Prediction of the final menstrual period in women taking Dienogest using estradiol and follicle-stimulating hormone values: a case-control study.

Dienogest (DNG) is widely used to treat dysmenorrhea associated with estrogen-dependent diseases such as endometriosis and adenomyosis. DNG becomes unnecessary after menopause when estrogen secretion declines drastically. However, there are no clear criteria for when to halt DNG in perimenopausal patients. Menstruation and dysmenorrhea often resume after discontinuation due to approaching menopause. This case-control study used serum estradiol and follicle-stimulating hormone (FSH) levels to predict whether menstruation would resume in perimenopausal women after discontinuation of DNG. The study enrolled patients aged ≥40 years with endometriosis and/or adenomyosis and who had either completed oral DNG therapy (DNG group) or had spontaneous menopause without hormone therapy (control group). We assessed estradiol and FSH values before DNG termination or the final menstrual period. DNG group members that resumed menstruation after DNG termination (D (+) group, n = 17) had significantly higher estradiol and lower FSH levels than those who did not (D (-) group, n = 22) up to four months before DNG termination but not from four to 12 months. Estradiol and FSH levels were not significantly different between the D (-) and control groups. Receiver operating characteristic curves created from the estradiol and FSH values indicated that menstruation resumed when levels were ≥17 pg/mL and <100 mIU/mL, respectively. In contrast, menstruation did not resume in cases of estradiol ≤20 pg/mL and FSH >80 mIU/mL. The study results provide useful criteria for deciding when to terminate DNG in perimenopausal patients that consider their tolerance for resuming menstruation. Applications to menopause-inducing therapy for uterine fibroids and other conditions are anticipated. Further large-scale studies are needed.

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917).

BACKGROUND: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. METHODS: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. RESULTS: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. CONCLUSIONS: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. TRIAL REGISTRATION: UMIN000038296 ; registered on 15 October 2019.

Association between self-reported walking speed and calcaneal stiffness index in postmenopausal Japanese women.

BACKGROUND: Osteoporosis and related fractures, a worldwide public health issue of growing concern, is characterized by compromised bone strength and an increased risk of fracture. Here we show an association between self-reported walking speed and bone mass among community-dwelling postmenopausal Japanese women aged 50 years and older. DESIGN; CROSS-SECTIONAL STUDY: Setting and Participants; The survey population included 1008 postmenopausal women 50-92 years of age residing in rural communities. METHODS: Self-reported walking speed was ascertained by asking the participants: "Is your walking speed faster than others of the same age and sex?" to which participants responded "yes (faster)" or "no (moderate/slower)." Calcaneal stiffness index was measured. RESULTS: Women with a faster self-reported walking speed were younger and had a lower BMI, higher stiffness index, and higher grip strength than women with a slower walking speed. Multiple linear regression analysis adjusted for age, BMI, grip strength, comorbidity, current smoking, and alcohol drinking status showed a significant association between faster self-reported walking speed and higher calcaneal stiffness index (p <  0.001). CONCLUSIONS: Our findings suggest that questionnaires of walking speed may be useful for predicting bone mass and that a fast self-reported walking may benefit bone health in postmenopausal women.

Neonatal isolation augments social dominance by altering actin dynamics in the medial prefrontal cortex.

Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.

[Association between fear of falling and activities of daily living among community-dwelling Japanese older adults].

Objectives　This study aimed to explore the association of difficulties in activities of daily living (ADL) (activities related to bending, spine extension, standing endurance, and walking) with fear of falling among community-dwelling older adults.Methods　We recruited 642 older adults (men, n=267; women, n=375) aged 65 years and over. The mean age was 72.2±5.1 years. Fear of falling, falls in the previous year, pain (low back pain or knee pain), comorbidity, and cataracts were assessed using a self-administered questionnaire. ADL difficulties were assessed individually, such as activities related to bending (getting in or out the car, picking up a lightweight object, putting on socks or stockings, and lifting a 5 kg object from the floor), spine extension (reaching an object above your head), standing endurance (standing on your feet for 2 h), and walking (walking 100 m on a level surface, climbing 10 steps without stopping, and walking down 10 steps). The independent association between fear of falling and each ADL difficulties was assessed using logistic regression analysis.Results　Participants with fear of falling, compared with those without fear of falling, had an older age (74.8 and 71.6 in men, 73.3 and 71.0 in women, respectively; P<0.01), more falls in the previous year (21% and 9% in men, 28% and 11% in women, respectively; P<0.05), pain (80% and 61% in men, 82% and 64% in women, respectively; P<0.01), and comorbidity (23% and 15% in women, respectively; P<0.05). Multivariate logistic regression analysis identified each ADL difficulties except walking 100 m on a level surface as being independently associated with fear of falling after adjusting for age, body mass index, sex, falls in the previous year, pain, and comorbidity.Conclusion　ADL difficulties, such as activities related to bending, spine extension, standing endurance, and walking, except for walking 100 m on a level surface, were associated with fear of falling.

The G7 presidency and universal health coverage, Japan's contribution.

PROBLEM: If universal health coverage (UHC) is to be achieved globally, it needs sustained promotion and political awareness and support. APPROACH: During its presidency of the Group of Seven (G7) industrialized nations in 2016, Japan aimed to raise the issue of UHC to the top of the global health agenda. LOCAL SETTING: Japan has promoted a health agenda at all of the G7 summits since 2000 that it has hosted. Human security has been the core foundation of Japan's foreign diplomacy for several decades and, consequently, there was no apparent opposition within Japan to the inclusion of UHC on the agenda of the summit in 2016. Other G7 governments appeared keen to promote such coverage. RELEVANT CHANGES: Since the 2016 summit, UHC has remained a central agenda item for the United Nations and World Health Organization, even though the leaders of both these global organizations have changed. In 2017, Japan hosted the UHC Forum in Tokyo. The participants, who were the heads of United Nations agencies, politicians and other decision-makers from all over the world, showed their continued commitment towards UHC. LESSONS LEARNT: In the raising of awareness of an item on the global health agenda, high-level champions are critical. Although they may be very diverse, all relevant stakeholders need to be connected and allowed to discuss policies with each other. Having too many allies can, however, lead to policy fragmentation, especially when there is commitment from the highest echelons within each country.

Long-term dienogest administration in patients with symptomatic adenomyosis.

AIM: Adenomyosis is a common gynecological disorder that causes dysmenorrhea, hypermenorrhea and metrorrhagia. Previously, we reported that 24 weeks of dienogest treatment is highly effective for pain in symptomatic adenomyosis. Up to present, there is no report that describes treatment of adenomyosis with long-term dienogest administration for more than 2 years. In this retrospective cohort study, we investigated the course of long-term dienogest treatment in patients with symptomatic adenomyosis. METHODS: This is a retrospective cohort study. Dienogest was continuously administered at a dose of 2 mg daily for patients with symptomatic adenomyosis. The outcome of long-term administration of dienogest was investigated, and the characteristics of patients were compared between discontinued cases and long-term administration cases. RESULTS: Two patients were excluded from this study because of transfer to another hospital or discontinuation due to infertility treatment. Twelve of 18 patients (66.7%) received dienogest until menopause or for a period of >80 months. Four cases (22.2%) discontinued dienogest treatment because of severe metrorrhagia. In the discontinued cases because of severe metrorrhagia, the pain score for dysmenorrhea and serum CA125 level at baseline significantly elevated, and the hemoglobin level at baseline and the frequency of type 2 adenomyosis significantly decreased, compared to those with long-term use. Moreover, long-term dienogest use did not decrease the serum estradiol level. CONCLUSION: Our report suggests that dienogest is tolerable for long-term use until menopause and can be an alternative treatment option in some patients, especially those with type 2 adenomyosis, to avoid hysterectomy.

X-ray irradiation induces local rearrangement of silica particles in swollen rubber.

X-ray photon correlation spectroscopy (XPCS) of swollen rubber containing spherical silica nanoparticles is reported. It is shown that irradiation by intense X-rays leads to the breakdown of cross-links, thereby inducing the local rearrangement of silica nanoparticles. This rearrangement process depends on the cross-link density and is characterized by a compressed exponential relaxation with aging behaviour, which resembles a common feature of complex fluids observed with XPCS.

Temporary balloon occlusion of the uterine arteries to control hemorrhage during hysterectomy in a case of uterine arteriovenous fistula.

Arteriovenous fistula is any abnormal connection between an artery and a vein that bypasses the normal capillary bed and shunts arterial blood directly to the venous circulation. Uterine arteriovenous fistula (UAVF) is a potentially life-threatening condition by causing massive bleeding. This report describes a case of UAVF with massive hemorrhage. Prior to surgery, endovascular catheters for balloon occlusion were placed within bilateral uterine arteries. During surgery, the surgeon requested temporary balloon inflation for navigating and identifying inflow arteries. The balloon was kept inflated during the ligation of the vessels. Once ligation was completed, the balloon was deflated to confirm hemostasis. A total hysterectomy with removal of the UAVF was successfully achieved without significant blood loss. The fistula, in the resected specimen, was confirmed histologically with Elastica van Gieson staining. The preoperative placement of endovascular balloon-occlusion catheters should be considered when hysterectomy is planned where UAVF is located at the cardinal ligament.

Dysphoric milk ejection reflex among Japanese mothers: a self-administered survey.

BACKGROUND: The dysphoric milk ejection reflex (D-MER) is a reflex that causes temporary discomfort during milk ejection. D-MER develops due to the effects of hormones involved in lactation, and it has been reported that it is a physiological symptom different from postpartum depression, but the actual situation is unknown in Japan. METHODS: This study was conducted using a self-administered, anonymous survey of mothers of children who had undergone health checkups at three years of age at five health centers in Kagoshima city and aimed to clarify the reality and perceptions of mothers regarding D-MER. The survey period was from May to September, 2022. The questionnaires were distributed to 389 mothers, and 216 (55.5% recovery rate) responses were received, of which 202 (valid response rate 93.5%) were included in the analysis. RESULTS: Regarding the experience of D-MER, 202 mothers in the study population had given birth to a total of 403 children and experienced D-MER when breastfeeding 62 children (15.4%). Of the 202 mothers included in the analysis, 47 (23.3%) answered that they had experienced D-MER with at least one child while breastfeeding. Sixty-six mothers (32.7%) knew about D-MER. Compared to those who had not experienced D-MER, those who had experienced D-MER had significantly higher scores on the items related to having had trouble breastfeeding (odds ratio (OR]: 3.78; 95% confidence interval (CI]: 1.57, 9.09) and knowing about D-MER (OR 2.41; 95% CI 1.20, 4.84). Regarding symptoms, irritability (n = 24, 51.1%), anxiety (n = 22, 46.8%), and sadness (n = 18, 38.3%) ranked high. Coping strategies included distraction, focusing on the child, and, in some cases, cessation of breastfeeding. Thirty mothers (63.8%) answered that they did not consult anyone, citing reasons such as a belief that no one would be likely to understand their symptoms, and that they could not sufficiently explain their symptoms. CONCLUSION: The low level of awareness of D-MER suggests that it is necessary to inform and educate mothers and the public about the physiological symptoms of D-MER. Moreover, it is necessary to listen to the feelings of mothers with D-MER and support them in coping with their symptoms.

Apoptosis-dependent externalization and involvement in apoptotic cell clearance of DmCaBP1, an endoplasmic reticulum protein of Drosophila.

To elucidate the actions of Draper, a receptor responsible for the phagocytic clearance of apoptotic cells in Drosophila, we isolated proteins that bind to the extracellular region of Draper using affinity chromatography. One of those proteins has been identified to be an uncharacterized protein called Drosophila melanogaster calcium-binding protein 1 (DmCaBP1). This protein containing the thioredoxin-like domain resided in the endoplasmic reticulum and seemed to be expressed ubiquitously throughout the development of Drosophila. DmCaBP1 was externalized without truncation after the induction of apoptosis somewhat prior to chromatin condensation and DNA cleavage in a manner dependent on the activity of caspases. A recombinant DmCaBP1 protein bound to both apoptotic cells and a hemocyte-derived cell line expressing Draper. Forced expression of DmCaBP1 at the cell surface made non-apoptotic cells susceptible to phagocytosis. Flies deficient in DmCaBP1 expression developed normally and showed Draper-mediated pruning of larval axons, but a defect in the phagocytosis of apoptotic cells in embryos was observed. Loss of Pretaporter, a previously identified ligand for Draper, did not cause a further decrease in the level of phagocytosis in DmCaBP1-lacking embryos. These results collectively suggest that the endoplasmic reticulum protein DmCaBP1 is externalized upon the induction of apoptosis and serves as a tethering molecule to connect apoptotic cells and phagocytes for effective phagocytosis to occur.

Pretaporter, a Drosophila protein serving as a ligand for Draper in the phagocytosis of apoptotic cells.

Phagocytic removal of cells undergoing apoptosis is necessary for animal development and tissue homeostasis. Draper, a homologue of the Caenorhabditis elegans phagocytosis receptor CED-1, is responsible for the phagocytosis of apoptotic cells in Drosophila, but its ligand presumably present on apoptotic cells remains unknown. An endoplasmic reticulum protein that binds to the extracellular region of Draper was isolated. Loss of this protein, which we name Pretaporter, led to a reduced level of apoptotic cell clearance in embryos, and the overexpression of pretaporter in the mutant flies rescued this defect. Results from genetic analyses suggested that Pretaporter functionally interacts with Draper and the corresponding signal mediators. Pretaporter was exposed at the cell surface after the induction of apoptosis, and cells artificially expressing Pretaporter at their surface became susceptible to Draper-mediated phagocytosis. Finally, the incubation with Pretaporter augmented the tyrosine-phosphorylation of Draper in phagocytic cells. These results collectively suggest that Pretaporter relocates from the endoplasmic reticulum to the cell surface during apoptosis to serve as a ligand for Draper in the phagocytosis of apoptotic cells.

Umbilical vein injection for the routine management of third stage of labour.

BACKGROUND: Postpartum haemorrhage is among the biggest contributor to maternal mortality worldwide. Prevention of this condition includes routine use of uterotonic in the third stage of labour, which has been recommended throughout the world. Use of umbilical route to deliver this uterotonic after delivery of the baby has been proposed. Therapeutic use of this has been assessed, although routine (prophylactic) use of this has not been evaluated. OBJECTIVES: To compare, from the best available evidence, the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus an alternative solution with or without any other uterotonic agent or expectant management or any other method for routine management of the third stage of labour, on maternal and perinatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2012) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials comparing the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus any other alternative methods. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and trial quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: We included nine studies involving 1118 women.We identified four comparisons. One comparison included six studies (which randomised 394 women) comparing umbilical vein injection of normal saline plus oxytocin versus that of normal saline, as well as three other comparisons, each of which includes one study. Comparing intraumbilical injection of normal saline plus oxytocin with intraumbilical injection of saline only, there was no evidence of difference in any of the relevant outcomes reported namely the number of women who required blood transfusion, the incidence of manual removal of placenta, blood loss, and length of the third stage of labour. Subgroup analyses by both total amount of solution administered and dose of oxytocin showed no evidence of difference. Other comparisons included only one study for each, and there was no relevant information available. AUTHORS' CONCLUSIONS: Routine use of oxytocin or any other uterotonics with normal saline via umbilical vein injection is not recommended until new evidence is available. Further research should be conducted to show effectiveness of oxytocin with normal saline via umbilical vein injection.

[General anesthesia in a orthopedic case with the Kommerell's diverticulum of right-sided aortic arch diagnosed on preoperative examination].

Kommerell's diverticulum is a rare anomaly of the aortic arch. A 59-year-old man was scheduled for open reduction and internal fixation of his right proximal tibial fracture under general anesthesia. We diagnosed right-sided aortic arch by the chest X-ray and thoracic computed tomography. His trachea and esophagus were compressed by the aortic arch. He had complained of no dyspnea or dysphagia. Respiratory difficulty might be caused by muscle relaxants, intermittent positive pressure ventilation, change of intrathoracic pressure, postural change and overloaded infusion during general anesthesia in a case of right-sided aortic arch. We performed lumbar epidural anesthesia and inserted an i-gel after general anesthesia induction preserving spontaneous respiration in preparation for controlled ventilation or tracheal intubation via an i-gel. We could accomplish the operation uneventfully and he was discharged on POD 53. A supraglottic airway such as an i-gel was a useful device in the present case of right-sided aortic arch with Kommerell's diverticulum.