbidity and mortality.Regular electrocardiogram (ECG) monitoring in patients with endocarditis of the aortic region is a simple yet effective approach to help evaluate for the development of aortic abscess. It is important to recognize this condition as it carries a high morbidity and mortality. We report a case of a 62-year-old Caucasian female diagnosed with methicillin-sensitive  Infective endocarditis is the inflammation and infection of the endocardium most often involving valvular structures. Predisposing risk factors include congenital heart defects, valve replacements, intravenous drug use, intra-cardiac devices, central line placements, immunosuppression, and recent dental or surgical procedures. The incidence is roughly 15 people per 100,000 people . It is aStaphylococcus aureus (MSSA) bacteremia from a dialysis catheter infection.A 62-year-old female with a past medical history of hypertension, end-stage renal disease on hemodialysis through an internal jugular tunneled dialysis catheter, and ovarian cancer presented with weakness and lethargy. She was having persistent fevers to 102°F, no leukocytosis but a C-reactive protein (CRP) of 386 mg/L. She was found to have methicillin-sensitive She had acute embolic infarcts in her spleen and brain. She subsequently had intracerebral hemorrhage due to hemorrhagic conversion of her cerebral infarcts. A large mobile superior vena cava vegetation was noted on imaging likely due to her hemodialysis line that was subsequently replaced. In the setting of persistent MSSA bacteremia and septic emboli, she underwent transthoracic and transesophageal echocardiographic  evaluation demonstrating mitral and aortic valve endocarditis with competent valves and without abscess formation or perforation. She was treated with IV antibiotics on presentation. The patient continued to remain persistently bacteremic and febrile to 102°F despite antibiotics prompting surgical evaluation.Given the hemorrhagic conversion of the cerebral infarcts, surgery was felt too high risk, and initial conservative management followed by planned surgery a few weeks later was felt the safest course of action. Despite the improvement of fever, the decline in CRP to 128 mg/L, and normal white cell count, serial ECGs obtained during the hospitalization showed PR interval prolongation from 132 ms to 178 ms (Figures This prolongation of PR interval prompted a repeat TEE, 11 days after the initial TEE. This showed the development of a new aortic abscess demonstrating the failure of antibiotics and the need for urgent surgery Figures , 4. The Infective endocarditis of aortic and prosthetic valves is most commonly associated with perivalvar infections, such as abscesses and fistulas . PeriannThe ability to identify endocarditis complications through regular ECGs with subsequent echocardiogram evaluation is underused in clinical practice and serves as an incredible tool to help identify complications such as aortic abscess. Monitoring the ECG is recommended for PR interval prolongation or the development of arrhythmias, which are indicators of endocarditis complications. If implemented in regular practice with prompt surgical intervention, the morbidity and mortality of such conditions would likely be improved.


Enterobacter strains are part of the human intestinal commensal microflora and important pathogens of hospital-acquired infections,such as bacteremia, lower respiratory tract infections, and urinary tract infections.In an era of increasing antibiotic resistance, bacteriophage therapy is one way to combat bacterial pathogens considering its unique merits,such as self-replicating, self-limiting, safe, and highly specific.Enterobacter were used to screen phages. Biological characteristics of all isolated phages were analyzed including host range determination with a panel of 50 Enterobacter strains and planktonic bacterial lysis assay of the host cells.All phages were subjected to genome sequencing.Bacteriophages were isolated from water samples collected from Jinjiang River in Chengdu, PR China and sewage water from a hospital of the same city.Twenty carbapenem-resistant clinical isolates represent common species of Straboviridae(n=17). Two phages are respectively members of Autographiviridae(n=1) and Casjensviridae(n=1) as novel genera.Four phages could not be matched into any known classification.Most phages could lyse multiple isolates of genus Enterobacter as well as one isolate of genus Huaxiibacter.Twenty-three lytic bacteriophages were isolated and most of which belong to three families,The determination of lytic activity in vitro revealed that most phages are able to Inhibit bacterial growth for 4-24 hours.taxonomic information of bacteriophages against EnterobacterPartial lytic profiles of bacteriophages against EnterobacterPlanktonic cell lysis curveEnterobacter-targeting phages has a wide lysis spectrum and some phages were significantly inhibited for an extended period of more than 24 hours.These results indicate the potential value of bacteriophages against Enterobacter infection in clinical treatment.All Authors: No reported disclosures


It has been hypothesized that abnormal microcirculation in the retina might predict the risk of ischemic damages in the brain. Direct comparison between the retinal and the cerebral microcirculation using similar animal preparation and under similar experimental conditions would help test this hypothesis.We investigated capillary red-blood-cell (RBC) flux changes under controlled conditions and bilateral-carotid-artery-stenosis (BCAS)-induced hypoperfusion, and then compared them with our previous measurements performed in the brain.We measured capillary RBC flux in mouse retina with two-photon microscopy using a fluorescence-labeled RBC-passage approach. Key physiological parameters were monitored during experiments to ensure stable physiology.We found that under the controlled conditions, capillary RBC flux in the retina was much higher than in the brain , and that BCAS induced a much larger decrease in capillary RBC flux in the retina than in the brain.We demonstrated a two-photon microscopy-based technique to efficiently measure capillary RBC flux in the retina. Since cerebral subcortical white matter often exhibits early pathological developments due to global hypoperfusion, our results suggest that retinal microcirculation may be utilized as an early marker of brain diseases involving global hypoperfusion. Many ischemic and neurodegenerative conditions that affect the brain may have manifestations in the retina.–,–As the retinal and cerebral vasculatures share similar anatomical and physiological characteristics, it was hypothesized that the retinal microvascular imaging markers could be utilized to predict the emergence and development of cerebrovascular diseases.,As reported, retinal microvascular alterations were linked with cerebral small vessel disease and cognitive decline. For example, retinal microvascular morphological changes, such as smaller arteriolar diameter and fractal dimension, larger venular diameter, and increased arteriolar tortuosity, are associated with the presence of multiple cerebral microbleeds in human patients—a marker for cerebral small vessel disease.In this study, we applied two-photon fluorescence microscopy to investigate the retinal capillary red-blood-cell (RBC) flux changes due to chronic hypoperfusion in the mouse model of bilateral-carotid-artery-stenosis (BCAS). Our results showed that BCAS significantly decreased the retinal capillary RBC flux. Interestingly, the BCAS-induced reduction of capillary RBC flux in the retina was significantly larger than those in the cortical gray matter (GM) and subcortical WM as reported in our previous work.22.1We used All surgical and experimental procedures were approved by the Massachusetts General Hospital Institutional Animal Care and Use Committee (IACUC) in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.2.2,We employed a home-built two-photon microscope in this work.2.3To image the RBC passages, we labeled the blood plasma with a redshifted fluorophore – Alexa680  angiography-based method features a fast and label-free detection of microvascular blood flow, but it only provides a qualitative estimation instead of the absolute measurement of capillary flow parameters, hindering its application when comparing across subjects.,,The retina, as the embryological projection of forebrain,,,–,We further found that in the control mice, capillary RBC flux in the retina  and GM (6.4%), of which the measurements were also performed 7 days post BCAS.–,–,Several limitations exist in this work. First, isoflurane-anesthesia-induced variation of systemic physiology between animals would be confounding factor to the measurements. Since key physiological parameters (e.g., MABP, in vivo measurements of capillary RBC flux in mouse retina using two-photon microscopic imaging of fluorescence-labeled RBC passages. This method is easily adopted with a standard two-photon microscope and features a high sampling efficiency. We found that retina exhibited a higher capillary RBC flux under normal physiological conditions but was much more vulnerable to global hypoperfusion, as compared with the cerebral cortical GM and subcortical WM. This finding suggests that assessment of the retinal microcirculation has potential as an early diagnostic marker of ischemic conditions in the brain. Further studies are necessary to better understand the link between retinal and cerebral hypoperfusion. Moreover, application of clinical and research imaging methods for assessment of retinal capillary perfusion, such as OCT angiography and AO retinal imaging, may potentially provide information about cerebral hypoperfusion in humans.In conclusion, we demonstrated a method for


The success of cephalometric analysis depends on the accurate detection of cephalometric landmarks on scanned lateral cephalograms. However, manual cephalometric analysis is time-consuming and can cause inter- and intra-observer variability. The purpose of this study was to automatically detect cephalometric landmarks on scanned lateral cephalograms with low contrast and resolution using an attention-based stacked regression network (Ceph-Net).The main body of Ceph-Net compromised stacked fully convolutional networks (FCN) which progressively refined the detection of cephalometric landmarks on each FCN. By embedding dual attention and multi-path convolution modules in Ceph-Net, the network learned local and global context and semantic relationships between cephalometric landmarks. Additionally, the intermediate deep supervision in each FCN further boosted the training stability and the detection performance of cephalometric landmarks.Ceph-Net showed a superior detection performance in mean radial error and successful detection rate, including accuracy improvements in cephalometric landmark detection located in low-contrast soft tissues compared with other detection networks. Moreover, Ceph-Net presented superior detection performance on the test dataset split by age from 8 to 16 years old.Ceph-Net demonstrated an automatic and superior detection of cephalometric landmarks by successfully learning local and global context and semantic relationships between cephalometric landmarks in scanned lateral cephalograms with low contrast and resolutions. A lateral cephalogram is widely used to analyze face and jaw growth and development to establish malocclusion diagnosis and plan orthodontic treatment such as braces or surgery. This can also provide information regarding the positions of the teeth, face, and jaw to monitor and plan orthodontic treatment . ChildreAn essential step in orthodontic treatment planning is cephalometric analysis in a lateral cephalogram, which provides quantitative information regarding the relationship between the dental and skeletal aspects of the human skull according to cephalometric landmarks , 3. The Analog cephalometric radiographs of poor quality can appear worse on screen and can lead to greater errors in digital technology . FurtherFor many years, analog and scanned radiographs were the standard in the medical field. Recently, advances in digital technologies have transformed the field of radiography, making it possible to obtain high-quality digital radiographs that can be used to diagnose and treat a wide range of medical conditions , 11. DigAutomatic landmark detection on scanned lateral cephalograms from children and adolescents remains challenging due to three major reasons. First, there are morphological variations in anatomy and growth among different children and adolescents, which lead to significant variations in anatomical landmarks . These mIn recent years, deep learning-based methods for cephalometric landmark detection outperformed other conventional image processing and machine-learning approaches , 16–18. The purpose of this study was to automatically detect cephalometric landmarks on scanned lateral cephalograms with low contrast and resolution using an attention-based stacked regression network (Ceph-Net). Ceph-Net was an end-to-end encoder-decoder architecture, which tied three two-dimensional (2D) FCNs including multi-scale inputs (MSI), a dual attention module (DSAM), a multi-path convolution module (MCM), and deep supervision. Ceph-Net was evaluated on a test dataset which consists of 400 scanned lateral cephalograms obtained over 8 years from 50 patients aged 8 to 16 except for 12 years old. We compared the detection performance of Ceph-Net with those of popular detection networks including U-Net , SegNet In this study, a total of 1286 scanned lateral cephalograms were used from 267 patients  who underwent lateral cephalography  for oral health status and diagnosis of oral diseases between 1995 and 2003. In 267 patients followed for 8 years, 502 images were intermittently obtained from 169 patients, while 784 images were obtained annually from 98 patients, one each year. Ethical approval (S-D20210028) for this study was obtained from the research ethics committee of Seoul National University, School of Dentistry, which waived the requirement for informed consent from all participants due to the nature of the retrospective study. All experiments were conducted in accordance with the approved guidelines.An experienced oral and maxillofacial radiologist manually annotated 19 cephalometric landmarks on a scanned lateral cephalogram using Labelbox . As shown in Fig. x and y coordinates of the cephalometric landmark  x and y coordinates of the cephalometric landmark i is the range of 1 to 19. The We adopted a heatmap-based landmark detection method that transfers cephalometric landmark coordinates into a 2D Gaussian heatmap . A set omentclass2pt{minimIn this study, the entire process of our proposed method was divided into five procedures Fig. . The firSoftmax activation function.In this study, we proposed an attention-based stacked regression network named Ceph-Net that directly regressed a 2D heatmap from an input image for cephalometric landmark detection. As shown in Fig. In automatic landmark detection tasks, landmarks require different semantics due to variations in the shape and size of anatomical structures among patients. Attention mechanisms in deep learning were inspired by the human visual cognition system, which could encourage deep networks to more focus on the relevant areas and ignore the background by weighting to different areas in an image , 34, 35.The SAM captures long-range spatial relationships in original feature maps. To extract the spatial attention map, the original feature map We used popular detection networks including U-Net , SegNet For network training, we employed CEL to measure the difference between the true probability distribution and the predicted probability distribution . CEL is –4, which decreased by a factor of 0.5 when the validation loss stopped decreasing for 25 epochs. A batch size of 8 and a single GPU with 24 GB RAM were used. All detection networks were implemented in Python3 using the Keras framework with the TensorFlow backend. The data augmentation procedure consisted of geometry and intensity transformation including random rotation (− 10–10 degrees), zoom (0.95–1.05), and intensity changes (− 50%–50%).The detection networks were trained using the RMSprop optimizer for 100 epochs with an initial learning rate of 10Ceph-Net was evaluated on a test dataset which consisted of 400 scanned lateral cephalograms obtained over 8 years from 50 patients aged 8 to 16 except for 12 years old. The detection performance for the 19 cephalometric landmarks was evaluated using the mean radial error (MRE) and the successful detection rate (SDR) . To extrSeven standard clinical measurements for classifications , 38–40 oThe landmark detection performance of Ceph-Net was compared with those of popular detection networks such as U-Net , SegNet entclass1pt{minimaWe also illustrated several representative examples of landmark detection results from Ceph-Net and popular detection networks. The results in Fig. From the ablation study in Table Given the detected cephalometric landmarks, the scanned lateral cephalograms were classified into seven anatomical types in each clinical measurement. The main reason for detecting cephalometric landmarks in the orthodontic treatment field is the classification of anatomical types and the evaluation of dentofacial growth and development, diagnosis of skeletal and dental anomalies, treatment planning, and treatment outcome assessment. Seven clinical measurements including ANB, SNB, SNA, ODI, ADPI, FHI, and FMA were considered. In clinical measurements, a scanned lateral cephalogram can be categorized into three anatomical types using different geometrical criteria such as angle or distance between specific cephalometric landmarks. For the classification of the anatomical types, the geometrical criteria for the seven clinical measurements are described in Table In orthodontics and maxillofacial surgery, cephalometric analysis is essential for accurate and reliable treatment planning and diagnosis. Cephalometric landmarks identify specific points on a scanned lateral cephalogram of the head, which is used as reference points for cephalometric analysis. The major challenges for cephalometric landmark detection are image quality and superimposed bilateral structures, which affect the reliability of landmark identification , 31. TheUnlike digital lateral cephalograms, however, scanned lateral cephalograms have low image qualities with low contrast and resolutions, which causes inter- and intra-observer variability in cephalometric landmark identification . MoreoveWe compared the detection performance of Ceph-Net with those of other popular detection networks such as U-Net, SegNet, Dense U-Net, and Attention U-Net. Ceph-Net achieved superior detection performance with lower MRE and higher SDR than the popular detection networks Table . Our metCeph-Net outperformed other detection networks in the classification results of anatomical types Table . Since tCompared with existing methods for cephalometric landmark detection , 23–25, Some cephalometric landmarks such as the porion, gonion, posterior nasal spine, and articulare are more challenging than the other landmarks . We alsoThe proposed method has several limitations. First, we only collected datasets of scanned lateral cephalograms from children and adolescents aged 8–16 years old to train detection networks. Therefore, when our method is extended to digital lateral cephalograms that are not used as training datasets, it is difficult to guarantee consistent detection performance of cephalometric landmarks. Second, Ceph-Net could have a potential limitation in generalizability when applied to external datasets because it was only evaluated using internal datasets. In future studies, we will improve the generalizability and clinical efficacy of Ceph-Net using large scanned and digital lateral cephalogram datasets acquired from both children and adults under various imaging conditions from multi-centers or devices. Further evaluation of linear distance measurements between cephalometric landmarks will be performed for applications in clinical practice such as analyzing the growth pattern. In addition, we plan to evaluate our methods using public datasets to ensure fairness and accuracy . We expeIn this study, we proposed Ceph-Net for the automatic detection of cephalometric landmarks on scanned lateral cephalograms with low contrast and resolutions. Ceph-Net was designed to learn different semantics of anatomical structures among patients and long-range relationships between cephalometric landmarks by embedding our proposed modules in an end-to-end manner. The experimental results showed the Ceph-Net outperformed the popular detection networks for the detection and analysis of cephalometric landmarks. Therefore, Ceph-Net demonstrated the automatic detection and analysis of cephalometric landmarks by successfully learning local and global context and semantic relationships between cephalometric landmarks in scanned lateral cephalograms with low contrast and resolutions. Ceph-Net could provide clinicians with automatic cephalometric analysis in a scanned lateral cephalogram while reducing manual annotation time and analysis effort.