[Analysis of the effect of modified cervical cerclage in the treatment of cervical insufficiency].

Objective: To discuss the surgical effect of modified cervical cerclage for the treatment of pregnant women with cervical insufficiency. Methods: The clinical data of 225 pregnant women who underwent modified cervical cerclage in Qilu Hospital (Qingdao) were selected for retrospective analysis from April 2014 to June 2020. Surgical success rate, full-term birth rate, preterm birth rate, prolonged pregnancy weeks and newborn birth weight were compared between singleton and twin pregnancies, preventive cerclage and emergency cerclage, surgery before and after 18 weeks, naturally and in vitro fertilization and embryo transfer (IVF-ET) conceived pregnant women respectively. Results: Among the 225 pregnant women, the gestational weeks of surgery were 14-24+5 weeks, mean gestational weeks of delivery were 38+2 weeks (35+5-39+3 weeks), the number of prolonged gestation were (20.3±5.2) weeks, and the newborn birth weight was (3 065±735) g; the overall surgical success rate was 92.9% (209/225), and the miscarriage rate was 7.1% (16/225); among the surviving newborns, the full-term birth rate was 73.7% (154/209), and the preterm birth rate was 26.3% (55/209). All cases had no intraoperative complications. Among the 225 pregnant women, 202 (89.8%, 202/225) cases were singleton pregnancies, and 23 (10.2%, 23/225) cases were twin pregnancies; 201 (89.3%, 201/225) cases underwent preventive cervical cerclage, and 24 (10.7%, 24/225) cases underwent emergency cervical cerclage; 190 (84.4%, 190/225) cases underwent the surgery before 18 weeks, and 35 (15.6%, 35/225) cases underwent the surgery after 18 weeks; 49 (21.8%, 49/225) cases were conceived by IVF-ET. There was no statistically significant difference in the overall surgical success rate of single and twin group (P>0.05). The full-term birth rate, newborn birth weight and prolonged pregnancy weeks of single group were higher than those of twin group (P<0.05). There were no statistical differences between preventive and emergency cerclage in overall surgical success rate, full-term birth rate, preterm birth rate, and newborn birth weight (all P>0.05). The pregnancy prolonged weeks of preventive cerclage was higher than that of emergency cerclage (P<0.05). There were no statistically significant differences in the overall surgical success rate, full-term birth rate, preterm birth rate and birth weight of newborns at different surgical timings (all P>0.05). The pregnancy prolonged week for those who underwent surgery before 18 weeks was higher than that of surgery after 18 weeks (P<0.05). The premature birth rate of IVF-ET was higher than that of naturally conceived pregnant women (P<0.05). Conclusion: The modified cervical cerclage could effectively prolong the gestational weeks of delivery, reduce the rate of preterm birth, and the operation is simple and easy to promote. It could be used as a surgical option for patients with cervical insufficiency.

[Comparison of balloon catheter dilatation and silicon intubation as the secondary treatment for congenital nasolacrimal duct obstruction after failed primary probing].

OBJECTIVE: To determine the success rates and compare the results of balloon catheter dilation and nasolacrimal intubation as treatment for congenital nasolacrimal duct obstruction after failed probing, stratified by category of age and type of obstruction. METHODS: It was a prospective, randomized, clinical trial that enrolled 189 children (245 eyes) aged between 6 months to 48 months who had a history of failed nasolacrimal duct probing. All eyes underwent either balloon catheter nasolacrimal duct dilation or nasolacrimal duct intubation randomly. The eyes were divided into 2 age categories: category 1 (6-24 months) and category 2 (>24 months) and into 2 types of obstructions: simple obstruction and complex obstruction. Treatment success was defined as absence of epiphora, mucous discharge, or increased lacrimal lake at the outcome visit 6 months after surgery. Complications were also compared. RESULTS: In 124 eyes treated with balloon catheter dilatation, 112 were successful (90.3%) comparing with 106 successful eyes (87.6%) in 121 eyes treated with nasolacrimal duct intubation. The risk ratio for success between intubation and balloon dilation was 0.971, and the 95% confidence interval was 0.95-1.22. Within each age category, the success rate varied but did not show significant difference: In those under 24 months, success rate was 89.7% in 97 eyes treated with intubation, and 91.9% in 99 eyes treated with balloon dilation (RR, 0.976; 95% CI, 0.590-0.956). In those above 24 months, success rate was 79.1% in 24 eyes treated with intubation, and 84.0% in 25 eyes treated with balloon dilation (RR, 0.942; 95%CI, 0.813-1.387). In the group of simple obstruction, success rate was 96.5% in 87 eyes treated with intubation, and 93.1% in 88 eyes treated with balloon dilation (RR, 1.036; 95% CI, 0.967-1.105). In the group of complex obstruction, Success rate was 64.7% in 34 eyes treated with intubation, and 86.1% in 36 eyes treated with balloon dilation. The success rate of balloon dilatation showed slightly higher than that of intubation (RR, 0.751; 95% CI, 0.590-0.956). There were 59 eyes showed complications in intubation group, while only 2 eyes in balloon dilation group. CONCLUSIONS: Both balloon catheter dilation and nasolacrimal duct intubation could alleviate the clinical signs of persistent nasolacrimal duct obstruction with a similar percentage of patients. In the complex obstruction group, balloon catheter dilation showed better efficacy than nasolacrimal duct intubation.

Automated Secchi disk depth measurement based on artificial intelligence object recognition.

Water transparency affects the degree of sunlight penetration in water, which is important to many water quality processes. It can be visually measured by lowering a Secchi disk (SD) into water and recording its disappearance depth - the Secchi disk depth (SDD). High frequency SDD measurement is manpower intensive, precluding better understanding of the daily and diurnal variation of water transparency. For the first time, an artificial intelligence based object detection algorithm was employed for the automatic detection of SD from images, mimicking SDD measurement by human eyes. The trained model was validated on a large number of images (about 2000 for a single day in daytime) obtained from a remote-controlled imaging system in a fish farm in a Hong Kong embayment, demonstrating high detection accuracy of 93 %. The work opens up opportunities in the nowcast and forecast of short-term water quality changes (e.g. algal blooms) in coastal waters.

Intramedullary spinal schwannoma: case report and review of preoperative magnetic resonance imaging features.

Intramedullary schwannomas are rare spinal cord tumours. Correct preoperative diagnosis is essential for proper surgical planning and complete resection. We present a case of cervical intramedullary schwannoma followed by discussion on its preoperative magnetic resonance imaging features and review of the literature.

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation.

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.

Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic factor, which is known to be upregulated in most cases of glioblastoma multiforme (GBM). The expression of VEGF and its receptors in ependymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been studied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 12 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Results showed that VEGF was moderately to strongly expressed in 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and glioblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression consistently seen in tumor cells around necrotic areas. The VEGF expression, although present at a lower level, also was shown in 4 of 12 oligodendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplastic astrocytomas, with a regional rather than diffuse pattern of positive result. The findings from the in situ hybridization study correlated with the expression index, as determined by reverse transcription polymerase chain reaction. Expression of VEGF was correlated significantly with vascular proliferation (p < 10(-5)) and necrosis (p < 10(-5)), as well as with microvessel density (p = 0.002, rs = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (Flt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necrosis, whereas the astrocytomas grade II, anaplastic astrocytomas, and oligodendroglioma tumors tended to express a weak to nondetectable signal. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vascular proliferation, followed by an accelerated phase of angiogenesis closely associated with VEGF induction around areas of necrosis and with the expression of VEGF receptors in the tumor vasculature.

Expression of vascular endothelial growth factor in von Hippel-Lindau syndrome-associated papillary cystadenoma of the epididymis.

Vascular endothelial growth factor (VEGF) is a hypoxia inducible angiogenic and vascular permeability factor. Although VEGF expression in glioblastoma is induced by hypoxia, its expression in renal cell carcinoma and hemangioblastoma is thought to be related to mutation of the von Hippel-Lindau (VHL) gene. It is not certain whether other lesions in VHL syndrome are associated with an elevated VEGF level. We report a VHL syndrome patient with multiple hemangioblastomas and bilateral epididymal clear cell papillary cystadenomas. In situ hybridization revealed high levels of VEGF mRNA in the clear cells of the epididymal tumor and the stromal cells of the hemangioblastoma. This lends support to the notion that upregulation of VEGF is caused by loss of the wild-type VHL protein. We postulate that the elevated VEGF levels may account for the cyst formation and vascularized stroma present in these VHL-associated tumors.

Esophagogastric anastomosis performed with a stapler: the occurrence of leakage and stricture.

The circular stapler has lowered the leakage rate of an esophageal anastomosis to a level hitherto achieved by only a few surgeons performing hand anastomosis on selected patients with carcinoma of the esophagus. However, the esophageal anastomosis performed with a stapler is also associated with a high stricture rate. Our prospective study was conducted to determine the leakage rate and the incidence of stricture after esophagogastric anastomosis was performed with a stapler, the relationship of stricture to the size of the stapler, and the risk of stricture in relation to time. In a group of 174 patients with carcinoma of the thoracic esophagus, resection was performed, and a one-stage esophagogastric anastomosis was constructed. There were 33 hand anastomoses, 64 anastomoses with an EEA stapler (U.S. Surgical Corp., Norwalk, Conn.), and 77 anastomoses with an ILS stapler (Ethicon Ltd., Edinburgh, U.K.). The anastomotic leakage rate was 3.4% (6/174); 3% with the hand technique and 3.5% with the stapler technique (4.7% for the EEA and 2.6% for the ILS). After leakages and hospital deaths were excluded, 133 discharged patients were evaluated for the occurrence of anastomotic strictures. Only those who complained of dysphagia were investigated. The incidence of stricture for hand anastomosis was 8.7%-EEA 20% and ILS 10%; the overall incidence of anastomoses with a stapler was 14.5%. The true incidence would probably be higher if all patients were assessed by endoscopic or radiologic examination after operation. All three sizes of EEA staplers had a high incidence of stricture. For the ILS stapler the 25 mm size had the highest stricture rate (28.6%) of all groups, but for the 29 and 33 mm sizes, the incidences were 5.3% and 0%, respectively. Actuarial analysis showed an increasing risk of stricture with a reduction in the size of stapler used and was 32.5% and 35%, respectively, for the ILS 25 mm and EEA 25 mm staplers at 131/2 months. The risk of stricture occurrence was highest in the first 4 months. Treatment by bougienage was satisfactory. In conclusion, esophagogastric anastomosis performed with a stapler is a very safe procedure with respect to leakage but is associated with a high risk of stricture, except when the largest ILS staplers are used. However, dilatation readily overcomes the stricture occurrence and adequately compensates for the reduced leakage rate and its attendant serious consequences.

Culture of neural cells on silicon wafers with nano-scale surface topograph.

The adherence and viability of central neural cells (substantia nigra) on a thin layer of SiO(2) on Si wafers with different surface roughness were investigated. Variable roughness of the Si wafer surface was achieved by etching. The nano-scale surface topography was evaluated by atomic force microscopy. The adherence and subsequent viability of the cells on the wafer were examined by scanning electron microscopy (SEM) and fluorescence immunostaining of tyrosine hydroxylase (TH). It is found that the surface roughness significantly affected cell adhesion and viability. Cells survived for over 5 days with normal morphology and expressed neuronal TH when grown on surfaces with an average roughness (Ra) ranging from 20 to 50 nm. However, cell adherence was adversely affected when surfaces with Ra less than 10 nm and rough surfaces with Ra above 70 nm were used as the substrate. Such a simple preparation procedure may provide a suitable interface surface for silicon-based devices and neurones or other living tissues.

An epithelial cyst in the cerebellopontine angle. Case report.

A case of a benign epithelial cyst in the posterior cranial fossa is described. It had the unique histological feature of a double-layered cuboidal epithelial lining. Detailed immunohistochemical and electron microscopic studies supported an endodermal origin. The differential diagnosis and the histogenesis of epithelial cysts in the central nervous system are discussed.

The significance of skull fracture in acute traumatic intracranial hematomas in adolescents: a prospective study.

A prospective study was conducted to validate the retrospective finding that adolescents (11 to 15 years old) with skull fractures were prone to develop acute traumatic intracranial hematoma (ICH). Over a 4-year period, 1178 consecutive adolescents attended the emergency room directly, of whom 760 were discharged well and 418 were admitted. All underwent skull x-ray studies. Immediate computerized tomography (CT) scans were performed in patients with Glasgow Coma Scale (GCS) scores of less than 15, in those with radiological and/or clinical evidence of skull fracture, and whenever clinically indicated. Of the 418 admitted patients, only 26 had skull fractures; 13 of these developed ICH. Four patients without skull fracture developed diffuse brain swelling. The remaining 401 patients were discharged after observation periods of up to 48 hours. Of the 13 patients with ICH, 10 had admission GCS scores of 15; however, four deteriorated rapidly and required urgent operation, and four remained stable but were operated on due to their large ICH. Two required conservative treatment only and both made good recovery. Three patients were in coma (GCS score less than or equal to 8) on admission. One patient had an epidural hematoma and made good recovery after surgery. Two developed delayed ICH after operations for associated systemic injuries despite initial CT showing diffuse brain swelling only, and both died despite evacuation of the ICH. Multivariate analysis showed that skull fracture was the only independent significant risk factor in predicting ICH in adolescents (sensitivity of 100% and specificity of 97%). A routine skull x-ray study is therefore mandatory in all head-injured adolescents and, if a skull fracture is detected, immediate CT may be performed for early detection of ICH.

Prospective double-blind placebo-controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications in high-risk neurosurgical patients.

To determine the efficacy of ranitidine in preventing clinically acute overt gastroduodenal (GD) complications (bleeding and/or perforation) after neurosurgery, 101 patients with nontraumatic cerebral disease considered at high risk of developing postoperative GD complications were randomized in a standard double-blind manner to receive either ranitidine (50 mg every 6 hours) or placebo medication preoperatively. Postoperative serial GD endoscopy was used to document the occurrence of complications: an overt symptomatic complication was defined as bleeding requiring blood transfusion and/or surgery. Fifty-two patients received ranitidine and 49 received a placebo preoperatively; 30 developed overt GD bleeding; nine of these received ranitidine and 21 received a placebo. Ranitidine significantly reduced the incidence of bleeding (p < 0.05). Multivariate logistic regression analysis revealed three factors of independent significance in predicting overt GD bleeding: use of a placebo drug, a gastric pH of less than 4, and a high daily volume of gastric output. The authors conclude that ranitidine is useful in preventing postoperative GD complications in high-risk neurosurgical patients.

Case report: intraventricular meningioma with cerebellopontine angle and drop metastases.

A 34-year-old Chinese woman underwent successful gross total excision of a benign fibroblastic meningioma, pre-operatively diagnosed by computed tomography (CT), arising from the left lateral ventricle of the brain. After a quiescent period of 5 years, CT and magnetic resonance imaging (MRI) demonstrated tumour recurrence at the same site. Despite two further excisions of progressively malignant intraventricular meningiomas and treatment with radiotherapy, the patient rapidly developed bilateral cerebellopontine angle and spinal drop metastases. CT and MRI were useful in demonstrating the location and extent of recurrent intraventricular meningiomas, as well as metastatic spread via the cerebrospinal fluid.

Metastatic adenocarcinoma masquerading as basal pontine tuberculoma.

Tuberculous infection of the central nervous system is common in Hong Kong. A 39-year-old woman presented with isolated right sixth nerve palsy which was non-progressive for 10 months. Neuro-imaging revealed a right pontine lesion. Cerebrospinal fluid (CSF) examination showed lymphocytic meningitis with negative bacteriological and cytological studies. Empirical antituberculous drugs with initial corticosteroid resulted in improved CSF parameters. A diagnosis of cerebral tuberculoma complicated by meningitis was made. She subsequently deteriorated clinically and radiologically. Despite a number of clinical features which were atypical of leptomeningeal metastasis, adenosquamous carcinoma was found on biopsy. Her relatively indolent clinical course might be due to the initial corticosteroid treatment. This report illustrates the importance of early tissue diagnosis in uncertain cases of chronic lymphocytic meningitis.

Retrograde suction decompression of paraclinoid aneurysm--a revised technique.

BACKGROUND: Aneurysms of the ophthalmic segment of the carotid artery are difficult lesions to handle. Batjer and Samson described the technique of suction decompression of the aneurysm by inserting a needle and aspirating blood from the internal carotid artery in the neck. However, this method carries a risk of arterial dissection and distal embolization. METHOD: We describe a revised technique for suction decompression of paraclinoid aneurysms. The method makes use of the anatomical advantage of the carotid bifurcation. Instead of direct clamping of the internal carotid artery, we isolated the common and external carotid arteries and decompressed the aneurysm via the external carotid artery. We also saved the aspirated blood for autotransfusion. RESULTS: We have used this technique in two elderly patients with good results. CONCLUSION: This technique avoids dissection of the internal carotid artery and minimizes the risk of embolization.

Perioperative deep vein thrombosis in Chinese patients undergoing craniotomy.

BACKGROUND: We attempted to determine the incidence of perioperative deep vein thrombosis (DVT) in Chinese patients undergoing elective craniotomy for brain tumors and to assess the efficacy of clinical and serial calf circumference assessment in detecting DVT. METHODS: Between June 1999 and February 2001, 100 consecutive patients who underwent elective craniotomy for brain tumors at the Department of Neurosurgery, University of Hong Kong Medical Centre were examined for perioperative DVT. The demographic data, Glasgow coma score (GCS), mobility status, and the operative details were recorded. Graduated compression stockings and intermittent pneumatic compression were applied perioperatively as prophylaxis against DVT. Serial duplex scans were performed before and after operation. Clinical examination was also performed daily to look for signs of DVT. The calf circumference was measured at fixed levels for both limbs before each duplex scan surveillance. RESULTS: The study group consisted of 44 males and 56 females, with a mean age of 54 +/- 15 years (range, 20-81 years). There was no preoperative DVT. Postoperative DVT was detected on duplex scan in four patients (4%), two of whom had bilateral involvement. The thrombosis was confined to the calf veins in two limbs. The demographic data, neurologic status and operative details of patients with and without DVT were similar. Patients with DVT had no clinically recognizable signs. The change in calf circumference measurement was also not predictive of DVT. CONCLUSIONS: The incidence of perioperative DVT in Chinese patients undergoing elective craniotomy for brain tumors appears to be low with the present mechanical prophylactic measures. Given the low incidence of proximal DVT as detected by duplex scan, the use of heparin prophylaxis may not be justified because of the increased risk of intracranial bleeding. Clinical assessment with calf circumference measurement is unreliable in the diagnosis of DVT.

A simple computerized tomography adapter for conventional stereotactic frame.

This paper introduces a new technique to convert a conventional Leksell stereotactic frame into a computerized tomography compatible system. Accurate calculation of the tumour coordinates can be made by means of two adapter plates with double diagonal lines on each side thus obviating the requirement of careful alignment of the scanner. The adapter plates are of simple design and easy to prepare.

Endonasal endoscopic removal of growth-hormone-secreting pituitary adenomas.

Trans-sphenoidal removal of pituitary tumours using the endonasal endoscopic technique, a novel application, is herein reported in five consecutive patients with growth-hormone-secreting pituitary adenomas seen at a teaching hospital in Hong Kong. All five patients demonstrated complete tumour removal on postoperative imaging and hormonal assessment following the procedure. Surgical morbidity and symptoms were minimal; postoperative obstructive nasal packing was not required with this technique, which greatly improved patient comfort. Preliminary experience suggests that the endonasal endoscopic approach is a safe and effective alternative to the conventional trans-septal microscopic method for the treatment of pituitary tumour. A randomised controlled trial comparing these two approaches is currently underway at this institution.

Myxofibrosarcoma of the sphenoid sinus.

Myxofibrosarcoma was originally described as the myxoid variant of malignant fibrous histiocytoma (MFH). It is uncommon in the head and neck region. We hereby report a case of myxofibrosarcoma in the sphenoid sinuses. The diagnostic and management difficulties are discussed. Close collaboration between surgeon, radiologist, histopathologist and clinical oncologist in makng accurate diagnosis and appropriate management of this rare tumour are emphasized.

Needs for providing overseas organ transplant medical function and information with eHealth telecare systems-instrument development for health professionals in Taiwan.

BACKGROUND: The use of eHealth systems for facilitating overseas organ transplantation (OOT) between 2 medical parties has been discussed. Nevertheless, little information is available about organ transplant health professionals' (OTHPs') needs in using the eHealth telecare systems (eHTSs) for providing OOT medical service. This project attempted to answer this question. METHODS: A purposive sample including OT surgeons (OTSs), registered nurses (RNs), and organ transplant coordinating nurses (OTCNs) was obtained from 5 hospitals in Taiwan. A Delphi research method was used in this research. The subjects were invited to respond to a sequence of surveys to learn their appraisal of the needs in using eHTSs for providing OOT medical service. RESULTS: Twenty-two subjects including surgeons (n = 10), RNs (n = 9), and OTCNs (n = 3) participated in this research. Their years working in the field ranged from 3 to 45 (mean 15.77) years. To learn OTHPs' appraisals of their needs in using eHTSs for providing OOT medical service, system function requirements (SFR) and system information requirements (SIR) for telecare were produced. SFR were identified to encompass the following 9 aspects: (a) safety in the supervisor mechanism for protection of privacy including account, password, and unediting mode of medical prescriptions; (b) unlimited to particular software or hardware; (c) options of related medical term language in English and traditional and simplified Chinese; (d) available any time and anywhere; (e) being able to save print and export medical records by E-mail systems under authorization; (f) friendly operation; (g) real-time and accurate information; (h) tape-recording functions (OTHPs may convey important medical information to others); and (i) online mutual communications between OTHPs and their clients. SIR included: (a) a comprehensive preoperative medical profile before departure for another country; (b) a comprehensive medical profile of OOT performed in another country; (c) a comprehensive postoperative treatment profile after return to original country; and (d) physiologic health indicators of long-term recovery in the community. CONCLUSIONS: In this project, OTHPs addressed their tangible needs for operating an eHTS to facilitate OOT. These findings would serve as a valuable reference for eHTS experts to continue to work with OTHPs to move to the next development stage.