Comparative cost analysis of cervical cancer screening programme based on molecular detection of HPV in Spain.

BACKGROUND: HPV cervical cancer screening (CCS) must use validated HPV tests based on the molecular detection of either viral mRNA (Aptima HPV Assay-AHPV) or DNA. AHPV has demonstrated the same cross-sectional and longitudinal sensitivity for the detection of HSIL/CIN2+ lesions but with greater specificity than HPV-DNA tests. The study aimed to estimate the total costs of a CCS with a primary HPV test based on the detection of mRNA compared to DNA in women aged 35-65 years for the National Health System. METHODS: A decision-tree-based model to estimate the cost of the CCS until the first colposcopy was designed based on Spanish CCS guidelines. The total cost (€, 2019) for CCS with AHPV or DNA tests (HC2 and Cobas) was calculated, including HPV test, liquid-based cytology (LBC) and colposcopy, for a population of 7,263,529 women aged 35-65 years (assuming 70% coverage). Clinical inputs derived from a literature review were validated by a multidisciplinary expert panel. Data from head-to-head studies between different HPV tests were selected. RESULTS: The use of AHPV showed reduction of 290,541 (- 35%) and 355,913 (- 40%) LBC compared to HC2 or Cobas, respectively. Furthermore, AHPV avoided 151,699 (- 47%) colposcopies versus HC2 and 151,165 (- 47%) versus Cobas. The total cost of CCS was € 282,747,877 with AHPV, € 322,587,588 with HC2 and € 324,614,490 with Cobas. Therefore, AHPV savings € - 39,839,711 versus HC2 and € - 41,866,613 versus Cobas. CONCLUSIONS: Assuming that 70% of women from 35 to 65 years attend the CCS programme, the cost of screening up to the first colposcopy using AHPV would provide cost savings of up to € 41.9 million versus DNA tests in Spain.

Impact of resveratrol on bone repair in rats exposed to cigarette smoke inhalation: histomorphometric and bone-related gene expression analysis.

This study investigated the effect of resveratrol on bone healing and its influence on the gene expression of bone-related markers in rats exposed to cigarette smoke. Two calvarial defects were created in each of 60 rats, which were assigned equally (n=20) to three groups: (1) resveratrol (10mg/kg)+smoke exposure (SMK+RESV); (2) placebo+smoke exposure (SMK+PLA); or (3) placebo+no smoke exposure (NS+PLA). Substances were administered daily for 30days following surgery. Smoke inhalation was started 7days before surgery and continued for 30days after surgery. One defect was processed for histomorphometric analysis and the other was used for mRNA quantification of bone-related gene expression by qPCR. The remaining defect was smaller in the SMK+RESV (2.27±0.61mm, P=0.0003) and NS+PLA (2.17±0.74mm, P=0.0005) groups than in the SMK+PLA group (3.12±0.47mm). Higher levels of Runx2 were observed in the NS+PLA group than in the smoke exposure groups (vs. SMK+PLA, P=0002; vs. SMK+RESV, P=0.052); levels of Lrp-5 were also higher in the no smoke exposure group (vs. SMK+RESV, P=0.009; vs. SMK+PLA, P=0.003). Resveratrol therapy decreased RANKL/OPG expression when compared to placebo (SMK+RESV vs. SMK+PLA, P=0.017). Dkk1 levels were decreased in the SMK+RESV group when compared to the SMK+PLA (P=0.006) and NS+PLA groups (P=0.005). In conclusion, resveratrol optimizes the repair of critical-sized bone defects, up-regulating the gene expression of important bone remodelling markers in rats exposed to cigarette smoke inhalation.

DNA methylation levels of SOCS1 and LINE-1 in oral epithelial cells from aggressive periodontitis patients.

OBJECTIVE: DNA methylation has been shown to be critical in the regulation of inflammatory genes. Infections are able to trigger susceptibility to disease and it can be considered as potential epimutagenic factors in reshaping the epigenome. Therefore, what would be the DNA methylation status in cells present in an infected and inflamed oral environment? The aim was to verify the DNA methylation pattern in oral epithelium cells from aggressive periodontitis (AgP) patients in a specific gene involved in the inflammation control, as suppressor of cytokine signalling (SOCS)1 and in a broader way through long interspersed nuclear element (LINE)-1. DESIGN: Genomic DNA from oral cells of 30 generalized AgP patients and 30 healthy patients were purified and modified by sodium bisulfite. DNA methylation patterns were analyzed using combined bisulfite restriction analysis (COBRA) for SOCS1 and LINE-1. RESULTS: An overall scenario of demethylation was seen for both groups, whereas the healthy group presented a higher percentage of demethylation (p<0.001), also presenting the majority of total demethylated samples (83.3% versus 70.8% in the AgP group). Total LINE-1 methylation or at each specific loci presented significant differences amongst groups. CONCLUSION: Epithelial cells, present in an infected and inflamed oral environment, show different DNA methylation status from those present in a healthy oral environment, regarding the SOCS1 and LINE-1. In addition, the investigation allows detecting alterations in the DNA in a non-limited manner, since the results observed might reflect a generalized condition of the oral epithelial cells, besides reflecting the condition of the gingival epithelium cells.

Urinary tract injury in gynecologic surgery

Fueron analizadas retrospectivamente 27 pacientes con lesiones del tracto urinario tras cirugía ginecológica durante el periodo de estudio desde el 1 de enero de 2001 al 31 de diciembre de 2009, considerando tipo y momento de la lesión, métodos diagnósticos y manejo de las fístulas urinarias. En los 6276 procedimientos de cirugía ginecológica realizados, sucedieron 27 lesiones urológicas, lo cual supuso una incidencia de 0,43%, incluyendo 12 lesiones ureterales y 15 lesiones vesicales, con una incidencia de 0,19% y 0,24% respectivamente. Las lesiones del tracto urinario fueron diagnosticadas intraoperatoriamente en 15 pacientes (55,5%) y en el postoperatorio en 12 pacientes (44,5%). Las fístulas urinarias aparecieron en 9 pacientes (33%).La mayor parte de las lesiones del tracto urinario secundarias a la cirugía ginecológica tuvieron un resultado óptimo cuando se diagnosticaron temprano y se manejaron correctamente (AU)

We retrospectively analyzed 27 patients with urinary tract injuries who underwent gynecologic surgery from January 1, 2001 to December 31, 2009. The type and timing of injury, diagnostic methods and management of urinary fistulas were evaluated.Twenty-seven urological injuries were incurred during 6,276 gynecologic surgical procedures, representing an incidence of 0.43%. There were 12 urethral injuries and 15 bladder injuries, with an incidence of 0.19% and 0.24%, respectively. Urinary tract injury was diagnosed intraoperatively in 15 patients (55.5%) and postoperatively in 12 (44.5%). Urinary fistulas occurred in nine patients (33%).Most of the urinary tract injuries occurring in gynecologic surgery had optimal results when diagnosed early and managed correctly (AU)

Dehiscencia de la pared abdominal y evisceración en cirugía ginecológica / Abdominal wound dehiscence and evisceration in gynecologic surgery

Realizamos un estudio retrospectivo de pacientes con evisceración tratadas en los últimos 9 años. Entre las 3.276 pacientes con patología ginecológica que se sometieron a laparotomía, fueron detectadas 13 evisceraciones. La edad media fue de 66 años. El diagnóstico fue de cáncer ginecológico en 9 pacientes. La cirugía tuvo carácter urgente en 2 pacientes. El hallazgo clínico más frecuente fue el manchado del apósito. La duración media de estancia en el hospital fue de 27 días. Una paciente falleció como consecuencia de la evisceración. Los factores de riesgo más frecuentes en nuestra serie fueron la edad superior a 65 años, el cáncer ginecológico, la obesidad exógena y la diabetes. Ya que los factores de riesgo pueden ser previstos, cuando varios se agrupan, deberíamos utilizar refuerzo en el cierre de la pared abdominal (AU)

We performed a retrospective study of patients with evisceration treated in the previous 9 years. Among 3276 patients with gynecologic diseases who underwent laparotomy, 13 eviscerations were detected. The mean age was 66 years. Diagnosis was gynecologic cancer in nine patients. Emergency surgery was performed in two patients. The main clinical finding was staining of the dressing. The mean length of hospital stay was 27 days. One patient died as a result of the evisceration. The most frequent risk factors in our series were age greater than 65 years, gynecologic cancer, exogenous obesity, and diabetes. Because these risk factors can be predicted, when several are grouped together, reinforcement should be used when closing the abdominal wall (AU)

Effects of long-term FK 506 therapy on the alveolar bone and cementum of rats.

Cyclosporine (CsA) and tacrolimus (FK 506) exert complex, incompletely understood actions on bone. The objective of the study was to evaluate the effects of long-term tacrolimus therapy on the periodontium. Rats were treated for 60, 120, 180, and 240 days with daily subcutaneous injections of 1 mg/kg body weight of FK 506. After the experimental period, we obtained serum levels of calcium and alkaline phosphatase (ALP). After histological processing, the alveolar bone and cementum, as well as volume densities of bone (V(b)) and osteoclasts (V(o)), were assessed at the regions of the lower first molar. There was a tendency toward a statistically significant decrease in ALP levels with FK 506; however, serum calcium levels increased during the long periods. At 60, 180, and 240 days of treatment with FK 506, we did not observe V(b) and V(o) alterations. At 120 days of treatment, there was an evident decrease in V(b), but it did not show alveolar bone loss. We did not observe any alterations of cementum among rats treated with FK 506. It may be concluded that FK 506 administration did not induce side effects on the periodontium.

Simvastatin therapy in cyclosporine A-induced alveolar bone loss in rats.

BACKGROUND AND OBJECTIVE: Cyclosporine A treatment is important in the therapy of a number of medical conditions; however, alveolar bone loss is an important negative side-effect of this drug. As such, we evaluated whether concomitant administration of simvastatin would minimize cyclosporine A-associated alveolar bone loss in rats subjected, or not, to experimental periodontal disease. MATERIAL AND METHODS: Groups of 10 rats each were treated with cyclosporine A (10 mg/kg/day), simvastatin (20 mg/kg/day), cyclosporine A and simvastatin concurrently (cyclosporine A/simvastatin) or vehicle for 30 days. Four other groups of 10 rats each received a cotton ligature around the lower first molar and were treated similarly with cyclosporine A, simvastatin, cyclosporine A/simvastatin or vehicle. Calcium (Ca(2+)), phosphorus and alkaline phosphatase levels were evaluated in serum. Expression levels of interleukin-1beta, prostaglandin E(2) and inducible nitric oxide synthase were evaluated in the gingivomucosal tissues. Bone volume and numbers of osteoblasts and osteoclasts were also analyzed. RESULTS: Treatment with cyclosporine A in rats, with or without ligature, was associated with bone loss, represented by a lower bone volume and an increase in the number of osteoclasts. Treatment with cyclosporine A was associated with bone resorption, whereas simvastatin treatment improved cyclosporine A-associated alveolar bone loss in all parameters studied. In addition, simvastatin, in the presence of inflammation, can act as an anti-inflammatory agent. CONCLUSION: This study shows that simvastatin therapy leads to a reversal of the cyclosporine A-induced bone loss, which may be mediated by downregulation of interleukin-1beta and prostaglandin E(2) production.

Treatment with tacrolimus enhances alveolar bone formation and decreases osteoclast number in the maxillae: a histomorphometric and ultrastructural study in rats.

Recent studies have suggested that tacrolimus monotherapy is a beneficial therapeutic alternative for the normalization of cyclosporin-induced bone loss in animal models and humans. The mechanism accounting for this action is unclear at present. In the present study, we attempted to determine the effect of tacrolimus monotherapy on alveolar bone using histological, histomorphometric and transmission electron microscopy (TEM). Groups of rats (n=10 each) were treated with either tacrolimus (1mg/kg/day, s.c.) or drug vehicle for 60 days. Fragments containing maxillary molars were processed for light microscopy to investigate the alveolar bone volume, trabecular separation, number of osteoclasts and osteoblasts, and transmission electron microscopy to investigate their ultrastructural basic phenotype. Treatment with tacrolimus monotherapy during 60 days may induce increases in alveolar bone volume (BV/TV,%; P<0.05) and a non-significant decrease in trabecular separation (Tb.Sp,mm; P>0.05), represented by a decrease in osteoclast number (N.Oc/BS; P<0.05) and maintenance of osteoblast number (N.Ob/BS; P>0.05). Osteoblasts were often observed as a continuous layer of active cells on the bone surface. Osteoclasts appeared to be detached from the resorbed bone surface, which was often filled by active osteoblasts and collagen-rich matrix. Moreover, osteoclasts in the treated group were frequently observed as inactive cells (without ruffled border, clear zone and detached from the bone surface). Within the limits of the present study, we conclude that tacrolimus leads to an increase in alveolar bone formation, which probably exerts action on osteoclasts. Tacrolimus could, therefore, play a crucial role in the control of both early osteoclast differentiations from precursors, as well as in functional activation.

The effects of up to 240 days of tacrolimus therapy on the gingival tissues of rats--a morphological evaluation.

BACKGROUND: Tacrolimus, an immunosuppressive drug used in organ transplantation, has been reported not to induce gingival overgrowth. However, prevalence studies are limited, and the methods used for assessing gingival overgrowth varies among studies. OBJECTIVE: The purpose of this study was to evaluate the effects of up to 240 days of tacrolimus therapy on gingival tissues of rats. MATERIALS AND METHODS: Rats were treated for 60, 120, 180 and 240 days with daily subcutaneous injections of 1 mg/kg body weight of tacrolimus. After histological processing, the oral and connective tissue, volume densities of fibroblasts (Vf), collagen fibers (Vcf) and other structures (Vo) were assessed in the region of the lower first molar. RESULTS: After 60 and 120 days of treatment with tacrolimus, gingival overgrowth was not observed. The gingival epithelium, connective tissue, as well as the values for Vf, Vcf, and Vo were similar to those of the control rats (P>0.05). After 180 and 240 days of the treatment, gingival overgrowth was associated with a significant increase in the gingival epithelium and connective tissue as well as an increase in the Vf and Vcf (P<0.05). CONCLUSIONS: Within the limits of the experimental study, it may be concluded that the deleterious side effects of tacrolimus on the gingival tissues of rats may be time-related.

Protective effects of Tacrolimus, a calcineurin inhibitor, in experimental periodontitis in rats.

OBJECTIVE: Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation with pathogenic features similar to those observed in other inflammatory diseases, such as arthritis. Since Tacrolimus, is an immunomodulatory drug used for the treatment of some cases of arthritis, we hypothesized that it may modulate periodontal disease. DESIGN: Using a murine model of ligature-induced periodontal disease, we assessed the effects of daily administrations of Tacrolimus (1mg/kg body weight) on bone loss, enzymatic (myeloperoxidase) analysis, differential white blood cells counts, airpouch exudate and cytokine expression for 5-30 days. RESULTS: Radiographic, enzymatic (myeloperoxidase) and histological analysis revealed that Tacrolimus reduced the severity of periodontitis. More specifically, Tacrolimus suppressed the expression of serum interleukin (IL-1beta), tumour necrosis factor (TNF-alpha), IL-6, airpouch exudate PGE(2) and leukocytosis usually observed after the induction of periodontitis. Tacrolimus treatment in periodontitis-induced rats conferred protection against the inflammation-induced tissue and bone loss associated with periodontitis, through a mechanism involving IL-1beta, TNF-alpha and IL-6. CONCLUSIONS: The effects of Tacrolimus on periodontal disease pathogenesis may provide clues to a novel approach to host modulation therapy in destructive periodontal disease.

Tratamiento conservador del embarazo ectópico cornual / Conservative treatment of cornual ectopic pregnancy

El embarazo cornual es una forma infrecuente de embarazo ectópico. El uso de la ecografía vaginal permite hacer un diagnóstico temprano y realizar un tratamiento conservador con metotrexato. La histeroscopia se puede utilizar como técnica complementaria en el seguimiento de estas pacientes. Presentamos 3 casos de embarazo ectópico cornual atendidos en nuestro hospital en el plazo de un año. La introducción de la ecografía vaginal permite hacer un diagnóstico temprano de este tipo de embarazos y plantear un tratamiento conservador con metotrexato, si la situación hemodinámica de la paciente lo permite. De los 3 casos que presentamos, 2 tuvieron una evolución favorable con metotrexato. En el tercer caso se produjo una rotura uterina a pesar del metotrexato y fue necesario realizar una resección cornual de urgencia

Cornual pregnancy is and infrequent type of ectopic pregnancy. With the use of transvaginal ultrasounds we can make an earlier diagnostic and try a conservative treatment with metotrexate. The hysteroscopy can be used as a complementary technique in the following of these patients. We present three cases of cornual ectopic pregnancies diagnosticated in our hospital during a year. With the use of transvaginal ultrasound we can made and early diagnosis and a conservative treatment with methotrexate if the hemodinamyc situation of de patient is good. In two of the cases we observed a satisfactory evolution with the methotrexate. In the third case there was a rupture in the uterus in addition of the methotrexate, and an emergency surgery was needed

Utilidad de la histeroscopia en el diagnóstico prequirúrgico de la invasión cervical por carcinoma de endometrio / Utility of hysteroscopy in the presurgical diagnosis of cervical invasion in endometrial carcinoma

Objetivos: Analizar el papel de la histeroscopia en nuestro centro para evaluar el grado de invasión cervical del cáncer de endometrio. Material y método: Estudio retrospectivo sobre las histeroscopias realizadas a pacientes con cáncer endometrial previamente a la cirugía. Se realiza una histeroscopia preoperatoria a 87 pacientes diagnosticadas de cáncer de endometrio entre los años 1999 y 2002. Posteriormente se contrastan los hallazgos histeroscópicos con los anatomopatológicos obtenidos de la pieza de histerectomía. Resultados: De las 87 neoplasias estudiadas, 75 se encontraban en estadio I, 9 en estadio II y 3 en estadio III. La histeroscopia presentó concordancia con la anatomía posquirúrgica, especialmente en los estadios I y concretamente en los tumores localizados o polipoides, con un valor predictivo negativo cercano al 100%. En la detección de la afectación cervical presentó un valor predictivo positivo del 80%. Conclusiones: La histeroscopia es un método diagnóstico útil para la detección o el descarte de invasión cervical en el cáncer de endometrio, ya que permite visualizar la cavidad uterina de forma directa y realizar biopsias dirigidas (AU)

Objectives: To analyze the role of hysteroscopy in the diagnosis of cervical invasion in endometrial carcinoma in our center. Material and method: A retrospective study was conducted of hysteroscopies performed before surgery in 87 patients with endometrial carcinoma diagnosed from 1999 to 2002. Subsequently, hysteroscopic results were compared with pathological findings obtained from the hysterectomy specimens. Results: Of the 87 neoplasms studied, 75 were stage I, 9 were stage II and 3 were stage III. Hysteroscopy and pathological assessment showed close agreement, especially in stage I tumors and in pedunculated or localized tumors, with a negative predictive value of nearly 100%. The positive predictive value of hysteroscopy in the detection of cervical invasion was 80%. Conclusions: Hysteroscopy is a useful method for assessing cervical invasion in endometrial carcinoma, as it allows direct visual inspection of the uterine cavity and guided biopsies (AU)

Aprendizaje diagnóstico y quirúrgico mediante endoscopia virtual y tutoría inteligente: proyecto Lahystotrain / Diagnostic and surgical learning through virtual endoscopy and intelligent tutoring: the Lahystotrain project

El proyecto Lahystotrain es una nueva posibilidad de aprendizaje de la endoscopia mediante realidad virtual, entorno multimedia y técnicas de tutoría inteligente (AU)

Resultados de la conización cervical con asa / Results of cervical conization with a loop

Objetivos. Evaluar los resultados de la técnica de conización con asa en nuestro servicio, las complicaciones y el seguimiento de esas pacientes. Material y métodos. Se han estudiado 77 pacientes que requieren conización con asa por lesión escamosa intraepitelial de alto grado (SIL AG), SIL BG persistente, discordancia citología-biopsia, sospecha de carcinoma microinvasor o de adenocarcinoma endocervical. Evaluamos las complicaciones y el seguimiento citológico a los 6 meses. Resultados. El 74 por ciento de las pacientes presentaba SIL en la pieza de conización, en el 20,7 por ciento no se observó lesión, en el 2,6 por ciento se localizó carcinoma microinvasor y en el 1,35 por ciento carcinoma invasor y endocervical. Conclusión. La concordancia es mayor cuando se trata de lesiones de alto grado. Las complicaciones son escasas, destacando un 7,6 por ciento de hemorragia. El seguimiento citológico muestra, a los 6 meses, una persistencia de lesión del 11,4 por ciento (AU)

Resultados de la resección histeroscópica de endometrio / Results of hysteroscopic endometrial resection

OBJETIVO: Evaluar nuestros resultados de la resección endometrial histeroscópica y el grado de satisfacción a medio-largo plazo de estas pacientes. SUJETOS Y MÉTODOS: Se estudia de forma prospectiva a 48 mujeres a las que se realiza una resección endometrial histeroscópica por hemorragia uterina anormal. Se estudian todas las intervenciones de este tipo que se practicaron entre abril de 1996 y abril de 2000, un total de 285 histeroscopias quirúrgicas. En todos los casos se había realizado una histeroscopia diagnóstica y biopsia en consulta y se había intentado tratamiento médico sin éxito. Entre 6 y 50 meses después de la cirugía, se realiza una encuesta telefónica para evaluar el grado de satisfacción. RESULTADOS: Hallamos un 8,3 por ciento de complicaciones, que en todos los casos fueron leves. En el estudio anatomopatológico destaca un caso de adenocarcinoma endometrial sobre un pólipo y otro de hiperplasia atípica de endometrio, a los que se realizó una histerectomía. Nuestros resultados a largo plazo pusieron de manifiesto que hubo que realizar otras 2 histerectomías (total, 11,4 por ciento). El grado de satisfacción en la encuesta realizada a nuestras pacientes fue alto (65,7 por ciento). CONCLUSIÓN: Nuestros datos revelan un 8,3 por ciento de complicaciones inmediatas por la resección endometrial histeroscópica. Un 11,4 por ciento de estas pacientes tuvo que someterse a cirugía posterior (histerectomía). La salud de estas mujeres mejoró mucho en el 71,4 por ciento de los casos (AU)

Hysteroscopy: an alternative to dilatation and curettage in the diagnosis of postmenopausal bleeding.

Data were collected prospectively on 100 women suffering from postmenopausal bleeding who were investigated by hysteroscopy in a 5-month period. Women using hormone replacement therapy were excluded. The most common hysteroscopic finding was atrophy (44%). Other findings were: endometrial cysts (13%), endometrial polyp (12%) and adenocarcinoma (6%). The sample was not representative in 41% of cases and the most frequent histopathological diagnosis was inactive endometrium (14%). Other diagnoses were: inactive endometrium (14%), adenocarcinoma (6%), hyperplasia (7%), endometrial polyp (3%), proliferation (5%) and atrophy (4%), Endometrial sampling was not performed in 13% of the cases. General anaesthesia was not needed and complications were minimal. We support hysteroscopy as a routine alternative to dilatation and curettage in the diagnosis of postmenopausal bleeding.

Uterine side effects of treatment with tamoxifen.

OBJECTIVE: To assess a causal the relationship between endometrial lesions and tamoxifen therapy in patients with breast cancer. DESIGN: Prospective longitudinal study and cross-sectional study. SETTING: Cancer prevention unit at Basurto Hospital, Bilbao. POPULATION AND METHODS: Three populations of breast cancer were studied: 43 before the beginning of tamoxifen; 78 after 5-72 months of tamoxifen, and 34 before tamoxifen and after 12-24 months of tamoxifen treatment (PAIRED GROUP). All of them were systematically studied with CO(2) diagnostic hysteroscopy and endometrial biopsy by the same clinician. RESULTS: Before tamoxifen, the following endometrial lesions were detected: endometrial polyps 9.3%; endometrial cysts 16.3%; synechiae 11.6%. In the paired group the ingestion of tamoxifen shows a direct causal effect with a significant increase in endometrial polyps (11.8% vs. 29.4%; OR=13; CI=7.9-18.1), in endometrial cysts (17.7% vs. 55.9%; OR=7.5; CI=5. 9-9.1) and in synechiae (14.7% vs. 35.5%; OR=8; CI=4.7-11.3). In the group under tamoxifen for 5-72 months, one endometrial carcinoma was detected. CONCLUSIONS: Breast cancer patients have a number of endometrial lesions before undergoing any hormonal therapy. Tamoxifen significantly increased benign endometrial lesions, usually after less than one year of treatment. No cases of endometrial carcinoma was found in our series of 34 patients with 1-2 years of tamoxifen treatment, and 1/78 in patients with 5-72 months of tamoxifen.

Histeroscopia quirúrgica en gestación incipiente / Surgical hysteroscopy in early pregnancy

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