Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

A nationwide survey of diagnostic procedures for abnormal uterine bleeding in Japan.

AIM: To clarify the diagnostic process of the causative disease of abnormal uterine bleeding (AUB) in Japan according to the International Federation of Gynecology and Obstetrics AUB diagnostic system. METHODS: Patients diagnosed with AUB were included in a nationwide survey of AUB conducted during any 2-week period between December 2019 and January 2020. The second survey included information on patient background, AUB symptoms, examinations for diagnosing AUB, the order in which they were performed, and the causative diseases of AUB. RESULTS: Correspondence analysis showed an association between hormonal testing, hysterosalpingography, and magnetic resonance imaging (MRI) in patients with amenorrhea, and heavy menstrual bleeding was strongly correlated with various examinations, such as coagulation tests, pelvic MRI, and endometrial cytology or biopsy. The results also indicated that each AUB causative disease can be diagnosed based on a specific examination profile. CONCLUSION: We clarified the process of diagnosing the causative disease of AUB in our country and determined that it was mainly diagnosed by imaging and pathological examination in cases of structural disease. The high rate of AUB-E and the low rate of AUB-C are possibly associated with specific examination trends in Japan. The results of this study will be useful for the development of a standard protocol for AUB diagnosis in our country.

Differences of Bone Mineral Density by Characteristics of Sports in Amenorrheic Athletes.

Hypothalamic amenorrhea leads to a hypoestrogenic state, causing decreased bone mineral density (BMD), while strong impact loading on bone has been shown to increase BMD. The purpose of this study is to compare BMD in female athletes based on menstrual status and their sports/events by impact loading characteristics. BMD at the lumbar spine was measured by dual-energy X-ray absorptiometry and hormone level. The subjects were classified into four groups and BMD and hormone levels were compared among the four groups, which were divided into amenorrheic athletes (AAs) and eumenorrheic athletes (EAs). This study recruited 410 female athletes (164 in the AAs and 246 in the EAs), 55 athletes in non-impact sports, 123 in low-impact sports, 141 in multidirectional sports, and 91 in high-impact sports. In the AAs group, BMD Z-score was lowest in low-impact sports (Z-score: -1.53 [-1.76, -1.30]), and was highest in high-impact sports (Z-score: 0.02 [-0.34, 0.38]). In multidirectional and high-impact sports, BMD Z-score in the AAs group did not show results lower than the average for non-athletes. When screening female athletes for low BMD, it is important to evaluate the risk of low BMD based on the impact loading characteristics of their sports/events, in addition to the menstrual state.

Major hepatectomy in elderly patients: possible benefit from robotic platform utilization.

INTRODUCTION: Robotic surgery has been increasingly utilized, yet its application for hepato-pancreato-biliary (HPB) procedures remains low due to technical complexity, perceived financial burden, and unproven clinical benefits. We hypothesized that the robotic approach would be associated with improved clinical outcomes following major hepatectomy compared with the laparoscopic approach among elderly patients who would benefit from the advantages of minimally invasive surgery. METHODS: A retrospective review of consecutive patients who underwent major hepatectomy between January 2010 and December 2021 at Carolinas Medical Center was performed. Inclusion criteria were age ≥ 65 years and major hepatectomy of three segments or more. Patients who underwent multiple liver resections, vascular/biliary reconstruction, or concomitant extrahepatic procedures (except cholecystectomy) were excluded. Categorical variables were compared using Chi-square or Fisher's exact test when more than 20% of cells had expected frequencies less than five, and Wilcoxon two-sample or Kruskal-Wallis tests were used for continuous or ordinal variables. Results are described as median and interquartile range (IQR). Multivariate analyses were used on postoperative admission days. RESULTS: There were 399 major hepatectomies performed during this time period, of which 125 met the criteria and were included. There were no differences in perioperative demographics among patients who underwent robotic hepatectomy (RH, n = 39) and laparoscopic hepatectomy (LH, n = 32). There was no difference in operative time, blood loss, or major complication rates. However, RH had lower rates of conversion to an open procedure (2.6% versus 31.3%, p = 0.002), shorter length of hospital stay [LOS, 4 (3-7) versus 6 (4-8.5) days, p ≤ 0.0001], cumulative LOS [4 (3-7) versus 6 (4.5-9) days, p ≤ 0.0001], and lower rates of intensive care unit (ICU) admission (7.7% versus 75%, p ≤ 0.001), with a trend toward fewer rehabilitation requirements. CONCLUSIONS: Robot major hepatectomy shows clinical advantages in elderly patients, including shorter hospital and ICU stays. These advantages, as well as reduced rehabilitation requirements associated with minimally invasive surgery, could overcome the current perceived financial disadvantages of robotic hepatectomy.

Expanding the utility of robotics for pancreaticoduodenectomy: a 10-year review and comparison to international benchmarks in pancreatic surgery.

BACKGROUND: Robotic pancreaticoduodenectomy (RPD) is an emerging alternative to open pancreaticoduodenectomy (OPD). Although RPD offers various theoretical advantages, it is used in less than 10% of all pancreaticoduodenectomies. The aim of this study was to report our 10-year experience and compare RPD outcomes with international benchmarks for OPD. METHODS: A retrospective review of a prospectively maintained institutional database was performed of consecutive patients who underwent RPD between January 2011 and December 2021. Patients were categorized into low-risk and high-risk groups according to the selection criteria set by the benchmark study. Their outcomes were compared to the international benchmark cut off values. Outcomes were then evaluated over time to identify improvements in practice and establish a learning curve. RESULTS: Of 201 RPDs, 36 were low-risk and 165 high-risk patients. Compared to the OPD benchmarks, outcomes of low-risk patients were within the cutoff values. High-risk patients were outside the cutoff for blood transfusions (26% vs. ≤ 23%), overall complications (78% vs. ≤ 73%), grade I-II complications (68% vs. ≤ 62%), and readmissions (22% vs ≤ 21%). Oncologic outcomes for high-risk patients were within benchmark cutoffs. Cases at the end of the learning curve included more pancreatic cancer (42% from 17%) and fewer low-risk patients (10% from 24%) than those at the beginning. After 41 RPD there was a decline in conversion rates and operative time. Between 95 and 143 cases operative time, transfusion rates, and LOS declined significantly. Complications did not differ over time. CONCLUSION: RPD yields results comparable to the established benchmarks in OPD in both low- and high-risk patients. Along the learning curve, RPD evolved with the inclusion of more high-risk cases while outcomes remained within benchmarks. Addition of a robotic HPB surgery fellowship did not compromise outcomes. These results suggest that RPD may be an option for high-risk patients at specialized centers.

Text mining in a literature review of abnormal uterine bleeding according to the FIGO classification.

AIM: Abnormal uterine bleeding, as proposed in 2007, is defined as unexpected uterine bleeding in women of reproductive age; the cause of the bleeding is categorized using the PALM-COEIN system. Identifying the diagnostic and treatment modalities for each cause might be intriguing. To summarize the options for abnormal uterine bleeding assessment, we employed text-mining analysis for each of its causes. METHODS: We analyzed abstracts based on PALM-COEIN from PubMed and Web of Science in March 2022. The literature was divided into categories; topics about the disorders were retrieved, and covalent network analysis was conducted to find information for evaluating abnormal uterine bleeding. RESULTS: Diagnostic approaches for PALM included histological and image analysis, including computerized tomography, magnetic resonance imaging, sonography, and hysteroscopy. The therapeutic approaches varied according to the cause. Diagnostic approaches for COEIN were mostly medical history interviews and blood sampling, and the therapeutic approaches for COEIN were ablation, hysteroscopy, and hormonal treatment. The PALM-COEIN classification co-occurrence search revealed each cause's diagnostic procedures, symptoms, and treatment procedures. CONCLUSION: Our text-mining methodology revealed comprehensive insights, important study themes, and clinical trends for abnormal uterine bleeding. A tailored approach to medical realities is required for treating abnormal uterine bleeding properly.

National survey of abnormal uterine bleeding according to the FIGO classification in Japan.

AIM: To investigate the status of abnormal uterine bleeding (AUB) in Japan using the International Federation of Gynecology and Obstetrics (FIGO) classification (AUB system 1 and 2; PALM-COEIN) and to clarify the relationship between AUB symptoms and the diseases causing AUB. METHODS: In a nationwide study, we enrolled first-time patients who visited target facilities during two consecutive weeks from December 1, 2019 to January 31, 2020. The FIGO classification was used to investigate patients with symptoms and causative diseases of AUB. Based on the proportion of patients in the nationwide study, 373 cases were included in the detailed survey. Survey items included symptoms of AUB according to AUB system 1, examination details, and causative diseases according to the PALM-COEIN classification. RESULTS: Within the study period, we encountered 61 740 first-time patients, of which 8081 (13.1%) were diagnosed with AUB. Among them, 39.9% had abnormal menstrual cycles and 56.9% had abnormal menstrual bleeding. In the survey, PALM had the highest percentage of AUB-L and COEIN had the highest percentage of AUB-O. Correspondence analysis showed that COEIN was strongly associated with abnormal menstrual cycles and PALM with abnormal menstrual bleeding. CONCLUSION: We conducted the first nationwide survey of AUB in Japan. The FIGO classification was a useful tool for the diagnosis of AUB, with a strong correlation between symptoms of AUB by AUB system 1 and the causative disease of AUB by PALM-COEIN. Conversely, a high percentage of AUB-N and AUB-E suggests that AUB system 1 and PALM-COEIN are ambiguous as diagnostic tools.

Hysteroscopic resection with temporary balloon catheter occlusion of bilateral internal iliac arteries for managing retained products of conception after spontaneous abortion: Two cases report.

Retained products of conception (RPOC) is a condition in which trophoblastic tissue remains in the uterus after pregnancy, causing massive hemorrhage in some cases. Though RPOC is commonly treated by intrauterine curettage or hysteroscopic resection uterine artery embolization or hysterectomy may be performed in case of massive bleeding. We experienced two cases of RPOC after surgery for missed abortion that failed to respond to conservative treatment and required surgical treatment. They were treated by hysteroscopic resection with temporary balloon catheter occlusion of bilateral internal iliac arteries for fertility preservation. After the balloon catheters were inflated, the reduction of blood flow to RPOC was observed under transvaginal ultrasound. In both cases, good visualization was maintained throughout the surgery with minimal bleeding. They were discharged the next day and resumed menstruation 1 month after surgery. This paper demonstrates the usefulness of this procedure as a minimally invasive and fertility-preserving surgery.

Robotic pancreatic necrosectomy and internal drainage for walled-off pancreatic necrosis.

BACKGROUND: Pancreatic necrosectomy with concomitant internal drainage is a single-stage treatment option for walled-off pancreatic necrosis (WOPN). However, an optimal minimally invasive technique has not been established. We evaluated the safety and single-intervention success rate of robotic pancreatic necrosectomy and internal drainage. METHODS: Patients with WOPN undergoing robotic pancreatic necrosectomy and internal drainage at a single institution from 2011-2022 were identified. The primary outcome was the rate of clinical symptom resolution following the index surgical intervention. RESULTS: 57 patients underwent robotic pancreatic necrosectomy and internal drainage, consisting of robotic cystgastrostomy (RCG, n = 37), robotic cystjejunostomy (RCJ, n = 13) and robotic fistulojejunostomy (RFJ, n = 7). Surgery was performed a median of 102 (range 28-1153) days following the onset of necrotizing pancreatitis. The median operative time was 187 (91-344) minutes and there were 2 (3.5%) conversions. The median length of hospital stay was 4 (2-38) days. Postoperative morbidity was 11%, and there was one (1.8%) 90-day mortality. At a median follow-up of 5.5 months, 53 (93%) patients had clinical symptom resolution after their index procedure and did not require any reintervention. CONCLUSION: In select patients, robotic pancreatic necrosectomy and internal drainage is safe and achieves a high single-intervention success rate.

Influence of laparoscopic surgery for endometriosis and its recurrence on perinatal outcomes.

Purpose: It is unknown whether surgery for endometriosis or recurrence of endometriosis affects obstetric outcomes. Methods: A total of 208 pregnant women with a history of endometriosis were analyzed. Patients who had endometriomas >3 cm and no history of laparoscopic surgery for endometriosis were defined as non-surgery group (n = 60), while those who had a history of surgery for endometriosis (n = 148) were defined as surgery group. We investigated the obstetric outcomes in 208 patients according to with or without postoperative recurrence of endometriosis and the time from surgery to pregnancy. Results: Among 177 cases of on-going pregnancy, in surgery group, there were lower prevalence of placenta previa compared with non-surgery group (8.5% vs. 23.4%; p = 0.020). Subgroup analysis revealed a decreased prevalence of placenta previa in postoperative non-recurrence group (6.0%: p = 0.007) compared with non-surgery (23.4%) and postoperative recurrence group (28.6%). Placenta previa was more prevalent in the patients who got pregnant more than 2 years after surgery (20.0%) than the patients who got pregnant within 2 years (2.4%: p = 0.002). Multivariate analysis revealed that the surgery was associated with a reduction in placenta previa (OR: 0.32, 95% CI [0.11-0.90]; p = 0.032). Conclusions: Pregnancy within two years after laparoscopic surgery for endometriosis may reduce placenta previa.

Hepatectomy after bile duct injury: a systematic review.

BACKGROUND: Bile duct injury (BDI) after cholecystectomy can lead to recurrent cholangitis, even after biliary reconstruction. This necessitates hepatectomy in a minority of patients. A systematic review was conducted, summarizing the pattern of biliary injury sustained in this group and their outcomes after hepatectomy. METHODS: A literature search included the MEDLINE, EMBASE, PubMed and Cochrane libraries. Retrospective cohort studies describing outcomes for hepatectomy after BDI, and the nature of the antecedent BDI, published between 1999 and 2019, were selected. RESULTS: Eight articles described a cohort of 2110 patients with BDI. Of these, 84 underwent hepatectomy. Complex vasculo-biliary injuries had been sustained in most cases. The mean time to hepatectomy was between 26 and 224 months after BDI. A right hepatectomy was performed in 67-89% of cases. Post hepatectomy, intra-abdominal infection (range 0-50%) and bile leaks (range 0-45%) occurred variably. Mortality occurred in three series. Nineteen percent of patients (16 of 84) developed recurrent symptoms at follow up. CONCLUSION: Hepatectomy after bile duct injury is an uncommon procedure and represents a salvage strategy when vasculo-biliary injury happens. Liver resection leads to resolution of symptoms in the majority of the cases however postoperative bile leaks and intra-abdominal infection are common.

Elevated levels of circulating mitochondrial DNA predict early allograft dysfunction in patients following liver transplantation.

BACKGROUND AND AIM: The role of circulating mitochondrial DNA (cmtDNA) in transplantation remains to be elucidated. cmtDNA may be released into the circulation as a consequence of liver injury; yet recent work also suggests a causative role for cmtDNA leading to hepatocellular injury. We hypothesized that elevated cmtDNA would be associated with adverse events after liver transplantation (LT) and conducted an observational cohort study. METHODS: Twenty-one patients were enrolled prospectively prior to LT. RESULTS: Postoperative complications were observed in 47.6% (n = 10). Seven patients (33.3%) had early allograft dysfunction (EAD), and six patients (28.5%) experienced acute cellular rejection within 6 months of LT. cmtDNA levels were significantly elevated in all recipients after LT compared with healthy controls and preoperative samples (1 361 937 copies/mL [IQR 586 781-3 399 687] after LT; 545 531 copies/mL [IQR 238 562-1 381 015] before LT; and 194 562 copies/mL [IQR 182 359-231 515] in healthy controls) and returned to normal levels by 5 days after transplantation. cmtDNA levels were particularly elevated in those who developed EAD in the early postoperative period (P < 0.001). In all patients, there was initially a strong overall positive correlation between cmtDNA and plasma hepatocellular enzyme levels (P < 0.05). However, the patients with EAD demonstrated a second peak in cmtDNA at postoperative day 7, which did not correlate with liver function tests. CONCLUSIONS: The early release of plasma cmtDNA is strongly associated with hepatocellular damage; however, the late surge in cmtDNA in patients with EAD appeared to be independent of hepatocellular injury as measured by conventional tests.

Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Effect of transdermal estradiol therapy on bone mineral density of amenorrheic female athletes.

BACKGROUND: The effects of transdermal estradiol treatment (HT) in amenorrheic athletes (AA) with low body weight (BW) and low bone mineral density (BMD) are unknown. PURPOSE: To investigate whether HT increases BMD in AA with low BW and to compare the results with levels in AA who have recovered spontaneous menstruation (SM). METHODS: Female athletes (n = 151) were recruited at the Japan Institute of Sports Sciences and the University of Tokyo. All participants were divided into four groups: an AA group (untreated group) (n = 36), a HT group (n = 55), a SM group (n = 21), and an eumenorrheic athletes (EA) group (n = 39). Height, body weight, blood tests, and dual-energy X-ray absorptiometry were measured at baseline and after 12 months. The HT group was treated daily for 12 months with transdermal estrogen therapy. In addition, participants received oral progestin for 7 days once every 3 months. RESULTS: After 12 months, BMD in the AA group was significantly lower than at baseline; however, BMD in the other three groups was significantly higher than at baseline. The ratio of the change in BMD values before and after 12 months was -1.6 ± 3.2% for the AA group, 5.3 ± 8.7% for the HT group, 11.1 ± 8.9% for the SM group, and 2.3 ± 5.7% for the EA group. The rate of change in BMD values in the SM group was greater than that in the HT group. CONCLUSION: HT increased BMD in AA with low BW, and the increase in those with SM was greater than that in those treated with HT.

Low Bone Mineral Density in Elite Female Athletes With a History of Secondary Amenorrhea in Their Teens.

OBJECTIVE: To determine whether secondary amenorrhea during teenage years influences bone mineral density (BMD) in female athletes in their 20s. DESIGN: Original research. SETTING: Japan Institute of Sports Sciences. PARTICIPANTS: Two hundred ten elite female athletes older than 20 years were included in the study. MAIN OUTCOME MEASURES: Information on the participants' past (ie, during their teenage years) and current menstrual cycle, training time, history of stress fractures, and blood tests for hormones received was obtained. Bone mineral density of the lumbar spine was evaluated by dual-energy x-ray absorptiometry; low BMD was defined as a Z-score ≤-1. We investigated the correlation factors for low BMD in athletes in their 20s by univariable and multivariable logistic regression analysis. RESULTS: A total of 39 (18.6%) female athletes had low BMD. Secondary amenorrhea in their teens [odds ratio (OR), 7.11, 95% confidence interval (CI), 2.38-21.24; P < 0.001] and present body mass index (BMI) (OR, 0.56, 95% CI, 0.42-0.73; P < 0.001) were independent correlation factors for low BMD in the multivariable logistic regression analysis. The average Z-score for those with secondary amenorrhea in their teens and 20s, secondary amenorrhea in their 20s only, and regular menstruation was -1.56 ± 1.00, -0.45 ± 1.21, and 0.82 ± 1.11 g/cm, respectively. CONCLUSIONS: Secondary amenorrhea for at least 1 year during teenage years in female athletes and BMI at present was strongly associated with low BMD in their 20s.

Quantitative analysis of ovarian cysts and tumors by using T2 star mapping.

AIM: The aim of this study was to investigate the efficacy of T2 star (T2*) mapping in diagnosing ovarian cysts/ tumors. METHODS: Pelvic magnetic resonance examinations including T2*WI were performed before surgery in 35 patients. The region of interest, consisted of a 10 mm2 diameter circle, was set as much as possible inside ovarian tumors/cysts to measure T2*values, and mean T2* values were compared in ovarian cyst/tumor types, retrospectively. Diagnoses of 40 ovarian cysts/tumors were determined by pathological reports, in which 17 were endometriomas, 13 were mature cystic teratomas, 6 were mucinous cystadenomas and 4 were serous cystadenomas. RESULTS: The average T2* values of endometrioma was 56.8 ± 8.7 ms (mean ± SEM), which was significantly lower than that of mucinous cystadenoma (334.2 ± 58.5 ms, mean ± SEM) or serous cystadenoma (237.0 ± 45.4 ms, mean ± SEM). There was no difference in T2* values between endometrioma and mature cystic teratoma (64.1 ± 22.6 ms, mean ± SEM). Receiver operating characteristics curve analysis revealed that optimal cut-off value for differential diagnosis of endometrioma and mucinous or serous cystadenoma was 149.2 ms as T2* value, which has an area under the curve of 0.95 (sensitivity = 92.4%, specificity = 78.6%). CONCLUSION: T2* values were useful to diagnose various types of ovarian cyst/tumor.

Relationship between tartrate-resistant acid phosphatase 5b and stress fractures in female athletes.

BACKGROUND: Approximately 10% of female athletes have a history of stress fractures, which most commonly occur between the ages of 16 and 17 years old. PURPOSE: We investigated whether tartrate-resistant acid phosphatase 5b (TRACP-5b), which is a bone resorption marker, can serve as a valid predictor of stress fractures in female athletes in their teens and 20s. METHODS: Three hundred and sixteen elite female athletes were recruited between 2013 and 2015. Serum TRACP-5b and various hormones were examined in blood samples. The serum TRACP-5b level was compared between athletes with and without stress fractures within 3 months after the initial collection of their blood samples. RESULTS: The 316 athletes were divided into two age groups: 13-19 years old and 20-29 years old. Thirty-six athletes (11.4%) experienced new stress fractures within 3 months after the initial collection of their blood samples. The median serum TRACP-5b level was significantly higher in teenage athletes with new stress fractures than in teenage athletes without new stress fractures. In univariate logistic regression analysis, the Z-score of serum TRACP-5b was a significant predictive factor of stress fractures in teenage athletes only (odds ratio: 1.87; 95% CI: 1.31-2.66; P < 0.0012). CONCLUSION: For teenage female athletes, TRACP-5b is a predictor of the risk of stress fractures, and measuring TRACP-5b levels may be useful to prevent stress fractures.

Trophoblast-Specific Conditional Atg7 Knockout Mice Develop Gestational Hypertension.

Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes using trophoblast-specific autophagy related (Atg)7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not the labyrinth layer, which significantly elevated blood pressure in dams. A marker of autophagy deficiency, sequestosome 1/p62, was accumulated in giant trophoblast cells and in the spongiotrophoblast layer, accompanying increased apoptosis. However, neither proteinuria in dams nor fetal growth restriction was observed. Regarding trophoblast function, the number of trophoblasts migrating into the maternal decidua was significantly reduced, and the wall/lumen ratio of the spiral arteries was significantly increased in cKO placentas, suggesting shallow trophoblast invasion and inadequate vascular remodeling. The relative expression of placental growth factor mRNA was significantly decreased in cKO placentas compared with the control, likely causing poor placentation; however, other factors were unchanged in cKO placentas. This is the first report of autophagy deficiency leading to impaired placentation complicated by maternal HDP attributable to trophoblast dysfunction, and it suggests that placental autophagy is required for normal placentation.

Oil-Soluble Contrast Medium (OSCM) for Hysterosalpingography Modulates Dendritic Cell and Regulatory T Cell Profiles in the Peritoneal Cavity: A Possible Mechanism by Which OSCM Enhances Fertility.

Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) is known to enhance fertility, although the mechanism is unclear. OSCM remains in the peritoneal cavity for several months after HSG. We hypothesized that OSCM that remains in the peritoneal cavity modulates dendritic cell (DC) and regulatory T cell (Treg) profiles and contributes to enhanced fertility. We characterized the profiles of DCs and Tregs in the peritoneal fluid from women who had undergone HSG. In vitro and in vivo effects of OSCM on monocyte-derived DCs and mouse peritoneal T cells were also evaluated. In comparison with women who have never experienced HSG, samples from women who had undergone HSG contained myeloid DCs with greater complexity and maturation, as well as had a marginally greater proportion of Tregs in their peritoneal fluid. OSCM is incorporated by monocyte-derived DCs, which causes their maturation and contributes to the increase in Treg proportions. Samples from OSCM-injected mice contained greater proportions of Tregs in comparison with controls. These studies demonstrate that OSCM modulates T cell profiles that are compatible with the condition observed in women who have undergone HSG. This study demonstrates that exogenous lipids administered to the peritoneal cavity are incorporated by DCs and that they significantly alter the immune environment in the peritoneal cavity. This immunological impact may contribute to enhanced fertility and the development of alternative therapeutic strategies for managing other pathological conditions associated with immunological abnormalities in the peritoneal cavity.

Risk factors of stress fractures due to the female athlete triad: Differences in teens and twenties.

BACKGROUND: The female athlete triad (Triad), defined by the American College of Sports Medicine as low energy availability (LEA) with or without disordered eating, menstrual dysfunction, and low bone mineral density (BMD), is associated with stress fractures and athletes aged 16-17 years are most susceptible. PURPOSE: To examine whether the Triad increases the risk of stress fractures, athletes were assigned to a "teenage" group and a "20s" group. METHODS: This prospective study enrolled 390 elite female athletes and was conducted from 2012 to 2016 at Japan Institute of Sports Sciences. Blood concentrations of various hormones were examined, and BMD was measured at the lumbar spine and throughout the whole body using dual-energy X-ray absorptiometry. LEA was defined as body weight ≤85% of the ideal body weight for teenage athletes, or BMI ≤17.5 for athletes in their 20s. Low BMD was defined as a BMD Z-score of <-1.0 in the lumbar spine and the whole body. RESULTS: Among 390 athletes enrolled, 36 developed new stress fractures within 3 months of registration. The risk for stress fractures due to the Triad in teenage athletes was higher than for athletes in their 20s. In teenage female athletes, secondary amenorrhea, low BMD for the whole body, and a low ratio of actual body weight to ideal body weight increased the risk for stress fractures by 12.9 times, 4.5 times, and 1.1 times, respectively. CONCLUSION: To prevent stress fractures in female athletes with the Triad, age of athletes should be taken into consideration.