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BACKGROUND: Tumorous diseases of the jaw demand effective treatments, often involving continuity resection of the jaw. Reconstruction via microvascular bone flaps, like deep circumflex iliac artery flaps (DCIA), is standard. Computer aided planning (CAD) enhances accuracy in reconstruction using patient-specific CT images to create three-dimensional (3D) models. Data on the accuracy of CAD-planned DCIA flaps is scarce. Moreover, the data on accuracy should be combined with data on the exact positioning of the implants for well-fitting dental prosthetics. This study focuses on CAD-planned DCIA flaps accuracy and proper positioning for prosthetic rehabilitation. METHODS: Patients post-mandible resection with CAD-planned DCIA flap reconstruction were evaluated. Postoperative radiograph-derived 3D models were aligned with 3D models from the CAD plans for osteotomy position, angle, and flap volume comparison. To evaluate the DCIA flap's suitability for prosthetic dental rehabilitation, a plane was created in the support zone and crestal in the middle of the DCIA flap. The lower jaw was rotated to close the mouth and the distance between the two planes was measured. RESULTS: 20 patients (12 males, 8 females) were included. Mean defect size was 73.28 ± 4.87 mm; 11 L defects, 9 LC defects. Planned vs. actual DCIA transplant volume difference was 3.814 ± 3.856 cm³ (p = 0.2223). The deviation from the planned angle was significantly larger at the dorsal osteotomy than at the ventral (p = 0.035). Linear differences between the planned DCIA transplant and the actual DCIA transplant were 1.294 ± 1.197 mm for the ventral osteotomy and 2.680 ± 3.449 mm for the dorsal (p = 0.1078). The difference between the dental axis and the middle of the DCIA transplant ranged from 0.2 mm to 14.8 mm. The mean lateral difference was 2.695 ± 3.667 mm in the region of the first premolar. CONCLUSION: The CAD-planned DCIA flap is a solution for reconstructing the mandible. CAD planning results in an accurate reconstruction enabling dental implant placement and dental prosthetics.

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BACKGROUND CONTEXT: Pedicle screw breach (PSB) is not uncommon following lumbar instrumentation, and in some instances, it may lead to vascular and/or neurologic complications. Previous literature suggested that screws crossing the vertebral midline on an anterior-posterior (AP) radiograph (or midsagittal on CT) are concerning for medial pedicle breach. OBJECTIVE: Our primary aim was to map out the safe zones (SZ) of bilateral pedicle instrumentation and their relationship at each lumbar vertebral level. Our secondary aim was to evaluate the presence of SZs' intersection at each lumbar level, denoting safe midline pedicle screw crossing not otherwise associated with medial pedicle breach. STUDY DESIGN/SETTING: Retrospective Anatomical Study. PATIENT SAMPLE: Adult patients in the from "The Cancer Imaging Archive" (TCIA) database who have not had thoraco-lumbo-sacral fusion. OUTCOME MEASURES: Physiologic measures obtained through 3D analysis of CT images and virtual pedicle screws. METHOD: CT scans of 51 patients were randomly selected from "The Cancer Imaging Archive" (TCIA) online database for analysis. The Sectra 3D Spine software was used to create 3D renderings, place virtual screws, and make measurements. At each lumbar vertebra, the right and left pedicle corridors were mapped. At each pedicle, two screw positions were templated, the "medial limit screw" (MLS) and the "lateral limit screw" (LLS). Each limit screw was the most extreme position that the screw could exist in without causing a medial or lateral breach. The safe zone was defined as the zone between MLS and LLS. Measurements were taken for each level (between L1 and L5) and side (Left, Right). RESULTS: A total of 253 lumbar vertebrae from 51 patients (mean age 53.1, 56.9% male) were included. Two vertebrae from two patients were removed for poor image quality. Out of the 506 screw positions analyzed in our study, 97.4% had overlapping SZ and crossed the midplane without medial pedicle breach. The significant factors (p<.01) for safe midplane-crossing screws included: the screw length (L1-L5); the laterality of the screw entry point (L1-L4); and the pedicle diameter (L2 and L5). CONCLUSIONS: A midline crossing pedicle screw on a lumbar AP radiograph is not necessarily indicative of a medial pedicle screw breach. Anatomical (ie, larger pedicle diameter) and technical (ie, longer screws, and lateral entry points) factors allow for safety zone intersections and indicate safe midline crossing by pedicle screws.

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Statistical Shape Models (SSMs) and Sparse Prediction Models (SPMs) based on regressions between cephalometric measurements were compared against standard practice in virtual surgery planning for reconstruction of mandibular defects. Emphasis was placed on the ability of the models to reproduce clinically relevant metrics. CT scans of 50 men and 50 women were collected and split into training and testing datasets according to an 80:20 ratio. The scans were segmented, and anatomical landmarks were identified. SPMs were constructed based on direct regressions between measurements derived from the anatomical landmarks. SSMs were developed by establishing correspondence between the segmented meshes, performing alignment, and principal component analysis. Anterior and bilateral defects were simulated by removing sections of the mandibles in the testing set. Measurement errors after reconstruction ranged from 1.07˚ to 2.2˚ and 0.66 mm to 2.02 mm for mirroring, from 0.45˚ to 3.67˚ and 0.66 mm to 2.54 mm for the SSMs, and from 1.74˚ to 5.01˚ and 0.64 mm to 2.89 mm for the SPMs. Surface-to-surface errors ranged from 1.01 mm to 1.29 mm and 1.06 mm to 1.33 mm for mirroring and SSMs, respectively. Based on the results, SSMs are recommended for VSP in the absence of normal patient anatomy.

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This meta-analysis was conducted to systematically evaluate the short-term efficacy and safety of the three-dimensional (3D) reconstruction visualization technology (3D-RVT) technique for hepatectomy. A systematic literature search was used to gather information on the 3D reconstruction visualization technology technique for hepatectomy from retrospective cohort studies and comparative studies. The retrieval period was up to March 2022. Publications and conference papers in English were manually searched and references in bibliographies traced. After evaluating the quality of selected studies, a meta-analysis was conducted using Review Manager 5.1 software. We included 12 studies comprising 2053 patients with liver disease. Our meta-results showed that 3D-RVT significantly shortened operation times [weighted mean differences (WMD) = -29.36; 95% confidence interval (CI): -55.20 to -3.51; P = 0.03], reduced intraoperative bleeding [WMD = -93.53; 95% CI: -152.32 to -34.73; P = 0.002], reduced blood transfusion volume [WMD = -66.06; 95% CI: -109.13 to -22.99; P = 0.003], and shortened hospital stays [WMD = -1.90; 95% CI: -3.05 to -0.74; P = 0.001]. Additionally, the technique reduced the use of hepatic inflow occlusion and avoided overall postoperative complications [odds ratio (OR) = 0.60; 95% CI: 0.46 to 0.79; P < 0.001]. 3D-RVT is safe and effective for liver surgery and provides safety assessments before anatomical hepatectomy.

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Nowadays, techniques and the use of patient specific implants seem to be the recent high technology standard in reconstructive surgery. Surgery planning is as old as the surgery procedures themselves. Any good surgeon, before entering the operating theatre, has a plan for how to proceed. It is based on knowledge and experience in combination of evaluation of all case relevant information. In fact, virtual surgery planning and CAD/CAM reflects the technological "state of the art" into the medical daily practice. Recently, 3D printing technologies became easy and accessible for everyone. Virtual 3D images substituted the plaster models, the film profile analysis switched to digital, 3D printed bone models of the case helped to understand the morphology of the deformity and prepare the osteotomies with "hands on the bone". The authors' own 20 years of experience on surgical planning, the development of digital technologies in oral and maxillofacial surgery is traced and comments on case examples are presented.

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Segmental Le Fort I surgery is an effective technique to correct complicated dentomaxillofacial deformities. This retrospective study evaluated the accuracy of segmental Le Fort I surgery under the guidance of virtual surgical planning (VSP). A total of 129 patients who accepted segmental Le Fort I surgery were investigated in this study. VSP was transferred to segmental surgery with different pieces precisely with the aid of 3D-printed surgical templates and splints. The surgical result was evaluated by postoperative complications, color distance maps, and quantitative accuracy analysis. Outcomes showed that the VSP was successfully transferred to actual surgery with high accuracy. The overall mean linear difference was 1.28 mm, and the overall mean angular difference was 2.4°. Except for one case of root injury, there was no serious complication recorded. The results suggested that VSP was a reliable assistance for segmental Le Fort I surgery.

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We aimed to produce a narrative review of planning orthognathic surgery, chronologically. Also, to present flaws of methods and the future of orthognathic surgery planning. The search was carried out mainly in PubMed, SCOPUS, Embase, and Cochrane databases. Also was complemented by manual search in reference lists from identified studies and in grey literature. The first orthognathic surgery was reported in 1849, and it took more than a century for the development of the traditional orthognathic 2D planning. Besides the advances, surgeons observed failures and lacks on 2D method in representing with reliability the facial and maxillary tridimensional structure (3D). With technological developments in 90s and 2000s, methodological improvements were granted, and the 3D protocol was created. The CASS and Charlotte protocols were the earliest 3D planning protocols conceived. Since then, some steps were simplified, and new technologies are being developed and added to create a more reliable and precise way of planning orthognathic surgery.

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We aimed to evaluate whether there is a consensus among bi- (2D) and three-dimensional (3D) evaluations of mandible condyle position and its rotation center. Also, if this data can be replicated in orthognathic surgery planning. The survey was carried out on the major databases (PubMed, SCOPUS, Embase, Cochrane). Human or human bio models evaluations in 2D or 3D of mandibular condylar position concerning its fossa and rotational axis for orthognathic surgery planning were eligible. The heterogeneity of the studies and uncertainties in methodological biases did not allow us to identify the superiority of 2D or 3D methodology in determination of the condylar rotational axis. There is a lot of divergences in the definition of occlusal relationships among dental specialties. Although there was no consensus regarding condylar position in relation to the fossa, the most reported axis of rotation was positioned posterior-inferior. Weak scientific evidence and divergences in dental vocabulary shows the need for clinical studies with more accurate and transparent methodological design to standardize concepts. Despite we cannot affirm, we can suggest that the centric relation (CR) is not the condylar position when clinically manipulated in the posterior superior direction. This condylar position is the retruded contact position (RCt) while CR is the functional position of the condyle. In this way, the orthognathic surgery has two occlusal relationships during planning and execution. The ideal axis of rotation for orthognathic surgery planning must be fixed, permit individualization for each condyle and be reproducible. The 2D planning is obsolete as cannot provide all the necessary tools for an accurate planning.

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PURPOSE: Surgery for nasal airway obstruction (NAO) has a high failure rate, with up to 50% of patients reporting persistent symptoms postoperatively. Virtual surgery planning has the potential to improve surgical outcomes, but current manual methods are too labor-intensive to be adopted on a large scale. This manuscript introduces an automatic atlas-based approach for performing virtual septoplasties. METHODS: A cohort of 47 healthy subjects and 26 NAO patients was investigated. An atlas of healthy nasal geometry was constructed. The automatic virtual septoplasty method consists of a multi-stage registration approach to fit the atlas to a target NAO patient, automatically segment the patient's septum and airway, and deform the patient image to have a non-deviated septum. RESULTS: Our automatic virtual septoplasty method straightened the septum successfully in 18 out of 26 NAO patients (69% of cases). In these cases, the ratio of the higher to the lower airspace cross-sectional areas in the left and right nasal cavities improved from 1.47 ± 0.45 to 1.16 ± 0.33 in the region surrounding the septal deviation, showing that the nasal airway became more symmetric after virtual septoplasty. CONCLUSION: This automated virtual septoplasty technique has the potential to greatly reduce the effort required to perform computational fluid dynamics (CFD) analysis of nasal airflow for NAO surgical planning. Future studies are needed to investigate if virtual surgery planning using this method is predictive of subjective symptoms in NAO patients after septoplasty.

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Virtual surgery planning is a non-invasive procedure, which uses digital clinical data for diagnostic, procedure selection and treatment planning purposes, including the forecast of potential outcomes. The technique begins with 3D data acquisition, using various methods, which may or may not utilize ionizing radiation, such as 3D stereophotogrammetry, 3D cone-beam CT scans, etc. Regardless of the imaging technique selected, landmark selection, whether it is manual or automated, is the key to transforming clinical data into objects that can be interrogated in virtual space. As a prerequisite, the data require alignment and correspondence such that pre- and post-operative configurations can be compared in real and statistical shape space. In addition, these data permit predictive modeling, using either model-based, data-based or hybrid modeling. These approaches provide perspectives for the development of customized surgical procedures and medical devices with accuracy, precision and intelligence. Therefore, this review briefly summarizes the current state of virtual surgery planning.

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OBJECTIVE: To examine the accuracy of computer-aided intraoperative navigation (Ci-Navi) in bimaxillary orthognathic surgery by comparing preoperative planning and postoperative outcome. METHODS: The study comprised 45 patients with congenital dentomaxillofacial deformities who were scheduled to undergo bimaxillary orthognathic surgery. Virtual bimaxillary orthognathic surgery was simulated using Mimics software. Intraoperatively, a Le Fort I osteotomy of the maxilla was performed using osteotomy guide plates. After the Le Fort I osteotomy and bilateral sagittal split ramus osteotomy of the mandible, the mobilized maxilla and the distal mandibular segment were fixed using an occlusal splint, forming the maxillomandibular complex (MMC). Realtime Ci-Navi was used to lead the MMC in the designated direction. Osteoplasty of the inferior border of the mandible was performed using Ci-Navi when facial symmetry and skeletal harmony were of concern. Linear and angular distinctions between preoperative planning and postoperative outcomes were calculated. RESULTS: The mean linear difference was 0.79 mm (maxilla: 0.62 mm, mandible: 0.88 mm) and the overall mean angular difference was 1.20°. The observed difference in the upper incisor point to the Frankfort horizontal plane, midfacial sagittal plane, and coronal plane was < 1 mm in 40 cases. CONCLUSIONS: This study demonstrates the role of Ci-Navi in the accurate positioning of bone segments during bimaxillary orthognathic surgery. Ci-Navi was found to be a reliable method for the accurate transfer of the surgical plan during an operation.

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PURPOSE: The management of complex mandible fractures, i.e. severely comminuted or fractures of edentulous/atrophic mandibles, can be challenging. This is due to the three-dimensional loss of bone, which limits the possibility for accurate anatomic reduction. Virtual surgery planning (VSP) can provide improved accuracy and shorter operating times, but is often not employed for trauma cases because of time constraints and complex user interfaces limited to two-dimensional interaction with three-dimensional data. METHODS: In this study, we evaluate the accuracy, precision, and time efficiency of the haptic assisted surgery planning system (HASP), an in-house VSP system that supports stereo graphics, six degrees-of-freedom input, and haptics to improve the surgical planning. Three operators performed planning in HASP on computed tomography (CT) and cone beam computed tomography (CBCT) images of a plastic skull model and on twelve retrospective cases with complex mandible fractures. RESULTS: The results show an accuracy and reproducibility of less than 2 mm when using HASP for virtual fracture reduction, with an average planning time of 15 min including time for segmentation in the software BoneSplit. CONCLUSION: This study presents an in-house haptic assisted planning tool for cranio-maxillofacial surgery with high usability that can be used for preoperative planning and evaluation of complex mandible fractures.

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OBJECTIVES: The digital technologies, in recent years, have integrated with temporomandibular joint reconstruction surgeries (TRS). Therefore, a systematic study was conducted to assess the impact of digital technologies in TRS. Besides, a brief comparison between the CAD/CAM and 3D printing (3DP) technologies is presented. MATERIALS & METHODS: We searched in PubMed, ProQuest and Science direct using PRISMA guidelines. Population = Patients undergoing TRS, Intervention=CAD/CAM or 3DP, Comparison= conventional TRS (cTRS) vs technology integrated TRS (tiTRS), Outcome= Advantages/disadvantages of technology and Subjective/objective symptoms, Study design= Type of study. The quality of observational study was assessed using ROBINS-1 Assessment tool. RESULTS: Out of 632 articles, 30 articles for CAD/CAM and 3DP were included in the study. A majority of TRS were done for ankylosis (new or re-entry), earlier failed surgery, osteoarthritis and neoplastic cases. The articles were divided into two groups. Group I: CAD/CAM(n = 16), Group II: 3DP (n = 14). DISCUSSION: tiTRS had definite advantages over cTRS with lesser surgery time, defined osteotomies, précised implant fitting and better final result outcome however, evidence for tiTRS in long-term follow-up is inconclusive. The cost, time, infrastructure and ethical/regulatory issues are the downsides of assisted surgeries. It was observed that 3DP technology is versatile and its adaptation in the fabrication of customized implants has outpaced CAD/CAM technology. However, literature data is feeble qualitatively and quantitatively. CONCLUSION: The TRS has leveraged the flexibility and precision of assisted surgeries. In future, tiTRS could successfully replace cTRS, provided that shortcomings should be dealt so that the technology can benefit the masses.

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Virtual surgical planning (VSP) promises higher accuracy, efficiency, and superior patient outcomes, helping normalize outcomes from surgeons of different experience levels. A systematic review was conducted in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The objective was to evaluate the accuracy and secondarily efficiency of VSP compared with free-hand surgery, for mandibular reconstruction with free flaps. Six studies met inclusion criteria and had quantitative data suitable for meta-analysis. Intercondylar distance and gonion angle were used to assess accuracy, evaluated by mean change from preoperative VSP and postoperative imaging. The mean weighted difference in VSP intercondylar distance was 2.0 mm, compared with 3.9 mm for free hand (P=0.101) and mean change in gonion angle for VSP was 3.6°, compared with 7.7° for free hand (P<0.05). Efficiency assessed by mean ischemia time, was 73.8min and 109.9min, for VSP and free hand, respectively (P=0.203), and by total operative time, which was 391.8 min and 457.6 min in the VSP and free hand, respectively (P=0.340). VSP is consistently proven to be more accurate and efficient than traditional free-hand surgery; however, a standardized method for accuracy and efficiency measurements is still missing, causing heterogeneity among the scientific reports.

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PURPOSE: A deviated nasal septum is the most common etiology for nasal airway obstruction (NAO), and septoplasty is the most common surgical procedure performed by ear-nose-throat surgeons in adults. However, quantitative criteria are rarely adopted to select patients for surgery, which may explain why up to 50% of patients report persistent or recurrent symptoms of nasal obstruction postoperatively. This study reports a systematic virtual surgery method to identify patients who may benefit from septoplasty. METHODS: One patient with symptoms of NAO due to a septal deviation was selected to illustrate the virtual surgery concept. Virtual septoplasty was implemented in three steps: (1) determining if septal geometry is abnormal preoperatively, (2) virtually correcting the deviation while preserving the anatomical shape of the septum, and (3) estimating the post-surgical improvement in airflow using computational fluid dynamics. Anatomical and functional changes predicted by the virtual surgery method were compared to a standard septoplasty performed independently from the computational analysis. RESULTS: A benchmark healthy nasal septum geometry was obtained by averaging the septum dimensions of 47 healthy individuals. A comparison of the nasal septum geometry in the NAO patient with the benchmark geometry identified the precise locations where septal deviation and thickness exceeded the healthy range. Good agreement was found between the virtual surgery predictions and the actual surgical outcomes for both airspace minimal cross-sectional area (0.05 cm2 pre-surgery, 0.54 cm2 virtual surgery, 0.50 cm2 actual surgery) and nasal resistance (0.91 Pa.s/ml pre-surgery, 0.08 Pa.s/ml virtual surgery, 0.08 Pa.s/ml actual surgery). CONCLUSIONS: Previous virtual surgery methods for NAO were based on manual edits and subjective criteria. The virtual septoplasty method proposed in this study is objective and has the potential to be fully automated. Future implementation of this method in virtual surgery planning software has the potential to improve septoplasty outcomes.

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PURPOSE: Virtual surgery planning based on computational fluid dynamics (CFD) simulations of nasal airflow has the potential to improve surgical outcomes for patients with nasal airway obstruction (NAO). Virtual surgery planning requires normative ranges of airflow variables, but few studies to date have quantified inter-individual variability of nasal airflow among healthy subjects. This study reports CFD simulations of nasal airflow in 47 healthy adults. METHODS: Anatomically accurate three-dimensional nasal models were reconstructed from cone beam computed tomography scans and used for steady-state inspiratory airflow simulations with a bilateral flowrate of 250 ml/s. Normal subjective sensation of nasal patency was confirmed using the nasal obstruction symptom evaluation and visual analog scale. Healthy ranges for several CFD variables known to correlate with subjective nasal patency were computed, including unilateral airflow, nasal resistance, airspace minimal cross-sectional area (mCSA), heat flux (HF), and surface area stimulated by mucosal cooling (defined as the area where HF > 50 W/m2). The normative ranges were targeted to contain 95% of the healthy population and computed using a nonparametric method based on order statistics. RESULTS: A wide range of inter-individual variability in nasal airflow was observed among healthy subjects. Unilateral airflow varied from 60 to 191 ml/s, airflow partitioning ranged from 23.8 to 76.2%, and unilateral mCSA varied from 0.24 to 1.21 cm2. These ranges are in good agreement with rhinomanometry and acoustic rhinometry data from the literature. A key innovation of this study are the normative ranges of flow variables associated with mucosal cooling, which recent research suggests is the primary physiological mechanism of nasal airflow sensation. Unilateral HF ranged from 94 to 281 W/m2, while the surface area stimulated by cooling ranged from 27.4 to 64.3 cm2. CONCLUSIONS: These normative ranges may serve as targets in future virtual surgery planning for patients with NAO.

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Segmental defect areas in the mandible can change immediately following osteotomy due to muscular traction, impacting on accurate reconstruction. The purpose of this article is to introduce a new technique based on virtual surgery planning to record the position of the bony parts prior to mandibulectomy, for use in precise mandibular reconstruction after segmental osteotomy. The position information for the bony parts is transferred to a plate with complementary surface contact and locating holes with specific directions and angles. This technique was performed for six patients with segmental defects and the results were compared to those of six previous patients in whom the technique was not utilized. The design of the location holes shortened the average operation time from 406 minutes to 349 minutes (P = 0.033) and decreased the average, maximum, and minimum graft deviation from 1.21 mm to 0.88 mm (P = 0.015), 1.28 mm to 0.99 mm (P = 0.027), and -1.15 mm to -0.77 mm (P = 0.077), respectively. The design of the locating holes in multiple plates shortened the time taken for the bony repositioning step and hence significantly shortened the total operation time. More importantly, it also increased the reconstructive accuracy.

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Three-dimensional surgical planning is used widely in orthognathic surgery. Although numerous computer programs exist, the accuracy of soft tissue prediction remains uncertain. The purpose of this study was to compare the prediction accuracy of Dolphin, ProPlan CMF, and a probabilistic finite element method (PFEM). Seven patients (mean age 18years; five female) who had undergone Le Fort I osteotomy with preoperative and 1-year postoperative cone beam computed tomography (CBCT) were included. The three programs were used for soft tissue prediction using planned and postoperative maxillary position, and these were compared to postoperative CBCT. Accurate predictions were obtained with each program, indicated by root mean square distances: RMSDolphin=1.8±0.8mm, RMSProPlan=1.2±0.4mm, and RMSPFEM=1.3±0.4mm. Dolphin utilizes a landmark-based algorithm allowing for patient-specific bone-to-soft tissue ratios, which works well for cephalometric radiographs but has limited three-dimensional accuracy, whilst ProPlan and PFEM provide better three-dimensional predictions with continuous displacements. Patient or population-specific material properties can be defined in PFEM, while no soft tissue parameters are adjustable in ProPlan. Important clinical considerations are the topological differences between predictions due to the three algorithms, the non-negligible influence of the mismatch between planned and postoperative maxillary position, and the learning curve associated with sophisticated programs like PFEM.

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Hemifacial microsomia (HFM) is a common congenital craniofacial deformity with a high prevalence. Orthognathic surgery and distraction osteogenesis are two conventionally used treatments of HFM. The main objective of this retrospective study was to evaluate the accuracy of two treatments with the help of virtual surgical planning in adult HFM patients. Sixty-eight adult patients with unilateral HFM were enrolled in this study. Preoperative surgical planning and simulation were performed on three-dimensional computed tomography models. Orthognathic surgery or distraction osteogenesis was performed under the guidance of three-dimensional surgical templates. Postoperative evaluation of the intervention was performed by comparison of the affected ramus height, chin deviation and the occlusal cant in surgical planning and actual result. Outcome and feedback information (an average of 14 months) showed that virtual surgical planning was accurately transferred to actual surgery in both surgical approaches. There were no statistical differences between the accuracy of affected ramus height and the occlusal cant in two surgical approaches. The orthognathic group showed significantly higher accuracy in chin deviation. In conclusion, virtual surgical planning and three-dimensional surgical templates were proved to facilitate treatment planning and offer an accurate surgical result in the treatment of adult HFM patients.

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