The postoperative renal function of persistent cloaca patients treated by posterior sagittal anorecto-urethro-vaginopalsty: results of a nationwide survey in Japan.

PURPOSE: We investigated the postoperative renal function in persistent cloaca (PC) patients who underwent posterior sagittal anorecto-urethro-vaginopalsty (PSARUVP) and factors influencing the renal functional outcomes. METHODS: A questionnaire survey was distributed to 244 university and children's hospitals across Japan. Of the 169 patients underwent PSARUVP, 103 patients were enrolled in the present study. Exclusion criteria was patients without data of renal prognosis. RESULTS: The present study showed that renal anomalies (p = 0.09), vesicoureteral reflux (VUR) (p = 0.01), and hydrocolpos (p = 0.07) were potential factors influencing a decline in the renal function. Approximately half of the patients had a normal kidney function, but 45.6% had a reduced renal function (Stage ≥ 2 chronic kidney disease: CKD). The incidence of VUR was significantly higher in the renal function decline (RFD) group than those in the preservation (RFP) group (p = 0.01). Vesicostomy was significantly more frequent in the RFD group than in the RFP group (p = 0.04). Urinary tract infections (p < 0.01) and bladder dysfunction (p = 0.04) were significantly more common in patients with VUR than in patients without VUR. There was no association between the VUR status and the bowel function. CONCLUSIONS: Prompt assessment and treatment of VUR along with bladder management may minimize the decline in the renal function.

Qualitative inductive analysis of the lives of women with persistent cloaca based on their narratives.

PURPOSE: The study aimed to explore and describe the lives of patients with persistent cloaca (PC) from childhood to adulthood. METHODS: Semistructured interviews were conducted with nine adult patients with PC. Their experiences and thoughts regarding this disease were analyzed qualitatively and inductively. RESULTS: After classifying the experiences and thoughts of patients with PC, 13 categories were extracted. The following five themes emerged from these categories. (1) Difficulties with excretion and vaginal management because of the disease. (2) The degree of understanding of those around them and society has a huge effect on their way of life. (3) The inferiority of a woman who is not a "normal woman." (4) A "never-ending disease" in which problems continue even after the transition period. (5) Differences in the central point of the narrative depending on the age group. CONCLUSIONS: In this study, qualitative and inductive analyses of data from semistructured interviews with patients with PC revealed their experiences and thoughts. The results will provide a guide for young patients and the medical professionals who treat them. Accordingly, monitoring their lives until adulthood is necessary.

Persistent Cloaca and Cloacal Variants in Males: Qualitative Review of a Neglected Anomaly.

Context: Cloacal malformations are rare and are typically reported in females. There are a few scattered reports in males. It is not clear why they are so rare in males since both sexes negotiate this stage of embryonal development. Aims: The present study aims to share our experience and review all the cases of persistent cloaca and cloacal variants in males reported in the literature. Materials and Methods: The male cloaca is defined as a single common channel of varying lengths with separate inlets for the urinary tract (urethra) anteriorly and the rectum posteriorly at its cranial end and with a solitary perineal orifice/opening for external drainage. We also carried out an electronic literature search for cloaca, persistent cloaca, common cloaca, cloacal dysgenesis, cloacal malformation, cloacal membrane agenesis, urorectal malformation sequence, rectourinary perineal fistula, sirenomelia, and caudal regression syndrome. Results: After eliminating other cloacal anomalies and persistent cloaca in females, we found a total of 22 males with persistent cloaca or cloacal variant reported in the literature. In addition, we are adding two cases we have managed since our previous report. Conclusions: An effort should be made to search for the presence of the common channel in male patients with a single perineal opening. Recognition of the anomaly, width of the common cloacal channel, location of the rectal pouch with relation to the sacrum or pubis, status of the spine and sacrum, and nature of the anal sphincter are vital pieces of information to successfully manage the anomaly. It would be worthwhile if future reports on the subject also include long-term information about urinary and fecal functions and continence.

Clinically diverse and perinatally lethal syndromes with urorectal septum malformation sequence.

Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco-abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component. Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS.

Analysis of the potential risk factors for defecation problems and their bowel management based on the long-term bowel function in patients with persistent cloaca: results of a nationwide survey in Japan.

AIM OF THE STUDY: We conducted a nationwide survey of persistent cloaca (PC) to determine its current status in Japan. This study clarifies the potential risk factors for defecation problems in patients with PC. METHODS: Patient information was obtained via questionnaire, and a total of 213 PC patients who responded to a questionnaire on defecation problems and their bowel functions were enrolled in this study. We evaluated the constipation, incontinence, and soiling as bowel functions. Univariate and multivariate analyses were performed using a logistic regression analysis to clarify the risk factors for defecation problems. RESULTS: Of 213 patients with PC, 55 (25.8%) had defecation problems. A multivariate logistic regression analysis showed that sacral agenesis, as an associated anomaly, was significantly associated with defecation problems (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.11-9.16, p = 0.03). The other multivariate logistic regression analysis showed that the PC patients who underwent antegrade continence enema and regularly took laxatives after anorectoplasty had defecation problems (OR 12.4, 95% CI 2.35-65.6, p = 0.003, OR 2.84, 95% CI 1.24-6.55, p = 0.01). CONCLUSION: Sacral agenesis is the potential risk factor of defecation problems in the patients with PC who underwent anorectoplasty. Those patients require vigorous defecation management.

Posterior sagittal anorecto-urethro-vagino-plasty in the late period was associated with the long-term bowel function in patients with persistent cloaca: results of a nationwide survey in Japan.

PURPOSE: After conducting a nationwide survey of persistent cloaca (PC), we assessed whether or not the timing of definitive anorectoplasty affects the long-term bowel function of patients with PC. METHODS: Patient information was obtained via questionnaire, and a total of 169 PC patients who underwent posterior sagittal anorectourethrovaginoplasty (PSARUVP) were enrolled in this study. Patients were classified into 2 groups based on their operative period, which was analyzed by the area under the receiver operating characteristic curve: the early group (EG) underwent anorectoplasty at ≤ 18 months old (n = 106), and the late group (LG) underwent anorectoplasty at > 18 months old (n = 63). The bowel function was evaluated using the evacuation score of the Japan Society of Anorectal Malformation Study Group. We also examined the postoperative results of vaginoplasty. RESULTS: The total evacuation score was significantly higher in the EG than in the LG (5.2 ± 1.7 vs. 4.2 ± 1.8, p = 0.003). The frequency of bowel movement and the constipation scores were significantly higher in the EG than in the LG (1.4 ± 0.6 vs. 1.2 ± 0.7, p < 0.05, 2.4 ± 1.0 vs. 2.1 ± 1.0, p < 0.05, respectively). Postoperative vaginal stenosis was observed in 18 cases (10.7%), of which 16 could be reconstructed transperineally. CONCLUSION: PSARUVP should be performed in early infancy and facilitate vaginal reconstruction.

The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene.

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

Annual report of the Women's Healthcare Committee, Japan Society of Obstetrics and Gynecology, 2021.

Our committee was founded in 2010 with the goal of improving women's health. This academic year we focused on the following five activities for the second consecutive year: cooperation between the department of pediatric surgery and the department of obstetrics and gynecology for the treatment of persistent cloaca and Mayer-Rokitansky-Küster-Hauser syndrome in Japan; assessment of the educational training of women's healthcare advisers; increasing screening for breast and cervical cancer; conducting the Nationwide Survey of Prescribing Practices for the Treatment of Menopausal Symptoms; and preventing osteoporosis in survivors of gynecologic cancer. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2021;73(6):684-699).

Persistent cloaca with fetal ascites: clinical features and perinatal management.

PURPOSE: Fetuses with persistent cloaca are known to develop urine or meconium backflow into the abdominal cavity caused by obstruction of the common channel, thus leading to fetal peritonitis with fetal ascites. We analyzed the impact of prenatal fetal ascites on postnatal clinical features and management. METHODS: This retrospective single-center cohort study was conducted to compare the perinatal parameters of patients with isolated persistent cloaca who were born and treated at our hospital between 1991 and 2021. The clinical features and management of those with and without fetal ascites were compared. RESULTS: Among the 17 eligible patients, fetal ascites were recognized in seven. The occurrence of fetal ascites was significantly related to preterm birth, higher birth weight z-score, birth via emergency cesarean delivery, low Apgar scores at 1 min and 5 min, higher C-reactive protein levels at birth, longer duration of oxygen administration, the need for a urinary drainage catheter at initial discharge, and shorter neonatal hospital stays. CONCLUSIONS: The postnatal management of patients with persistent cloaca with fetal ascites differed significantly from that of patients without fetal ascites. For patients with unexplained fetal ascites, magnetic resonance imaging may be helpful for determining the definite diagnosis of persistent cloaca.

Annual report of the Women's Health Care Committee, Japan Society of Obstetrics and Gynecology, 2020.

Our committee was founded in 2010 with the goal of improving women's health. This academic year, we focused on five activities: cooperation between the departments of pediatric surgery and obstetrics and gynecology for the treatment of persistent cloaca and Mayer-Rokitansky-Küster-Hauser syndrome in Japan; assessment of the educational training of women's health-care advisers; increasing screening for breast and cervical cancer; conducting the Nationwide Survey of Prescribing Practices for the Treatment of Menopausal Symptoms; and preventing osteoporosis in survivors of gynecologic cancer. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2020;72(6):697-707).

Prenatal ultrasound findings of covered bladder exstrophy and persistent cloaca.

Unlike classic exstrophy, covered bladder exstrophy is a rare variant characterized by a cycling bladder and intact abdominal wall. We present a case of covered bladder exstrophy diagnosed prenatally and associated persistent cloaca (PC) noted only after delivery. This case report demonstrates that prenatal diagnosis of covered bladder exstrophy is possible and PC can present without any abdominal cysts, bowel, or renal findings. Covered bladder exstrophy should be considered in the differential of cystic protrusion of the bladder to the abdominal wall.

Treatment guidelines for persistent cloaca, cloacal exstrophy, and Mayer-Rokitansky-Küster-Häuser syndrome for the appropriate transitional care of patients.

We developed treatment guidelines (TGs) for appropriate transitional care of the genitourinary system in patients with persistent cloaca (PC), cloacal exstrophy (CE), or Mayer-Rokitansky-Küster-Häuser syndrome (MRKH). These TGs are in accordance with the Medical Information Network Distribution Service (Minds), published in 2014 in Japan. Clinical questions (CQs) concerning treatment outcomes of the genitourinary system, pregnancy and delivery, and quality of life in adulthood were prepared as six themes for PC and CE and five themes for MRKH. We were able to publish statements on chronic renal dysfunction, hydrometrocolpos, and pregnancy, based on four CQs about PC, four about CE, and two about MRKH, respectively. However, due to the paucity of proper manuscripts, we were unable to make conclusions about the correct timing and method of vaginoplasty for patients with PC, CE, and MRKH or the usefulness of early bladder closure for patients with CE. These TGs may help clarify the current treatments for PC, CE, and MRKH in childhood, which have been carried out on an institutional basis. To improve clinical outcomes, systematic clinical trials revealing comprehensive clinical data of the urinary and reproductive systems, especially the length of the common channel in PC, are essential.

Clinical and risk factor analysis of cloacal defects in the National Birth Defects Prevention Study.

Cloacal exstrophy (CE) and persistent cloaca (PC) (alternatively termed urorectal septum malformation sequence [URSMS]), represent two major cloacal defects (CDs). Clinical characteristics and risk factors often are studied for both defects combined, rather than exploring if these defects have different etiologies. We enumerated clinical features for 47 CE and 54 PC (inclusive of URSMS) cases from the National Birth Defects Prevention Study. Thirty-three CE cases were classified as isolated and 14 as multiple (presence of unassociated major defects); respective totals for PC cases were 26 and 28. We compared selected child and maternal characteristics between 11,829 non-malformed controls and CE and PC cases using chi-square or Fisher's exact tests. Compared to controls, CE and PC cases were statistically more likely (p < 0.05) to be preterm; CE cases were more likely to be multiple births. We conducted logistic regression analysis to estimate odds ratios and 95% confidence intervals for any CD, CE, and PC with selected self-reported maternal prepregnancy and periconceptional (one month prior to 3 months following conception) exposures. In crude and adjusted analyses, we observed significant positive associations for any CD, CE, and PC with use of any fertility medication or assisted reproductive technology procedure. Significant positive associations observed only in crude analyses were any CD with maternal obesity or use of progesterone, any CD and CE with any x-ray, and any CD and PC with use of folate antagonist medications. Our findings provide some of the first insights into potential differing etiologies for CE and PC.

Fibronectin glomerulopathy complicated with persistent cloaca and congenital esophageal atresia: a case report and literature review.

BACKGROUND: Fibronectin glomerulopathy is a rare, inherited, autosomal dominant, glomerular disease characterized by proteinuria, microscopic hematuria, hypertension, massive glomerular deposits of fibronectin, and slow progression to end-stage renal failure. Because the incident of fibronectin glomerulopathy is extremely low, the pathophysiology, genetic abnormalities, epidemiology, and mechanisms remain to be elucidated. CASE PRESENTATION: We report a 21-year-old woman with fibronectin glomerulopathy, who had been diagnosed with persistent cloaca and congenital esophageal atresia at birth. She developed proteinuria and hematuria 7 months before admission. Urinary protein and serum creatinine levels were 3.38 g/gCr and 0.73 mg/dL. Renal biopsy showed severe mesangial widening due to massive deposits, which was positive periodic acid-Schiff and negative methenamine silver. Immunostaining was negative for immunoglobulin but positive for fibronectin. Electron microscopy showed diffuse mesangial granular deposits. Thus she was diagnosed with fibronectin glomerulopathy, despite a negative family history of kidney disease and lack of any known missense mutations of fibronectin 1 gene. CONCLUSION: We report a patient who developed fibronectin glomerulopathy during the clinical course of extremely rare congenital malformations, including persistent cloaca and congenital esophageal atresia. We describe a case of this condition in detail and summarize the 75 case reports of fibronectin glomerulopathy.

Giant fetal hydrometrocolpos associated with cloacal anomaly causing postnatal respiratory distress.

Persistent cloaca is a rare presentation wherein the urethra, vagina, and rectum converge into a common channel with a single perineal opening. Fetal hydrometrocolpos can result if fluid accumulates behind an obstruction of this common channel. A 29-year-old woman (G4P1021) was referred at 36 2/7 weeks of gestation for evaluation of a fetal abdominal cystic mass. Detailed ultrasonography and magnetic resonance imaging showed two symmetric cystic masses, bilateral hydronephrosis, and oligohydramnios. Elective cesarean delivery was performed at 37 0/7 weeks; the baby weighed 4043 g with Apgar scores of 5 and 6 at 1 and 5 min. Intubation was performed for respiratory distress, and the infant was noted to have an imperforate anus; persistent cloaca was diagnosed. Drainage of the hydrometrocolpos improved the infant's breathing remarkably, and extubation was achieved. This child's imaging findings are among the largest ever reported, and resulted in neonatal respiratory distress.

The current profile of persistent cloaca and cloacal exstrophy in Japan: the results of a nationwide survey in 2014 and a review of the literature.

PURPOSE: The current profile of persistent cloaca (PC) and cloacal exstrophy (CE) in Japan was first examined in 2014. MATERIALS AND METHODS: Information was obtained by sending a questionnaire to 244 university hospitals and children's hospitals. RESULTS: Responses from 113 institutions reported 466 PC cases and 229 CE cases. The incidences of PC and CE from 1980 to 2012 were 0.97 and 0.49 per 100,000 live births, respectively. In the previous 5 years, antenatal abnormalities were found in 57.6% of PC and 72.7% of CE patients. Myelomeningocele was observed in 45.6% of CE patients. As a result of various surgical treatments used in the neonatal and infantile periods, the respective rates of bladder dysfunction, clean intermittent catheterization, and permanent enterostomy were 32.6, 22.5, and 7.3% in PC patients and 60.7, 28.4, and 73.8% in CE patients. Menstrual outflow obstruction was found in 22.5% of PC and 48.9% of CE patients with menstruation. CONCLUSION: The clinical outcomes of PC and CE remain unsatisfactory. Therefore, the establishment of treatment guidelines might be a useful objective for improving the current status of PC and CE.

Congenital Risk Factors for Chronic Kidney Disease in Patients With Persistent Cloaca: Results From a Nationwide Survey in Japan.

BACKGROUND: We conducted a nationwide survey of persistent cloaca (PC) to investigate the renal function outcomes and factors affecting chronic kidney disease (CKD) in patients with PC. METHOD: Information from 466 patients with PC was obtained via a questionnaire in this study. The 290 patients (62.2%) with renal function data were classified into 2 groups based on their estimated glomerular filtration rate: advanced CKD group (<30 mL/min/1.73 m2 [or post-renal replacement therapy]) and non-advanced CKD group (≥30 mL/min/1.73 m2). Univariate and multivariate analyses were performed to identify risk factors for CKD that may affect the renal function, including renal and urinary tract malformations, associated anomalies, and urinary tract treatment. The advanced CKD group was divided into two groups based on age to evaluate age-related differences (younger- and older-age CKD groups). RESULTS: A regression analysis revealed that congenital renal malformations (odds ratio [OR]: 14.06, 95% confidence interval [CI]:3.07-131.65, p < 0.0001), urinary tract obstruction (OR:4.28, 95%CI:1.12-24.23, p < 0.05), and sacral agenesis (OR:4.54, 95% CI:0.84-30.67, p < 0.05) were significantly associated with advanced CKD. In the univariate analysis of factors affecting the renal prognosis, clean intermittent catheterization (CIC) (OR:4.18, 95%CI:1.21-16.45, p = 0.015), vesicostomy (OR:3.65, 95%CI:1.11-12.98, p = 0.019), and surgery for vesicoureteral reflux (OR:5.43, 95%CI:1.41-22.73, p = 0.006) were significantly associated with advanced CKD. Based on the univariate analysis, hydrometrocolpos was significantly more prevalent in the older-age CKD group compared to the younger-age CKD group (p < 0.05). CONCLUSION: CKD development in patients with PC is influenced by a complex interplay of factors, including renal malformations and neurogenic bladder dysfunction due to spinal anomalies. LEVEL OF EVIDENCE: III (Study of Diagnostic Test, Study of nonconsecutive patients, and/or without a universally applied "gold" standard).

Antenatal three-dimensional sonographic diagnosis of persistent cloaca.

We present a case of fetal persistent cloaca diagnosed by two- (2D) and three-dimensional (3D) sonography and the HDlive rendering mode. 2D sonography revealed a bicornate uterus with hydrometra, bilateral hydrosalpinx, a single umbilical artery, and ascites. 3D sonography and the HDlive rendering mode clearly showed these intra-abdominal structures. To the best of our knowledge, this is the first report of persistent cloaca employing antenatal 3D sonography and the HDlive rendering mode.

Risk factor analysis of irreversible renal dysfunction based on fetal ultrasonographic findings in patients with persistent cloaca: Results from a nationwide survey in Japan.

AIM OF THE STUDY: We conducted a nationwide survey of persistent cloaca (PC) to determine its current status in Japan. We focused on the relationship between fetal ultrasonographic findings and irreversible renal dysfunction in PC. METHOD: Patient information was obtained via questionnaire, and 466 PC patients were ultimately enrolled in this study. Fifteen patients (3.2%) who required dialysis or kidney transplantation were compared to those who were able to survive with their native kidney. Univariable and multivariable analyses were performed using a logistic regression analysis to clarify the relationship between irreversible renal dysfunction and fetal ultrasonographic findings. RESULTS: A multivariable logistic analysis showed that fetal ultrasonic findings of oligohydramnios independently increased the risk of irreversible renal dysfunction (adjusted odds ratio [OR] 5.8, 95% confidence interval [CI] 1.7-20, p = 0.005). A regression analysis showed that fetal ultrasonographic findings of hydroureteronephrosis (crude OR 5.6, 95% CI 0.9-24, p = 0.03) tended to be associated with irreversible renal dysfunction. In the PC patients with oligohydramnios, however, the ultrasonographic findings and associated anomalies did not affect the renal prognosis. The 15 renal dysfunction patients were treated as follows: hemodialysis (n = 4), peritoneal dialysis (n = 3), living donor renal transplantation (n = 8), and cadaveric renal transplantation (n = 1). CONCLUSION: Fetal ultrasonographic findings of oligohydramnios increase the risk of irreversible renal dysfunction. Such findings suggest we consider the need for earlier therapeutic intervention, such as fetal and postnatal treatment, to prevent the progression of renal dysfunction. LEVEL OF EVIDENCE: III (Study of diagnostic test, study of nonconsecutive patients and/or without a universally applied "gold" standard).

A Review of Diagnosis and Management: Persistent Cloaca Treated by a Posterior Sagittal Approach With a Normal Functional Outcome.

Cloacal malformation (CM) is a severe, complex, and extremely rare category of anorectal and urogenital tract malformations. Prenatal diagnosis is illusory and vague; therefore, magnetic resonance imaging (MRI) is the most effective test point toward an accurate diagnosis. Thus, careful investigation and evaluation are mandatory since they could be associated with syndromes and other anomalies, including urogenital tract, vertebral, and cord abnormalities. Despite the severity and complexity of the deformity, CM cases are curable, not desperate, and can have an excellent prognosis with great surgical correction. However, managing persistent cloaca necessitates a careful assessment because corrective surgeries require inclusive surgical planning, multidisciplinary, expert, and highly specialized medical center. In surgically repaired malformations, fecal and urinary incontinence has been a major issue, which was resolved when Dr. Pena Alberto suggested safer dissection and less harmful techniques for neurovascular structures and great functional corrected anomaly to ensure fertility and less incontinence. For improved results and prognosis on quality of life, patients should be scheduled for extended bowel training along with the clinical evaluation follow-up. In this article, we present a case successfully treated with the posterior sagittal approach, Pena operation, and anorecto-vagino-urethroplasty with feminizing clitoroplasty and highlight the value and impact of prenatal evaluation, diagnosis, and management. The rarity of the case and excellent results, including fair to normal bowel and urinary control, prompted us to report it and assert the significance of assessment, surgical management and technique, challenges, postoperative bowel training, and clinical investigation and examination.