Hybrid simulation: bringing motivation to the art of teamwork training in the operating room.

BACKGROUND AND AIMS: Crew resource management-based operating room team training will be an evident part of future surgical training. Hybrid simulation in the operating room enables the opportunity for trainees to perform higher fidelity training of technical and non-technical skills in a realistic context. We focus on situational motivation and self-efficacy, two important factors for optimal learning in light of a prototype course for teams of residents in surgery and anesthesiology and nurses. MATERIAL AND METHODS: Authentic operating room teams consisting of residents in anesthesia (n = 2), anesthesia nurses (n = 3), residents in surgery (n = 2), and scrub nurses (n = 6) were, during a one-day course, exposed to four different scenarios. Their situational motivation was self-assessed (ranging from 1 = does not correspond at all to 7 = corresponds exactly) immediately after training, and their self-efficacy (graded from 1 to 7) before and after training. Training was performed in a mock-up operating theater equipped with a hybrid patient simulator (SimMan 3G; Laerdal) and a laparoscopic simulator (Lap Mentor Express; Simbionix). The functionality of the systematic hybrid procedure simulation scenario was evaluated by an exit questionnaire (graded from 1 = disagree entirely to 5 = agree completely). RESULTS AND CONCLUSIONS: The trainees were mostly intrinsically motivated, engaged for their own sake, and had a rather great degree of self-determination toward the training situation. Self-efficacy among the team members improved significantly from 4 to 6 (median). Overall evaluation showed very good result with a median grading of 5. We conclude that hybrid simulation is feasible and has the possibility to train an authentic operating team in order to improve individual motivation and confidence.

Mixed virtual reality simulation--taking endoscopic simulation one step further.

This pilot study aimed to assess medical students' appraisals of a "mixed" virtual reality simulation for endoscopic surgery (with a virtual patient case in addition to a virtual colonoscopy) as well as the impact of this simulation set-up on students' performance. Findings indicate that virtual patients can enhance contextualization of simulated endoscopy and thus facilitate an authentic learning environment, which is important in order to increase motivation.

Evaluation of the response to treatment in patients with idiopathic achalasia by the timed barium esophagogram: results from a randomized clinical trial.

To choose which treatment would be most effective for the individual patient with newly diagnosed achalasia is difficult for the tending physician. A diagnostic tool that would allow prediction of the symptomatic and functional response after treatment for achalasia is therefore needed. The timed barium esophagogram (TBE) is a method that allows objective assessment of esophageal emptying, but the value of TBE in the clinical management of achalasia remains to be clarified. The aim of this study was first, to assess the ability of TBE to predict symptoms and treatment failure during post-treatment follow-up. Second, to determine whether esophageal emptying as assessed by TBE differs after treatment with pneumatic dilatation or laparoscopic myotomy. Fifty-one patients with newly diagnosed achalasia were prospectively randomized to pneumatic dilatation (n = 26) or laparoscopic myotomy (n = 25). Evaluation with TBE was performed before (n = 46) and after treatment (n = 43). The median interval between treatment and post-treatment TBE was 6 months, and the median follow-up time after the post-treatment TBE was 18 months. Following therapeutic intervention, TBE parameters did not differ significantly between treatment groups. However, significant correlations were found between the height of the barium column at 1 min and the symptom scores at the end of follow up for 'dysphagia for liquids' (P < 0.05, rho = 0.47), 'chest pain' (P < 0.05, rho = 0.42), and the 'Watson dysphagia score' (P < 0.05, rho = 0.46). Patients with less than 50% improvement in this TBE-parameter (height at 1 min) post-treatment had a 40% risk of treatment failure during follow-up. In summary, pneumatic balloon dilatation and laparoscopic myotomy similarly affected esophageal function as assessed by TBE-emptying. Lack of improvement in barium-column height post-treatment was associated with an increased risk of treatment failure which should motivate close surveillance in order to detect symptomatic recurrence at an early stage.

Visual working memory influences the performance in virtual image-guided surgical intervention.

BACKGROUND: This study addresses for the first time the relationship between working memory and performance measures in image-guided instrument navigation with Minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR) and GI Mentor II (a simulator for gastroendoscopy). In light of recent research on simulator training, it is now prime time to ask why in a search for mechanisms rather than show repeatedly that conventional curriculum for simulation training has effect. METHODS: The participants in this study were 28 Swedish medical students taking their course in basic surgery. Visual and verbal working memory span scores were assessed by a validated computer program (RoboMemo) and correlated with visual-spatial ability (MRT-A test), total flow experience (flow scale), mental strain (Borg scale), and performance scores in manipulation and diathermy (MD) using Procedicus MIST-VR and GI Mentor 11 (exercises 1 and 3). RESULTS: Significant Pearson's r correlations were obtained between visual working memory span scores for visual data link (a RoboMemo exercise) and movement economy (r = -0.417; p < 0.05), total time (r = -0.495; p < 0.01), and total score (r = -0.390; p < 0.05) using MIST-MD, as well as total time (r = -0.493; p < 0.05) and efficiency of screening (r = 0.469; p < 0.05) using GI Mentor 11 (exercise 1). Correlations also were found between visual working memory span scores in rotating data link (another RoboMemo exercise) and both total time (r = -0.467; p < 0.05) and efficiency of screening (r = -0.436; p < 0.05) using GI Mentor 11 (exercise 3). Significant Pearson's r correlations also were found between visual-spatial ability scores and several performance scores for the MIST and GI Mentor II exercises. CONCLUSIONS: Findings for the first time demonstrate that visual working memory for surgical novices may be important for performance in virtual simulator training with two well-known and validated simulators.

Health economic evaluation of therapeutic strategies in patients with idiopathic achalasia: results of a randomized trial comparing pneumatic dilatation with laparoscopic cardiomyotomy.

BACKGROUND: We have prospectively collected information concerning the costs incurred during the management of patients allocated to either forceful dilatation or to an immediate laparoscopic operation because of newly diagnosed achalasia. METHODS: Fifty-one patients with newly diagnosed achalasia were randomized to either pneumatic dilatation to a diameter of 30-40 mm or to a laparoscopic myotomy to which was added a posterior partial fundoplication. Follow-ups were scheduled at 1, 3, 6, and 12 months after inclusion. At each follow-up visit a study nurse interviewed the patients regarding symptoms and their quality of life (QoL) and a health economic questionnaire was completed. In the latter questionnaire, patients were asked to report the presence and character of contacts with the healthcare system since the last visit. RESULTS: In the dilatation group six patients (23%), including the patient who was operated on because of perforation, were classified as failures during the first 12 months of follow-up compared to one (4%) in the myotomy group (p = 0.047). Five of those classified as failures in the dilatation group subsequently had a surgical myotomy and the sixth patient was treated with repeated dilatations. The patient classified as failure in the myotomy group was treated with endoscopic dilatation. The initial treatment cost and the total costs were significantly higher for laparoscopic myotomy compared to a pneumatic dilatation-based strategy (p = 0.0002 and p = 0.0019, respectively). When the total costs were subdivided into the different resources used, we found that the single largest cost item for pneumatic dilatation was that for hospital stay and that for laparoscopic myotomy was the actual operative treatment (operating room time). The cost-effectiveness analysis, relating to the actual treatment failures, revealed that the cost to avoid one treatment failure (incremental cost-effectiveness ratio) amounted to 9239 euros. CONCLUSION: The current prospective, controlled clinical trial shows that despite a higher level of clinical efficacy of laparoscopic myotomy to prevent treatment failure in newly diagnosed achalasia, the cost effectiveness of pneumatic dilatation is superior, at least when a reasonable time horizon is applied.

Pneumatic dilatation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. Results of a randomized controlled trial.

BACKGROUND: The most effective therapeutic strategy in newly diagnosed achalasia is yet to be established. Therefore we designed a study in which pneumatic dilatation was compared to laparoscopic cardiomyotomy to which was added a partial posterior fundoplication. PATIENTS AND RESULTS: A series of 51 patients (24 males, mean age 44 years) were randomly allocated to the therapeutic modalities (dilatation = 26, surgery = 25). All patients were followed for at least 12 months, and during that period the pneumatic dilatations strategy had significantly more treatment failures (P = 0.04). Only minor differences emerged between the study groups when symptoms, dysphagia scorings, and quality-of-life assessments were evaluated 12 months after initiation of therapy. CONCLUSIONS: Laparoscopic myotomy was found to be superior to an endoscopic balloon dilatation strategy in the treatment of achalasia when studied during the first 12 months after treatment.

Characteristics of timed barium esophagogram in newly diagnosed idiopathic achalasia: clinical and manometric correlates.

PURPOSE: To describe timed barium esophagogram (TBE) characteristics in patients with newly diagnosed idiopathic achalasia, and to correlate these with clinical and manometric variables. MATERIAL AND METHODS: Forty-six consecutive patients with newly diagnosed achalasia were examined with TBE. Esophageal emptying was assessed using the height, area, and volume of the barium column. Subjective evaluation was performed according to a standardized protocol in all patients. Objective diagnostic evaluation included manometry. RESULTS: At the 1-min time point after contrast ingestion, the static parameters median height, maximum, and mean width of the barium column were 16.0, 4.4, and 3.3 cm, respectively. Emptying, expressed as volume of barium, showed significant inverse correlation with the resting and the maximal relaxing pressure of the lower esophageal sphincter (LES) (R = -0.34 and R = -0.54, respectively). There was also an inverse correlation between emptied volume at TBE and the duration of symptoms (R = -0.36), and between barium column width and postprandial chest pain (R = -0.44). CONCLUSION: All patients with newly diagnosed achalasia presented with delayed emptying of barium the esophagus at TBE. The estimated emptied volume of barium (related to the ingested volume) correlated inversely with the basal tone and the relaxation pressure of the LES. Including estimation of the volume of emptied barium at TBE resulted in closer correlation with manometric values of LES tone than using the parameters traditionally recorded.

High-level visual-spatial ability for novices correlates with performance in a visual-spatial complex surgical simulator task.

BACKGROUND: This study addresses how high-level visual-spatial ability of surgical novices is related to performance of two simulator tasks with (KSA) and without (MIST) anatomic graphics and haptic feedback, differing in visual-spatial complexity. METHODS: Visual-spatial test scores assessed by Mental Rotation Test (MRT) and BasIQ and performance scores for Instrument Navigation (IN) in Key Surgical Activities (Procedicus KSA) and Manipulate and Diathermy (MD) in Minimally Invasive Surgical Trainer (Procedicus MIST) were correlated for 54 Swedish surgical novices. RESULTS: Significant Pearson's r correlations were obtained between visual-spatial scores measured by MRT-C and total score from the last trial for IN (r = 0.278, p < 0.05). Visual-spatial scores (measured by BasIQ) also correlated with total score from the first trial (r = 0.443, p < 0.05) and from the last trial (r = 0.489, p < 0.05). CONCLUSION: High-level visual-spatial ability is important for surgical novices to possess in the early training phase of a visual-spatial complex task in KSA.

Early exposure to haptic feedback enhances performance in surgical simulator training: a prospective randomized crossover study in surgical residents.

BACKGROUND: In the literature of skill acquisition and transfer of skills, it often is assumed that the rate of skill acquisition depends on what has been learned in a similar context (i.e., surgical simulators providing haptic feedback). This study aimed to analyze whether the addition of haptic feedback early in the training phase for image-guided surgical simulation improves performance. METHODS: A randomized crossover study design was used, in which 38 surgical residents were randomized to begin a 2-h simulator training session with either haptic or nonhaptic training followed by crossover after 1 h. The graphic context was a virtual upper abdomen. The residents performed two diathermy tasks. Two validated tests were used to control for differences in visual-spatial ability: the BasIQ general cognitive ability test and Mental Rotation Test A (MRT-A). RESULTS: After 2 h of training, the group that had started with haptic feedback performed the two diathermy tasks significantly better (p < 0.05, unpaired t-test). Only the group that had started with haptic training significantly improved during the last 1-h session (p < 0.01, paired t-test). CONCLUSION: The findings indicate that haptic feedback could be important in the early training phase of skill acquisition in image-guided surgical simulator training.

Objective assessment of visuospatial and psychomotor ability and flow of residents and senior endoscopists in simulated gastroscopy.

BACKGROUND: Advanced medical simulators have predominantly been used to shorten the learning curve of endoscopy for medical students and young residents. Rarely have the effects of visuospatial ability and attitudes of intermediately experienced and experienced specialists been studied with regard to simulator training. The aim of this study was to assess the effects of visuospatial ability and attitude on performance in simulator training. METHODS: Eighteen surgical residents were included in the study. Prior to the simulated gastroscopy task, they performed a visuospatial test (the card rotation test). After the simulated gastroscopy task, they completed a questionnaire regarding flow experiences. Their results were compared with those of 11 expert endoscopists who performed the same tests. RESULTS: Total gastroscopy time was significantly shorter for the expert endoscopists compared to residents (2 min 11 sec, p = 0.003). There was also a trend of more mucosa inspected (p = 0.088) and higher efficiency of screening (p = 0.069) by the experts. The residents made fewer errors in the card rotation test than the expert endoscopists (2.5 +/- 0.8 vs 5.5 +/- 1.2, respectively; p = 0.034), and their visuospatial card rotation test results correlated better with their performance in the simulated gastroscopy. CONCLUSIONS: A virtual gastroscopy task presents more of an emotional as well as a psychomotoric challenge to intermediately experienced endoscopists than to senior experts. Our study demonstrates that these differences can be objectively assessed by the use of visuospatial ability tests, flowsheets, and an endoscopic simulator.

Histology of esophageal mucosa from patients with achalasia.

When achalasia becomes far advanced and leads to esophageal resection, inflammation of the esophageal mucosa is almost universal. The histology of the esophageal mucosa in less advanced cases of achalasia has not been firmly established. We have studied endoscopic biopsies obtained during evaluation of patients with achalasia. Two to four endoscopic biopsies from the lower esophagus of 26 patients with manometrically verified achalasia were mounted on mesh, serially sectioned, stained, coded and interpreted by two independent observers using recognized criteria. The histological findings were correlated with clinical data. Ten of 26 patients had at least one abnormal biopsy. Five of these 10 patients had a previous Heller myotomy; another patient had several pneumatic dilatations, and two other patients had endoscopically proven candida infections. Of the 16 patients with normal histology, four had prolonged stasis, five had heartburn and one patient had both heartburn and stasis. Unless the patient with achalasia has had a Heller myotomy, balloon dilatation, or a candida infection, the esophageal mucosa on biopsy appears to be within normal limits, even in patients with years of esophageal stasis or complaints of heartburn.

Training in tasks with different visual-spatial components does not improve virtual arthroscopy performance.

BACKGROUND: We earlier showed that training in the Procedicus KSA Simulator improves the performance of tasks done later in the same simulator. However, it is still unclear how performance in a specific visual-spatial simulator context may change after training in other simulators with different visual-spatial components. In particular, the aim of this study was to test whether performance in the Procedicus Virtual Arthroscopy (VA) Knee Simulator would remain unchanged after a training session in three other simulators with different visual-spatial components. METHODS: Twenty-eight medical students participated in a quasi-transfer study. They were randomly allocated to an experimental group ( n = 14) and a control group ( n = 14). RESULTS: Performance in the Procedicus VA Knee Simulator did not improve after training in other simulators with different visual-spatial components ( t-test p = NS). No significant correlation was found between the Procedicus VA Knee and the Minimally Invasive Surgical Trainer (MIST) simulators. CONCLUSION: One hour of training in different visual-spatial contexts was not enough to improve the performance in virtual arthroscopy tasks. It cannot be excluded, however, that experienced trainees could improve their performance, because perceived similarity between different situations is influenced by many psychological factors, such as the knowledge or expertise of the person performing the transfer task.

Heller's esophagomyotomy with or without a 360 degrees floppy Nissen fundoplication for achalasia. Long-term results from a prospective randomized study.

Heller's esophagomyotomy relieves dysphagia but does not restore esophageal peristalsis. The myotomy may induce reflux and the addition of a 360 degrees fundoplication may be hazardous with regard to the remaining aperistaltic esophagus. The aim of this prospectively randomized clinical trial was to compare the outcome for patients with uncomplicated achalasia who underwent an anterior Heller's esophagomyotomy (H group) with or without an additional floppy Nissen fundoplication (H + N group). Between 1984 and 1995, 20 patients were prospectively randomized to one or other of the performed operations, 10 patients per group. Esophagitis including Barrett's esophagus (n = 2) was seen under medical treatment, in 6 of 9 in the H group but none in the H + N group. No patient in the H + N group required postoperative continuous acid-reducing drugs. Twenty-four-hour esophageal pH-studies in median 3.4 years after surgery showed pathological reflux expressed as a percentage of time below pH 4 of 13.1% in the H group compared to 0.15% (P < 0.001) in H + N group. One patient with recurrent dysphagia in the H + N group later had an esophagectomy. The remaining patients reported significant improvement of dysphagia without symptoms of reflux at 8.0 years follow-up. Heller's esophagomyotomy eliminates dysphagia, but can induce advanced reflux that requires medical treatment. The addition of a 360 degrees fundoplication eliminates reflux without adding dysphagia in the majority of patients and can be recommended for most patients with uncomplicated achalasia.

Validation and learning in the Procedicus KSA virtual reality surgical simulator.

BACKGROUND: Advanced simulator training within medicine is a rapidly growing field. Virtual reality simulators are being introduced as cost-saving educational tools, which also lead to increased patient safety. METHODS: Fifteen medical students were included in the study. For 10 medical students performance was monitored, before and after 1 h of training, in two endoscopic simulators (the Procedicus KSA with haptic feedback and anatomical graphics and the established MIST simulator without this haptic feedback and graphics). Five medical students performed 50 tests in the Procedicus KSA in order to analyze learning curves. One of these five medical students performed multiple training sessions during 2 weeks and performed more than 300 tests. RESULTS: There was a significant improvement after 1 h of training regarding time, movement economy, and total score. The results in the two simulators were highly correlated. CONCLUSION: Our results show that the use of surgical simulators as a pedagogical tool in medical student training is encouraging. It shows rapid learning curves and our suggestion is to introduce endoscopic simulator training in undergraduate medical education during the course in surgery when motivation is high and before the development of "negative stereotypes" and incorrect practices.

[Simulator training in medicine and health care. A new pedagogic model for good patient safety]. / Simulatorträning inom medicinsk verksamhet. Ny pedagogisk modell för god patientsäkerhet.

Advanced simulation within medicine and health care is a rapidly growing field. Simulator based training can be applied in minimal invasive surgery, in endoscopic procedures as well as in anaesthesia and critical care management. At Huddinge University Hospital a center for advanced simulation of both endoscopic surgery and anaesthesia/critical care management is currently being set up. The objective is to focus on improved medical and health care training and thus improving patient safety by reducing medical errors.

Omeprazole and CYP2C19 polymorphism: effects of long-term treatment on gastrin, pepsinogen I, and chromogranin A in patients with acid related disorders.

BACKGROUND: The polymorphic enzyme CYP2C19 is of importance for the metabolism and effects of omeprazole during short-term treatment. AIM: To investigate the relationship between CYP2C19 genotype and the effects of long-term omeprazole treatment. MATERIAL AND METHODS: A total of 180 patients with acid related disorders were genotyped for wild type and mutated CYP2C19 alleles by allele-specific PCR amplification. Gastrin and chromogranin A were assessed by radioimmunoassays, and pepsinogen I and H. pylori serology were assessed by ELISA methods. RESULTS: In 108 of the patients, who received a single dose of 20 mg omeprazole, there was no difference in gastrin and chromogranin A concentrations between the three CYP2C19 genotypes. In 72 patients on long-term treatment (> 1 year) with 20 mg omeprazole daily, serum gastrin as well as plasma chromogranin A concentrations (mean +/- s.e.) were both about threefold higher in the wild type/mutated (52.1 +/- 7.6 pM and 7.3 +/- 1.3 nM (n=19), respectively) compared to wild type/wild type (14. 7 +/- 0.9 pM and 2.5 +/- 0.1 nM (n=52), respectively; both comparisons P=0.0001). In a single mutated/mutated patient on long-term treatment, both gastrin and chromogranin A were high (88 pM and 13.7 nM, respectively). Serum pepsinogen I concentration was significantly lower in wild type/mutated (n=19) patients on long-term treatment, compared with the corresponding wild type/wild type (n=49) group (147 +/- 19 microg/L vs. 193 +/- 12 microg/L, P=0. 04). CONCLUSION: Patients with one (and probably also with two) mutated CYP2C19 allele(s) on long-term treatment with omeprazole had significantly affected serum gastrin and pepsinogen I and plasma chromogranin A concentrations compared with patients with two normal alleles. This indicates that changes in gastric mucosal morphology during omeprazole treatment might be dependent upon the degree of the individual's capacity to metabolize omeprazole.

Gastric stasis in neuronal nitric oxide synthase-deficient knockout mice.

BACKGROUND & AIMS: Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut. This study aimed to identify the effect of chronic deprivation of NO derived from neuronal (nNOS) or endothelial (eNOS) nitric oxide synthase on gastric emptying. METHODS: nNOS-deficient (knockout) mice were compared with wild-type mice for gastric size, fluoroscopic appearance after gavage of contrast, and histology of the pyloric sphincter. Wild-type mice treated with the NOS inhibitor N(omega)-nitro L-arginine (L-NA) and eNOS-deficient mice were also compared with wild-type and nNOS-deficient mice for liquid and solid gastric emptying. RESULTS: nNOS-deficient mice showed gastric dilation. Fluoroscopy showed delayed gastric emptying of radiologic contrast. There was no marked localized hypertrophy or luminal narrowing at the pyloric sphincter by histology of relaxed wild-type, nNOS-deficient, and eNOS-deficient tissues. Gastric emptying of both solids (28% +/- 27%) and liquids (22% +/- 18%) was significantly delayed in nNOS-deficient mice compared with control wild-type mice (82% +/- 22% for solids; 48% +/- 17% for liquids). eNOS-deficient mice showed no significant difference from wild-type mice (74% +/- 28% for solids; 47% +/- 23% for liquids). Wild-type mice treated acutely with L-NA showed delay in emptying of solids (43% +/- 31%) but not liquids (39% +/- 15%). CONCLUSIONS: Chronic depletion of NO from nNOS, but not eNOS, results in delayed gastric emptying of solids and liquids.

Laparoscopic myotomy without fundoplication in patients with achalasia.

OBJECTIVE: Analysis of outcome after laparoscopic myotomy for achalasia. DESIGN: Prospective audit. SETTING: Teaching hospital, Sweden. SUBJECTS: All patients with achalasia who had a laparoscopic myotomy without a simultaneous fundoplication. INTERVENTIONS: Questionnaire, pH-measurements, radiography and manometry. MAIN OUTCOME MEASURES: Operative and postoperative complications and reoperations. RESULTS: Twenty-one patients were scheduled for laparoscopic myotomy. Three were converted to open operations, and four were reoperated on transabdominally for persistent or recurrent symptoms. All patients were satisfied afterwards. Follow-up in 14 patients, after a median of 22 months (range, 6-40), included manometry, questionnaire, and 24-hour pH measurements, and showed significant reduction in the lower oesophageal sphincter pressure together with relief of symptoms. Three patients had reflux symptoms and abnormal pH readings. An additional five patients had abnormal pH measurements but no symptoms of reflux. CONCLUSIONS: Heller myotomy can safely be done laparoscopically. Whether a simultaneous antireflux procedure is needed remains to be seen.

Gastroesophageal reflux in obese patients is not reduced by weight reduction.

BACKGROUND: The present study tested the hypothesis that weight reduction improves the subjective and objective manifestations of gastroesophageal reflux. METHODS: Twenty obese patients with gastroesophageal reflux as shown by 24-h pH measurement and with symptoms requiring daily medication were studied. The patients were randomized into a group (A) treated with very low-caloric diet (VLCD) and a control group (B). Objective measurements were repeated after 6 months. Group B was then treated with VLCD and reexamined. RESULTS: Patients in group A lost 10.8 +/- 1.4 kg whereas group B gained 0.6 +/- 0.7 kg (P < 0.001). There was no reduction in reflux according to pH measurement. Furthermore, there were no significant changes in reflux symptoms. After VLCD treatment, group B lost 9.7 +/- 1.6 kg, but reflux indicators remained unchanged. All patients except one in group B remained dependent on daily anti-reflux medication. CONCLUSION: Weight reduction does not improve the subjective or objective manifestations of reflux.

Comparison of oral treatment with zinc sulphate and placebo in acne vulgaris.

In a double-blind study 91 patients with acne vulgaris were treated either with oral zinc sulphate (0.4 g daily) or with a placebo. Forty-eight patients received zince treatment and 43 patients placebo. Significantly better results were demonstrated in favour of zince after 12 weeks.