Heparin regimes in head and neck cancer flap surgery: A retrospective cohort study of free flap complications graded by Clavien-Dindo.

The purpose of the current study was to compare two different antithrombotic protocols for free flap reconstruction in head and neck squamous cell carcinoma (HNSCC) patients. Postoperative complications were graded using the Clavien-Dindo (CD) classification and compared between the two groups: the low-molecular-weight heparin (LMWH) group (n = 57) and the unfractionated heparin (UFH) group (n = 59). Patients with HNSCC from January 2010 to January 2022 were included. A total of 116 patients with a mean age of 60.46 years (range 43-83 years) were included in this study. In all, 81 were male (69.8%), and 35 were female (30.2%). Most patients (48.3%) had only grade 1 or 2 complications. CD grades (1-5) were similar between the two groups. Flap loss occurred in 2 patients (1.7%) in the LMWH group (p = 239). Prognostic factors of flap loss were high BMI, hypertension, high T stage, and high N stage. No differences were found between the groups in regard to age, sex, operating times, flap source, recipient vessels and overall complications. The results of this study demonstrate that UFH was as safe and effective as LMWH regarding postoperative complications. Free flap surgery is safe and effective for head and neck reconstruction.

Surgical site infections in maxillofacial trauma surgery - Single-dose versus prolonged antibiotic prophylaxis.

Open reduction with internal fixation (ORIF) for facial fractures has frequently been associated with the occurrence of surgical site infections (SSIs). Perioperative antibiotic prophylaxis is customarily recommended for ORIF. Thus, the comparison of two different antibiotic regimens (i.e., single-dose and prolonged antibiotic prophylaxis) concerning the rate and severity of SSIs in facial fracture patients undergoing ORIF was the main purpose of this study. This retrospective analysis included patients who underwent ORIF for facial fractures. They were distributed into two groups. The single-dose antibiotic prophylaxis group (SDAP) received single-dose perioperative antibiotic prophylaxis, whereas the prolonged antibiotic prophylaxis group (PAP) were administered prophylactic antibiosis over a course of 5 days. 122 patients were included in the study. Nine patients in the SDAP group and 15 patients in the PAP group were affected by SSIs; no significant difference in the incidence of SSIs was found (p = 0.218). Moreover, the severity of SSIs did not significantly differ between the two groups (p = 0.982).

Facial scars resulting from a transbuccal approach during osteosynthesis of a sagittal split osteotomy: A retrospective study.

The purpose of the current study was to assess the quality of facial linear scars. The Stony Brook Scar Evaluation Scale (SBSES) was developed and validated as a tool to assess postoperative scars. Postoperative facial scars were rated using high-quality macrophotographs and SBSES by three independent raters at baseline and three months thereafter. Percentage agreement (PA) and intraclass correlation coefficient (ICC) were used to measure interrater and intrarater reliability. Scar outcomes ranging from 0 (worst) to 5 (best) were evaluated against age and gender. One-hundred-sixty-six patients with a mean age of 30.6 years (range of 17-59) were included in this study. Forty-four were male (26.5%), and 122 were female (73.5%). Mean total SBSES scores were 4.63 (range of 4.56-4.76) at baseline and 4.60 (range of 4.54-4.72) at three months. As patient's age increased, mean total SBSES scores also decreased significantly (r = -0.216, p = 0.005). Gender did not significantly affect raters' perception of scar cosmesis (p = 0.847). Interrater reliability showed an ICC of 0.675 (95% CI, 0.609-0.731) and a PA of 65.4% at baseline, and an ICC of 0.655 (95% CI, 0.585-0.715) and a PA of 64.2% at three months. Intrarater reliability found ICCs ranging from 0.988 to 0.990 and a PA of 96.8% with 3 separate raters. Within the limitations of the study it seems that the transbuccal approach during osteosynthesis of a sagittal split osteotomy seems still to be acceptable when the patient gives his or her informed consent and advanced instruments like an angled screwdriver are not available.

[Local anesthetics with elderly patients]. / Die Anwendung von Lokalanästhetika bei Patientinnen und Patienten im Alter.

When choosing local anesthetics, risk factors such as underlying diseases, use of other medications and allergies have to be taken into consideration. Systematic complications might occur if a specific limit in the plasma concentration is exceeded. Articaine and prilocaine are metabolized extrahepatically. In case of an absolute contraindication for vasoconstrictors, the use of mepivacaine, bupivacaine or articaine is recommended.

Donor Site Morbidity and Quality of Life after Microvascular Head and Neck Reconstruction with a Chimeric, Thoracodorsal, Perforator-Scapular Flap Based on the Angular Artery (TDAP-Scap-aa Flap).

Extensive defects in the head and neck area often require the use of advanced free flap reconstruction techniques. In this study, the thoracodorsal perforator-scapular free flap technique based on the angular artery (TDAP-Scap-aa flap) was postoperatively evaluated regarding the quality of life and the donor site morbidity using the standardized SF-36 and DASH questionnaires (short form health 36 and disabilities of the arm, shoulder and hand scores). Over a five-year period (2016−2020), 20 selected cases (n = 20) requiring both soft and hard tissue reconstruction were assessed. On average, the harvested microvascular free flaps consisted of 7.8 ± 2.1 cm hard tissue and 86 ± 49.8 cm2 soft tissue components. At the donor site (subscapular region), only a mild morbidity was observed (DASH score: 21.74 ± 7.3 points). When comparing the patients' postoperative quality of life to the established values of the healthy German norm population, the observed SF-36 values were within the upper third (>66%) of these established norm values in almost all quality-of-life subcategories. The mild donor site morbidity and the observed quality of life indicate only a small postoperative impairment when using the TDAP-Scap-aa free flap for the reconstruction of extensive maxillofacial defects.

[Metronidazole - spectrum of activity, use and side effects]. / Metronidazol ­ Wirkungsspektrum, Anwendung und Nebenwirkungen.

This contribution gives an overview of the use, therapeutic effects and side effects of the antibiotic substance Metronidazole. Metronidazole is effective in the treatment support of paradontitis, microbial-caused halitosis, perioral skin infections and odontogenic hard or soft tissue abscess formations related to anaerobic bacterial infections. Due to its anti- parasitic effect, Metronidazole is also effective in the treatment of protozoa. In adults and children from 12 years on, 200 mg Metronidazole to a maximum of 2000 mg Metronidazole per day can be administered. In children below 12 years of age, an antibiotic dose of Metronidazole between 20 to 30 mg per kilogram body weight is advised.

Diabetes Mellitus and Oral Cancer: A Retrospective Study from Austria.

AIM: This study aimed to analyse the possible linkage between diabetes mellitus (DM) and oral cancer among Austrians. PATIENTS AND METHODS: We performed a retrospective DM and/or impaired fasting glucose (IFG) screening in 573 patients who underwent maxillofacial surgery under general anaesthesia between January 1, 2018 and December 31, 2019. RESULTS: Of the total patients, 26.5% (n=152) had cancer diagnosis, whereas the remaining 73.5% (n=421) formed the control group. The prevalence of glucose metabolism disorder (GMD) was significantly (p<0.00001) more common among cancer patients (59.9% vs. 36.5%). Squamous cell carcinoma and sublingual tumours represented the most common tumour type (93.4%) and location (35.5%), respectively. Smoking was significantly (p=0.00093) more common within the cancer group. CONCLUSION: Our data suggest an association between GMD and oral cancer.

Intravenous ibuprofen versus diclofenac plus orphenadrine in orthognathic surgery: a prospective, randomized, double-blind, controlled clinical study.

OBJECTIVES: The aim of this prospective, randomized, double-blind, controlled clinical study was to evaluate the analgesic effect of ibuprofen versus diclofenac plus orphenadrine on postoperative pain in orthognathic surgery. MATERIAL AND METHODS: Patients who underwent orthognathic surgery were randomized into two groups to receive intravenously either 600 mg of ibuprofen (I-group) or 75 mg diclofenac plus 30 mg orphenadrine (D-group), both of which were given twice daily. Additionally, both groups were given metamizole 500 mg. Rescue pain medication consisted of acetaminophen 1000 mg and piritramide 7.5 mg as needed. To assess the pain intensity, the primary end point was the numeric rating scale (NRS) recorded over the course of the hospital stay three times daily for 3 days. RESULTS: One hundred nine patients were enrolled (age range, 18 to 61 years) between May 2019 and November 2020. Forty-eight bilateral sagittal split osteotomies (BSSO) and 51 bimaxillary osteotomies (BIMAX) were performed. Surgical subgroup analysis found a significant higher mean NRS (2.73 vs.1.23) in the BIMAX D-group vs. I-group (p = 0.015) on the third postoperative day. Additionally, as the patient's body mass index (BMI) increased, the mean NRS (r = 0.517, p = 0.001) also increased. No differences were found between age, gender, length of hospital stay, weight, operating times, number of patients with complete pain relief, acetaminophen or piritramide intake, and NRS values. No adverse events were observed. CONCLUSION: The results of this study demonstrate that ibuprofen administration and lower BMI were associated with less pain for patients who underwent bimaxillary osteotomy on the third postoperative day. Therefore, surgeons may prefer ibuprofen for more effective pain relief after orthognathic surgery. CLINICAL RELEVANCE: Ibuprofen differs from diclofenac plus orphenadrine in class and is a powerful analgetic after orthognathic surgery.

Gender-specific differences in haemostatic parameters and their influence on blood loss in bimaxillary surgery.

OBJECTIVE: The objectives of this prospective cohort study were to establish gender-related differences in blood loss and haemostatic profiles associated with bimaxillary surgery. In addition, we aimed to identify if any gender differences could be established which might help predict blood loss volume. MATERIALS AND METHODS: Fifty-four patients (22 males; 32 females) undergoing bimaxillary surgery for skeletal dentofacial deformities were eligible for inclusion. Blood samples were taken 1 day preoperatively and 48 h postoperatively for detailed gender-specific coagulation analysis incorporating global coagulation assays (endogenous thrombin potential) and specific coagulation parameters. Blood loss was measured at two different time points: (1) the end of surgery, visible intraoperative blood loss (IOB) using 'subtraction method'; and (2) 48 h postoperatively perioperative bleeding volume (CBL-48 h) using 'haemoglobin-balance method' and Nadler's formula. Correlation and regression analyses were performed to identify relevant parameters affecting the amount of blood loss. RESULTS: Significant differences in IOB and CBL-48 h were observed (p < 0.001). Men had higher IOB versus women, lacking statistical significance (p = 0.056). In contrast, men had significantly higher CLB-48 h (p = 0.019). Reduced CBL-48 h was shown to be most closely associated with the level of Antithrombin-III being decreased in females. CONCLUSIONS: Male gender is associated with higher IOB and CBL-48 compared with females. Gender does not affect IOB regarding haemostatic profile but does correlate strongly with procedure length. Conversely, CBL-48 is closely associated with gender-specific imbalances in the anticoagulant system. CLINICAL RELEVANCE: Knowledge of gender-related differences will help clinicians establish predictive factors regarding excessive blood loss in orthognathic surgery and identify at-risk patients.

Expect the unexpected: The course of the inferior alveolar artery - Preliminary results and clinical implications.

INTRODUCTION: The anatomical position of the inferior alveolar artery (IAA) within the mandibular canal and in relation to the substructures of the neurovascular mandibular bundle has been sparsely described to date. More detailed information on the exact IAA position would be beneficial for both dental and maxillofacial surgical procedures to minimize complications such as bleeding, nerve compression hematoma, and sensory deficiency. MATERIAL AND METHODS: In 31 Thiel-preserved and fresh-frozen cadaver hemimandibles the position of the IAA in relation to the structures of the inferior alveolar neurovascular bundle and the mandible borders was analyzed anatomically and histologically. RESULTS: In 77.4% of the cases, rotation of the IAA around the mental nerve was apparent, resulting in a typical site-dependent IAA position. While the IAA was situated buccally within the pterygomandibular space, buccal-inferior in the mandibular foramen, superior in the molar region, and lingually in the premolar region. In 12.9% of the cases, a persistent lingual position of the IAA was observed for the entire mandibular canal. In one case, an additional mandibular canal and an accessory IAA were identified. DISCUSSION: This study provides new and encompassing information on the complete course and position of the IAA. This course is of practical use for oral implantology and various surgical procedures in dental- and maxillofacial surgery. Variations in the typical IAA course and site-dependent positional changes may be referred to as mandible growth and functional adaption to occlusion anomalies. This report helps enhance the morphological and functional understanding of IAA relationship during mandible development.

[Local anesthesia in children: standard and limits]. / Lokalanästhesie bei Kindern: Standard und Grenzen.

The use of local anesthetics is known to be safe and efficient in surgical and dental treatments. Local anesthetics are essential in dentistry for appropriate pain control as they inhibit nociception generated during surgical and dental procedures. However, among other precautions, attention has to be paid to the individual maximum dose of the local anesthetics that is administered. This is especially important for children who are, due to their low body weight, more prone to adverse events following substance overdose. Therefore, this contribution gives advice for general dentists on the accurate use and maximum dose of local anesthetics in children.

Dilemma in the Treatment of a Central Giant Cell Granuloma.

Management of central giant cell granuloma (CGCG) presents a clinical challenge. While eradicating a lesion known for its high recurrence rate calls for radical surgical approaches, these cause significant esthetic and functional impairment. We present an eight-year-old boy suffering from an extraordinarily large CGCG expanding into the mandible and base of the mouth in the whole anterior region. Combined treatment with surgical intervention and corticosteroid application was successfully applied, and all six attached dental germs could be preserved. Different approaches for clinical management in pediatric cases are discussed.

[Application of tranexamic acid within the field of dentistry]. / Die Anwendung von Tranexamsäure (Cyklokapron®) in der Zahnmedizin.

The antifibrinolytic agent tranexamic acid (TXA) is well known for its capacity to effectively reduce intraoperative blood loss. The effect mechanism of TXA is based on the indirect inhibition of fibrin degradation, whereby existing blood clots within the surgical area are stabilized. Consecutively, the amount of blood loss can be reduced. Due to its great efficacy to minimize blood loss and its low rate of unintended side effects, TXA is regularly used in different surgical fields. Within the field of dentistry TXA is not applied on a regular basis, however, it presents a highly effective and convenient treatment option to reduce bleeding complications.

Effects of Pre-Operative Risk Factors on Intensive Care Unit Length of Stay (ICU-LOS) in Major Oral and Maxillofacial Cancer Surgery.

OBJECTIVE: This study aimed to investigate the effect of certain pre-operative parameters directly on the post-operative intensive care unit (ICU)-length of stay (LOS), in order to identify at-risk patients that are expected to need prolonged intensive care management post-operatively. MATERIAL AND METHODS: Retrospectively, patients managed in an ICU after undergoing major oral and maxillofacial surgery were analyzed. Inclusion criteria entailed: age 18-90 years, major primary oral cancer surgery including tumor resection, neck dissection and microvascular free flap reconstruction, minimum operation time of 8 h. Exclusion criteria were: benign/borderline tumors, primary radiation, other defect reconstruction than microvascular, treatment at other centers. Separate parameters used within the clinical routine were set in correlation with ICU-LOS, by applying single testing calculations (t-tests, variance analysis, correlation coefficients, effect sizes) and a valid univariate linear regression model. The primary outcome of interest was ICU-LOS. RESULTS: This study included a homogenous cohort of 122 patients. Mean surgery time was 11.4 (±2.2) h, mean ICU-LOS was 3.6 (±2.6) days. Patients with pre-operative renal dysfunction (p < 0.001), peripheral vascular disease-PVD (p = 0.01), increasing heart failure-NYHA stage categories (p = 0.009) and higher-grade categories of post-operative complications (p = 0.023) were identified as at-risk patients for a significantly prolonged post-operative ICU-LOS. CONCLUSIONS: At-risk patients are prone to need a significantly longer ICU-LOS than others. These patients are those with pre-operative severe renal dysfunction, PVD and/or high NYHA stage categories. Confounding parameters that contribute to a prolonged ICU-LOS in combination with other variables were identified as higher age, prolonged operative time, chronic obstructive pulmonary disease, and intra-operatively transfused blood.

Is there a hidden blood loss in orthognathic surgery and should it be considered? Results of a prospective cohort study.

The aim of this prospective observational study was to investigate the parameter 'hidden blood loss' (HBL) in the context of orthognathic surgery, incorporating undetected bleeding volumes occurring intra- and postoperatively. Orthognathic bleeding volumes were recorded at three different time points. At the end of the operation the visible intraoperative blood loss (VBL) was measured. Additionally, the perioperative blood loss was calculated 24 h and 48 h postoperatively using the 'haemoglobin balance method'. Analysis of the HBL was based on the difference between the visible intraoperative blood loss (VBL) and calculated blood loss (CBL), determined 48 h after surgery. 82 patients (male 33, female 49) were included in this study, of whom 41 underwent bimaxillary surgery and of whom 41 underwent Bilateral Sagittal Split Osteotomy (BSSO). Statistically significant differences with reference to the absolute bleeding volumes were found when comparing the two treatment modalities. In terms of HBL, a bleeding volume of 287.2 ml (±265.9) in the bimaxillary group and 346.9 ml (±271.3) in the BSSO cohort was recorded. This accounted for 32.2% (bimaxillary surgery) and 62.6% (BSSO) of the CBL after 48 h (BIMAX vs. BSSO, p < 0.001). HBL is a valuable adjunct to record within the perioperative management of orthognathic surgery to further improve patient safety and postoperative outcomes.

Complex Mandibular Reconstruction for Head and Neck Squamous Cell Carcinoma-The Ongoing Challenge in Reconstruction and Rehabilitation.

Large head and neck squamous cell carcinoma (HNSCC) tumors affecting the mandible require a versatile reconstruction to maintain form, function, and quality of life. Large defect reconstruction of soft and hard tissue in the head and neck necessitates, at best, one vascular system including various tissues by large dimensions. The subscapular flap system seems to meet these standards. A retrospective study was conducted focusing on clinical data, including an analysis of the quality of life with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires, (QLQ-C30 and QLQ-H&N43). A total of 154 patients (122 males, 32 females; age range: 31-71 years, mean: 54.5 years) treated at our department from 1983 through to 2019 were included. Of the subscapular system free flaps (SFFs), 147 were based on the angular artery branch of the thoracodorsal pedicle (95.45%), and the remaining seven cases (4.55%) were lateral scapular border flaps. Mean mandible defect length was 7.3 cm. The mean skin paddle dimension was 86.8 cm2. The most common recipient artery was the thyroid superior artery (79.22%). Major postoperative complications occurred in 13 patients (8.44%). This study confirms that SFFs offer excellent soft and hard tissue quality, component independence, a large arc of rotation length, and a large gauge of pedicle, making them the gold standard for the reconstruction of large composite defects of mandibular HNSCC tumors.

Biofunctional Glycol-Modified Polyethylene Terephthalate and Thermoplastic Polyurethane Implants by Extrusion-Based Additive Manufacturing for Medical 3D Maxillofacial Defect Reconstruction.

This work addresses the topic of extrusion-based additive manufacturing (filament-based material extrusion) of patient-specific biofunctional maxillofacial implants. The technical approach was chosen to overcome the shortcomings of medically established fabrication processes such as a limited availability of materials or long manufacturing times. The goal of the work was a successful fabrication of basic implants for defect reconstruction. The underlying vision is the implants' clinic-internal and operation-accompanying application. Following a literature search, a material selection was conducted. Digitally prepared three-dimensional (3D) models dealing with two representative mandible bone defects were printed based on the material selection. An ex-vivo model of the implant environment evaluated dimensional and fitting traits of the implants. Glycol-modified PET (PETG) and thermoplastic polyurethane (TPU) were finally selected. These plastics had high cell acceptance, good mechanical properties, and optimal printability. The subsequent fabrication process yielded two different implant strategies: the standard implant made of PETG with a build-up rate of approximately 10 g/h, and the biofunctional performance implant with a TPU shell and a PETG core with a build-up rate of approximately 4 g/h. The standard implant is meant to be intraoperatively applied, as the print time is below three hours even for larger skull defects. Standard implants proved to be well fitting, mechanically stable and cleanly printed. In addition, the hybrid implant showed particularly cell-friendly behavior due to the chemical constitution of the TPU shell and great impact stability because of the crack-absorbing TPU/PETG combination. This biofunctional constellation could be used in specific reconstructive patient cases and is suitable for pre-operative manufacturing based on radiological image scans of the defect. In summary, filament-based material extrusion has been identified as a suitable manufacturing method for personalized implants in the maxillofacial area. A further clinical and mechanical study is recommended.

Weight gain in infants with Pierre Robin sequence.

OBJECTIVE: To determine weight gain during treatment with the modified palatal plate (MPP) in infants with isolated and syndromic Pierre Robin Sequence (PRS) suffering from micrognathia, upper airway obstruction (UAO), and failure to thrive (FTT), the authors conducted a retrospective study of infants treated with the MPP. METHODS: The main outcome measure was infant weight (g) for up to three months after birth. Demographic and outcome data (associated syndromes, comorbidities, presence of cleft lip or palate, intubation attempts, tracheotomy and cleft repair) were collected. RESULTS: 14 children born January 2010 - December 2019 were included. The majority (86%) of infants showed highly significant weight gain (p < 0.001) within a 3-month period (mean pretreatment weight 3147 g with a SD of 425 g vs mean weight at three months 4435 g with a SD of 635 g). Syndromic PRS was found in 7% of infants. 43% of nonsyndromic PRS patients were found to have other congenital anomalies. Genetic testing showed normal karyotypes in 93% of infants and a microdeletion in 7% of infants. 21% of infants required tracheotomy, but no patients required mandibular distraction (MDO) or tongue-lip adhesion (TLA) to relieve UAO. CONCLUSION: PRS infants treated with the MPP showed highly significant weight gain within a 3-month period and did not require mandibular surgery for early airway management, but faster gain of weight might have implications for strategies to perform surgery at an earlier point in time.

Facial model collection for medical augmented reality in oncologic cranio-maxillofacial surgery.

Medical augmented reality (AR) is an increasingly important topic in many medical fields. AR enables x-ray vision to see through real world objects. In medicine, this offers pre-, intra- or post-interventional visualization of "hidden" structures. In contrast to a classical monitor view, AR applications provide visualization not only on but also in relation to the patient. However, research and development of medical AR applications is challenging, because of unique patient-specific anatomies and pathologies. Working with several patients during the development for weeks or even months is not feasible. One alternative are commercial patient phantoms, which are very expensive. Hence, this data set provides a unique collection of head and neck cancer patient PET-CT scans with corresponding 3D models, provided as stereolitography (STL) files. The 3D models are optimized for effective 3D printing at low cost. This data can be used in the development and evaluation of AR applications for head and neck surgery.

A review on multiplatform evaluations of semi-automatic open-source based image segmentation for cranio-maxillofacial surgery.

BACKGROUND AND OBJECTIVES: Computer-assisted technologies, such as image-based segmentation, play an important role in the diagnosis and treatment support in cranio-maxillofacial surgery. However, although many segmentation software packages exist, their clinical in-house use is often challenging due to constrained technical, human or financial resources. Especially technological solutions or systematic evaluations of open-source based segmentation approaches are lacking. The aim of this contribution is to assess and review the segmentation quality and the potential clinical use of multiple commonly available and license-free segmentation methods on different medical platforms. METHODS: In this contribution, the quality and accuracy of open-source segmentation methods was assessed on different platforms using patient-specific clinical CT-data and reviewed with the literature. The image-based segmentation algorithms GrowCut, Robust Statistics Segmenter, Region Growing 3D, Otsu & Picking, Canny Segmentation and Geodesic Segmenter were investigated in the mandible on the platforms 3D Slicer, MITK and MeVisLab. Comparisons were made between the segmentation algorithms and the ground truth segmentations of the same anatomy performed by two clinical experts (n = 20). Assessment parameters were the Dice Score Coefficient (DSC), the Hausdorff Distance (HD), and Pearsons correlation coefficient (r). RESULTS: The segmentation accuracy was highest with the GrowCut (DSC 85.6%, HD 33.5 voxel) and the Canny (DSC 82.1%, HD 8.5 voxel) algorithm. Statistical differences between the assessment parameters were not significant (p < 0.05) and correlation coefficients were close to the value one (r > 0.94) for any of the comparison made between the segmentation methods and the ground truth schemes. Functionally stable and time-saving segmentations were observed. CONCLUSION: High quality image-based semi-automatic segmentation was provided by the GrowCut and the Canny segmentation method. In the cranio-maxillofacial complex, these segmentation methods provide algorithmic alternatives for image-based segmentation in the clinical practice for e.g. surgical planning or visualization of treatment results and offer advantages through their open-source availability. This is the first systematic multi-platform comparison that evaluates multiple license-free, open-source segmentation methods based on clinical data for the improvement of algorithms and a potential clinical use in patient-individualized medicine. The results presented are reproducible by others and can be used for clinical and research purposes.