Impact of extracorporeal blood pump gap sizes on the performance and hemocompatibility under off-design operation.

BACKGROUND: Hemocompatibility remains the dominant challenge in rotary blood pumps, and more information on the relationship between individual pump design features, hemodynamics, and blood trauma in various operation conditions is necessary. The study evaluated the variation of gap sizes in extracorporeal blood pumps concerning their influence on blood compatibility, particularly during off-design conditions. METHODS: We developed a parametric generic blood pump framework for in-silico and in-vitro design feature analysis. Thirty-six designs with varying axial and radial gap sizes between 0.5 mm and 3 mm were generated. CFD was applied to calculate and compare device hemodynamics and evaluate the performance and hemocompatibility during off-design and target operation conditions. The following quantities were analyzed: pressure difference, hemolysis potential, residence times, hydraulic efficiency, and recirculation ratio. RESULTS: The in-vitro prototype showed excellent agreement with in-silico predictions regarding hydraulic performance (R2 = 0.996 with a RMSE = 2.07). Our results show a modest impact of gap size variations ±10% on key metrics. Domain-resolved analyses revealed a significant contribution of the gap regions to the device's overall hemolytic performance, with an increasing contribution for off-design flow rates. Overall elevated hemolysis levels were identified if at least one gap size was held minimal. CONCLUSIONS: We introduced and showed the feasibility of a parametric rotary blood pump framework to systematically investigate design feature impact. Results suggest, larger and uniformly sized gaps being overall beneficial regarding hemocompatibility.

Reference intervals and percentiles for soluble transferrin receptor and sTfR/log ferritin index in healthy children and adolescents.

OBJECTIVES: Soluble transferrin receptor (sTfR) is a marker of both erythropoiesis and iron status and is considered useful for detecting iron deficiency, especially in inflammatory conditions, but reference intervals covering the entire pediatric age spectrum are lacking. METHODS: We studied 1,064 (48.5 % female) healthy children of the entire pediatric age spectrum to determine reference values and percentiles for sTfR and the ratio of sTfR to log-ferritin (sTfR-F index) using a standard immunoturbidimetric assay. RESULTS: Soluble TfR levels were highly age-specific, with a peak in infancy and a decline in adulthood, whereas the sTfR-F index was a rather constant parameter. There were positive linear relationships for sTfR with hemoglobin (Hb) (p=0.008) and transferrin (females p<0.001; males p=0.003). A negative association was observed between sTfR and ferritin in females (p<0.0001) and for transferrin saturation and mean corpuscular volume (MCV) in both sexes (both p<0.0001). We found a positive relationship between sTfR and body height, body mass index (BMI) and inflammatory markers (CrP p<0.0001; WBC p=0.0172), while sTfR-F index was not affected by inflammation. CONCLUSIONS: Soluble TfR values appear to reflect the activity of infant erythropoiesis and to be modulated by inflammation and iron deficiency even in a healthy cohort.

Non-Syndromic and Syndromic Defects in Children with Extracranial Germ Cell Tumors: Data of 2610 Children Registered with the German MAKEI 96/MAHO 98 Registry Compared to the General Population.

GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case-control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Comparing a virtual reality head-mounted display to on-screen three-dimensional visualization and two-dimensional computed tomography data for training in decision making in hepatic surgery: a randomized controlled study.

OBJECTIVE: Evaluation of the benefits of a virtual reality (VR) environment with a head-mounted display (HMD) for decision-making in liver surgery. BACKGROUND: Training in liver surgery involves appraising radiologic images and considering the patient's clinical information. Accurate assessment of 2D-tomography images is complex and requires considerable experience, and often the images are divorced from the clinical information. We present a comprehensive and interactive tool for visualizing operation planning data in a VR environment using a head-mounted-display and compare it to 3D visualization and 2D-tomography. METHODS: Ninety medical students were randomized into three groups (1:1:1 ratio). All participants analyzed three liver surgery patient cases with increasing difficulty. The cases were analyzed using 2D-tomography data (group "2D"), a 3D visualization on a 2D display (group "3D") or within a VR environment (group "VR"). The VR environment was displayed using the "Oculus Rift ™" HMD technology. Participants answered 11 questions on anatomy, tumor involvement and surgical decision-making and 18 evaluative questions (Likert scale). RESULTS: Sum of correct answers were significantly higher in the 3D (7.1 ± 1.4, p < 0.001) and VR (7.1 ± 1.4, p < 0.001) groups than the 2D group (5.4 ± 1.4) while there was no difference between 3D and VR (p = 0.987). Times to answer in the 3D (6:44 ± 02:22 min, p < 0.001) and VR (6:24 ± 02:43 min, p < 0.001) groups were significantly faster than the 2D group (09:13 ± 03:10 min) while there was no difference between 3D and VR (p = 0.419). The VR environment was evaluated as most useful for identification of anatomic anomalies, risk and target structures and for the transfer of anatomical and pathological information to the intraoperative situation in the questionnaire. CONCLUSIONS: A VR environment with 3D visualization using a HMD is useful as a surgical training tool to accurately and quickly determine liver anatomy and tumor involvement in surgery.

Inter-Rater Reliability of Proliferative Diabetic Retinopathy Assessment on Wide-Field OCT-Angiography and Fluorescein Angiography.

Purpose: To assess inter-rater reliability in the detection of proliferative diabetic retinopathy (PDR) changes using wide-field optical coherence tomography angiography (WF-OCTA) versus fluorescein angiography (FA). Methods: This retrospective, cross-sectional study included patients with severe nonproliferative and PDR. Images were acquired with 12 × 12 mm WF-OCTA and FA with a 55° lens. Images were cropped to represent the exact same field of view. Qualitative (detection of neovascularization at the disc [NVD] and elsewhere [NVE], enlarged foveal avascular zone [FAZ], vitreous hemorrhage [VH]) and quantitative analyses (FAZ area, horizontal, vertical, and maximum FAZ diameter) were performed by 2 masked graders using ImageJ. Inter-rater reliability was calculated using unweighted Cohen's kappa coefficient (κ) for qualitative analyses and intraclass correlation coefficients (ICC) for quantitative analyses. Results: Twenty-three eyes of 17 patients were included. Inter-rater reliability was higher for FA than for WF-OCTA in qualitative analyses: κ values were 0.65 and 0.78 for detection of extended FAZ, 0.83 and 1.0 for NVD, 0.78 and 1.0 for NVE, and 0.19 and 1 for VH for WF-OCTA and FA, respectively. In contrast, inter-rater reliability was higher for WF-OCTA than for FA in the quantitative analyses: ICC values were 0.94 and 0.76 for FAZ size, 0.92 and 0.79 for horizontal FAZ diameter, 0.82 and 0.72 for vertical FAZ diameter, and 0.88 and 0.82 for maximum FAZ diameter on WF-OCTA and FA, respectively. Conclusions: Inter-rater reliability of FA is superior to WF-OCTA for qualitative analyses whereas inter-rater reliability of WF-OCTA is superior to FA for quantitative analyses. Translational Relevance: The study highlights the specific merits of both imaging modalities in terms of reliability. FA should be preferred for qualitative parameters, whereas WF-OCTA should be preferred for quantitative parameters.

Women's Reasons to Seek Bariatric Surgery and Their Expectations on the Surgery Outcome - a Multicenter Study from Five European Countries.

PURPOSE: Understanding patients' reasons for having bariatric surgery and their expectation on surgery outcomes is important to provide the best clinical practice and reduce unrealistic expectations. It is unknown if reasons and expectations differ between countries. We aimed to investigate the reasons for seeking bariatric surgery and expectations of surgical outcomes among patients in five European countries. METHODS: In total, 250 women accepted for bariatric surgery were recruited: 50 women each from Finland, Germany, Norway, Sweden, and the Netherlands. Participants ranked 14 reasons for seeking surgery, and reported the three primary reasons. They also reported expectations on weight loss and impact of surgery vs. lifestyle on weight loss outcomes. RESULTS: Mean age and body mass index were 42.9 ± 11.5 years and 45.1 ± 6.2 kg/m2, respectively. Weight loss and improved co-morbidity were ranked as the most important reasons. Participants expected to lose between 70.8 and 94.3% of their excessive weight. The expected impact of surgery as a driver of weight loss was higher in Germany and the Netherlands compared to in Finland, Norway, and Sweden where participants expected lifestyle changes to also have an impact. CONCLUSION: Weight loss and improved co-morbidities were the main reasons for undergoing bariatric surgery. Expectations on weight loss were generally very high, but expectations of surgery vs. lifestyle as the main driver of weight loss differed between countries. While some patients understand the importance of lifestyle change and maintenance of a healthy lifestyle after surgery in order to obtain a successful weight loss, other may need additional counselling.

Long-term Remission of Type 2 Diabetes and Patient Survival After Biliopancreatic Diversion with Duodenal Switch.

PURPOSE: This study investigates the long-term effects of biliopancreatic diversion with duodenal switch (BPD-DS) on patients with advanced type 2 diabetes mellitus (T2DM) while paying special attention to preoperative diabetes severity. MATERIALS AND METHODS: A retrospective analysis was conducted using prospective and current data on patients who underwent an open BPD-DS 6-12 years ago. Patients were stratified according to preoperative diabetes severity into 4 groups (group 1: oral antidiabetic drugs only; group 2: insulin < 5 years; group 3: insulin 5-10 years; group 4: insulin > 10 years). The primary endpoint was T2DM remission rate 6-12 years after BPD-DS as a function of preoperative diabetes severity. RESULTS: Ninety-one patients with advanced T2DM were included. Sixty-two patients were available for follow-up (rate of 77%). Follow-up was performed (mean ± SD) 8.9 ± 1.3 years after surgery. Glycated hemoglobin (HbA1c) levels were 9.4 ± 2.0% before surgery and decreased to 5.1 ± 0.8% after 1 year and 5.4 ± 1.0% after 6-12 years. Insulin discontinuation rate after surgery as well as the rate of long-term remission decreased steadily from groups 1 to 4, while long-term mortality increased. T2DM remission rates were 93%, 88%, 45%, and 40% in groups 1, 2, 3, and 4, respectively. Late relapse of T2DM occurred in 3 patients (5%). CONCLUSIONS: BPD-DS causes a rapid and long-lasting normalization of glycemic metabolism in patients with advanced T2DM. T2DM remission rate after 6-12 years varies significantly (from 40% to more than 90%) and is highly dependent on preoperative diabetes severity.

[Developing a competence center for obesity and metabolic surgery-Experiences from two different clinics]. / Der Weg zum Kompetenzzentrum für Adipositas und metabolische Chirurgie ­ Erfahrungen aus 2 verschiedenen Kliniken.

BACKGROUND: Due to the high incidence of obesity and the effectiveness of obesity (metabolic) surgery, the number of metabolic operations and the formation of certified obesity centers continue to increase. The aim of this study was to compare the experiences of two hospitals during establishing a certified obesity center in Heidelberg/Salem (HD/Salem) and in Baden-Baden (Bad). MATERIAL AND METHODS: The operation numbers, surgical procedures, the need for revision and the length of hospital stay were analyzed from August 2012 to June 2015 in HD/Salem and from May 2017 to December 2021 in Bad. In addition, a structured survey of patients took place to find out the preferred discharge date. The statistical evaluation was carried out with T-tests and χ2-tests for binary data. RESULTS: This analysis comprised 387 patients (181 patients Bad). There were 258 female patients (131 Bad). The mean age of all patients was 44.6 years (44.0 years Bad), the mean body mass index was 47.5 kg/m2 (47.0 kg/m2 Bad). In 12 of 206 patients (5.8%) from HD/Salem and 8 of 181 patients (4.4%) from Bad a revision was necessary. The average length of hospital stay decreased in HD/Salem from 6.5 days to 4.4 days (p < 0.05) and from 3.7 days to 3.4 days in Bad. Late revisions were necessary in HD/Salem in 4 of 206 patients (2.2%) and in Bad in 8 out of 181 patients (4.4%). The needed number of yearly operations required for certification was achieved for the first time in HD/Salem after 7 years and in Bad after 4 years. CONCLUSION: Building an obesity center at a different location from scratch to certification can be initiated and carried out by one experienced surgeon without loss of treatment quality regarding morbidity and mortality. From the start, the team should be familiar with early and late complications of metabolic surgery.

Development and validity evidence of an objective structured assessment of technical skills score for minimally invasive linear-stapled, hand-sewn intestinal anastomoses: the A-OSATS score.

INTRODUCTION: The aim of this study was to develop a reliable objective structured assessment of technical skills (OSATS) score for linear-stapled, hand-sewn closure of enterotomy intestinal anastomoses (A-OSATS). MATERIALS AND METHODS: The Delphi methodology was used to create a traditional and weighted A-OSATS score highlighting the more important steps for patient outcomes according to an international expert consensus. Minimally invasive novices, intermediates, and experts were asked to perform a minimally invasive linear-stapled intestinal anastomosis with hand-sewn closure of the enterotomy in a live animal model either laparoscopically or robot-assisted. Video recordings were scored by two blinded raters assessing intrarater and interrater reliability and discriminative abilities between novices (n = 8), intermediates (n = 24), and experts (n = 8). RESULTS: The Delphi process included 18 international experts and was successfully completed after 4 rounds. A total of 4 relevant main steps as well as 15 substeps were identified and a definition of each substep was provided. A maximum of 75 points could be reached in the unweighted A-OSATS score and 170 points in the weighted A-OSATS score respectively. A total of 41 anastomoses were evaluated. Excellent intrarater (r = 0.807-0.988, p < 0.001) and interrater (intraclass correlation coefficient = 0.923-0.924, p < 0.001) reliability was demonstrated. Both versions of the A-OSATS correlated well with the general OSATS and discriminated between novices, intermediates, and experts defined by their OSATS global rating scale. CONCLUSION: With the weighted and unweighted A-OSATS score, we propose a new reliable standard to assess the creation of minimally invasive linear-stapled, hand-sewn anastomoses based on an international expert consensus. Validity evidence in live animal models is provided in this study. Future research should focus on assessing whether the weighted A-OSATS exceeds the predictive capabilities of patient outcomes of the unweighted A-OSATS and provide further validity evidence on using the score on different anastomotic techniques in humans.

Comparison of Conventional Methods for Bowel Length Measurement in Laparoscopic Surgery to a Novel Computer-Assisted 3D Measurement System.

PURPOSE: Accurate laparoscopic bowel length measurement (LBLM), which is used primarily in metabolic surgery, remains a challenge. This study aims to three conventional methods for LBLM, namely using visual judgment (VJ), instrument markings (IM), or premeasured tape (PT) to a novel computer-assisted 3D measurement system (BMS). MATERIALS AND METHODS: LBLM methods were compared using a 3D laparoscope on bowel phantoms regarding accuracy (relative error in percent, %), time in seconds (s), and number of bowel grasps. Seventy centimeters were measured seven times. As a control, the first, third, fifth, and seventh measurements were performed with VJ. The interventions IM, PT, and BMS were performed following a randomized order as the second, fourth, and sixth measurements. RESULTS: In total, 63 people participated. BMS showed better accuracy (2.1±3.7%) compared to VJ (8.7±13.7%, p=0.001), PT (4.3±6.8%, p=0.002), and IM (11±15.3%, p<0.001). Participants performed LBLM in a similar amount of time with BMS (175.7±59.7s) and PT (166.5±63.6s, p=0.35), but VJ (64.0±24.0s, p<0.001) and IM (144.9±55.4s, p=0.002) were faster. Number of bowel grasps as a measure for the risk of bowel lesions was similar for BMS (15.8±3.0) and PT (15.9±4.6, p=0.861), whereas VJ required less (14.1±3.4, p=0.004) and IM required more than BMS (22.2±6.9, p<0.001). CONCLUSIONS: PT had higher accuracy than VJ and IM, and lower number of bowel grasps than IM. BMS shows great potential for more reliable LBLM. Until BMS is available in clinical routine, PT should be preferred for LBLM.

Influence of Body Mass Index and Gender on Stigmatization of Obesity.

BACKGROUND: Stigmatization and discrimination of people with obesity due to their weight are a common problem that may lead to additional weight gain. This study evaluated the influence of different parameters on the stigmatization of obesity. MATERIAL AND METHODS: Participants of six groups (general population, patients with obesity, medical students, physicians, nurses in training and nurses; n = 490) answered the short-form fat phobia scale (FPS) between August 2016 and July 2017. The influence of body mass index (BMI), gender and other factors on total scores and single adjective pairs was analyzed. RESULTS: A total of 490 participants were evaluated. The total mean FPS rating was 3.5 ± 0.6. FPS was significantly lower (more positive) in participants with obesity (3.2 ± 0.7) compared with participants without obesity (3.5 ± 0.5, p < 0.001). Individuals with obesity and diabetes rated the FPS significantly lower (more positive), whereas age and gender did not have a significant influence. Participants with obesity linked obesity more often with good self-control (p < 0.001), being shapely (p = 0.002), industrious (p < 0.001), attractive (p < 0.001), active (p < 0.001), self-sacrificing (p < 0.001) and having more willpower (p < 0.001) than the participants without obesity. Females rated more positive in shapely versus shapeless (p = 0.038) and attractive versus non-attractive (p < 0.001) than males. CONCLUSIONS: The present study shows that stigmatization of obesity is present in medical professionals as well as the general population. People affected by obesity characterized other people with obesity more positively (e.g. attractive or active), whereas people without obesity linked negative characteristics with obesity. Gender had an influence only on single items of FPS but did not affect overall stigmatization of obesity.

Naturally occurring point mutation Cys460Trp located in the I-EGF1 domain of integrin ß3 alters the binding of some anti-HPA-1a antibodies.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by the destruction of platelets in the fetus or newborn by maternal platelet alloantibodies, mostly against human platelet antigen (HPA)-1a. Recent studies indicate that two anti-HPA subtypes exist: Type I reacts with epitopes residing on the plexin-semaphorin-integrin (PSI) and type II with plexin-semaphorin-integrin/integrin epidermal growth factor 1 (I-EGF1) domains of the ß3 integrin. Here, we evaluated whether a Cys460Trp mutation in the I-EGF1 domain found in a patient with Glanzmann thrombasthenia can alter the binding of anti-HPA-1a. METHODS: Stable HEK293 cell lines expressing wild-type and mutant αIIbß3 and αvß3 were generated to prove the reactivity of different antibodies against HPA-1a. RESULTS: Flow cytometry analysis of wild-type (Cys460) and mutant (Trp460) expressed on HEK293 cells showed equal surface expression of αIIbß3 and αvß3. When tested with mutant αIIbß3 cells, reduced binding was observed in Type II but not in Type I anti-HPA-1a. These results could be confirmed with platelets carrying Cys460Trp mutation. Interestingly, reduced binding of Type I antibodies was detected with mutant αvß3 cells. Both antibody types were found in maternal sera from FNAIT cases by an antigen-capture assay with use of HEK293 transfected cells. CONCLUSIONS: These observations confirm the existence of Type I and Type II anti-HPA-1a. Furthermore, this study underlines different immunogenicity of HPA-1a antigen(s) residing on either αIIbß3 or αvß3. Further analysis of FNAIT cases from mothers having a fetus with and without intracranial bleedings with use of such an approach may highlight the functional relevance of different anti-HPA-1a subtypes.

Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO).

INTRODUCTION: In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. METHODS: Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. RESULTS: We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. CONCLUSIONS: Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

Platelet dysfunction caused by a novel thromboxane A2 receptor mutation and congenital thrombocytopenia in a case of mild bleeding.

Chronic hemorrhagic diathesis in patients showing normal levels of plasmatic clotting factors strongly suggests for congenital platelet disorders. We report on a pediatric patient (male, 3 years, D1) with mild bleeding. A sibling (D2), his mother (D3) and father (D4) were included for laboratory investigation. Platelet counts in D1, D2 and D4 indicated mild thrombocytopenia (100 Gpt/L). D1 and D3 platelets showed significantly diminished aggregation response on arachidonic acid and U46619 stimulation. Immunostaining for platelet proteins on blood smears of D1 and D2 indicated defects in ß1-tubulin. Exon sequencing of TBXA2R and TUBB1 revealed heterozygosity for the novel TBXA2R*c.908T>C (p.L303P) mutation in D1 and D3. TUBB1 was either wild type (D2, D3) or heterozygous (D1, D4) for the common polymorphism TUBB1*c.920G>A (rs6070697; p.R307H). In conclusion, the bleeding phenotype of the index patient can be explained by a diminished platelet function caused by the TBXA2R*c.908T>C mutation inherited from the mother and a mild thrombocytopenia with unknown molecular basis that is inherited from the father.

Heller myotomy versus endoscopic balloon dilatation for achalasia: A single center experience.

This study aimed to compare clinical results, symptom relief, quality of life and patient satisfaction after the 2 most common procedures for achalasia treatment: laparoscopic Heller myotomy (LHM) and endoscopic balloon dilatation (EBD).Patients treated at University Hospital of Heidelberg with LHM or EBD were included. A retrospective chart review of perioperative data and a prospective follow-up of therapeutic efficiency, Gastrointestinal Quality of Life Index (GIQLI) and patient satisfaction was conducted.Follow-up data (mean follow-up: 75.1 ±â€Š53.9 months for LHM group and 78.9 ±â€Š45.6 months for EBD) were obtained from 36 patients (19 LHM; 17 EBD). Eckardt score (median (q1,q3): 2 (1,4) in both groups, P = .91, GIQLI (LHM: 117 (91.5, 126) vs EBD: 120 (116, 128), P = .495) and patient satisfaction (3 (2,3) vs 3 (2,4), P = .883) did not differ between groups. Fifteen patients (78.9%) in LHM group and 11 (64.7%) in EBD group (P = .562) stated they would undergo the intervention again. All patients with EBD had at least 2 dilatations (100%), whilst only 2 patients (10.5%) had dilatation after LHM (P < .001). There were no complications after EBD, but 2 after LHM (10.5%, P = .517).Both LHM and EBD are able to control symptoms and provide similar quality of life and patient satisfaction. However, reintervention rate was higher following EBD, hence LHM provided a more sustained treatment than EBD.