MISpheroID: a knowledgebase and transparency tool for minimum information in spheroid identity.

Spheroids are three-dimensional cellular models with widespread basic and translational application across academia and industry. However, methodological transparency and guidelines for spheroid research have not yet been established. The MISpheroID Consortium developed a crowdsourcing knowledgebase that assembles the experimental parameters of 3,058 published spheroid-related experiments. Interrogation of this knowledgebase identified heterogeneity in the methodological setup of spheroids. Empirical evaluation and interlaboratory validation of selected variations in spheroid methodology revealed diverse impacts on spheroid metrics. To facilitate interpretation, stimulate transparency and increase awareness, the Consortium defines the MISpheroID string, a minimum set of experimental parameters required to report spheroid research. Thus, MISpheroID combines a valuable resource and a tool for three-dimensional cellular models to mine experimental parameters and to improve reproducibility.

Nocturia in Menopausal Women: The Link Between Two Common Problems of the Middle Age.

INTRODUCTION AND HYPOTHESIS: The aim of this review is to discuss the link between menopause and nocturia and to give an overview of the increasing prevalence, risk factors, causative factors, treatment needs and options for nocturia in peri-menopausal women. METHODS: This opinion article is a narrative review based on the expertise and consensus of a variety of key opinion leaders, in combination with an extensive literature review. This literature search included a thorough analysis of potential publications on both the PubMed Database and the Web of Science and was conducted between November 2022 and December 2022. The following key words were used "nocturia" and "menopause" or "nocturnal frequency and menopause." Moreover, key words including "incidence," "prevalence," "insomnia," "estrogen therapy," "metabolic syndrome," and "hot flushes" were used in combination with the aforementioned key words. Last, the reference lists of articles obtained were screened for other relevant literature. RESULTS: The perimenopause can be a trigger for inducing nocturia. Typically, obesity, body mass index (BMI), and waist circumference are risk factors for developing peri-menopausal nocturia. Presumably the development of peri-menopausal nocturia is multifactorial, with interplay among bladder, sleep, and kidney problems due to estrogen depletion after the menopause. First, impaired stimulation of estrogen receptors in the urogenital region leads to vaginal atrophy and reduced bladder capacity. Moreover, menopause is associated with an increased incidence of overactive bladder syndrome. Second, estrogen deficiency can induce salt and water diuresis through blunted circadian rhythms for the secretion of antidiuretic hormone and the activation of the renin-angiotensin-aldosterone system. Additionally, an increased incidence of sleep disorders, including vasomotor symptoms and obstructive sleep apnea signs, is observed. Oral dryness and a consequent higher fluid intake are common peri-menopausal symptoms. Higher insulin resistance and a higher risk of cardiovascular diseases may provoke nocturia. Given the impact of nocturia on general health and quality of life, bothersome nocturia should be treated. Initially, behavioral therapy should be advised. If these modifications are inadequate, specific treatment should be proposed. Systemic hormone replacement is found to have a beneficial effect on nocturia, without influencing sodium and water clearance in patients with nocturnal polyuria. It is presumed that the improvement in nocturia from hormonal treatment is due to an improvement in sleep disorders.

Menopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer's disease.

INTRODUCTION: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women. METHODS: We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-ß (Aß) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration. RESULTS: We report a prominent and significant treatment response at the Aß pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment. DISCUSSION: To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.

Nocturia through the menopausal transition and beyond: a narrative review.

INTRODUCTION AND HYPOTHESIS: Nocturia, defined as the act of waking to pass urine during sleeping, is a common problem in older women and is associated with significant morbidity and impairments in health-related quality of life. The aim of this review was to synthesize the current evidence regarding the incidence, impact, pathophysiology, and specific diagnostic approach of nocturia in the postmenopausal population. METHODS: We searched PubMed and Web of Science databases to identify relevant studies published through June 2020. Reference lists of the reviews obtained were screened for other articles deemed pertinent by the authors. RESULTS: Genitourinary symptoms attributed to the menopause have been reported to occur in nearly 90% of postmenopausal women, and nocturia is one of the most common. The relative deficiency in endogenous estrogen production after the menopause is thought to exacerbate all major pathophysiological mechanisms that may underlie nocturia, including reduced bladder capacity, nocturnal polyuria, global polyuria, and sleep disorders. Diminished estrogen may induce anatomical and physiological bladder changes, contributing to a reduction in functional bladder capacity. Excess nocturnal urine production can also be provoked by estrogen depletion, either via free water-predominant diuresis by an impaired secretion of antidiuretic hormone, or a salt-predominant diuresis owing to diminished activation of the renin-angiotensin-aldosterone axis. Additionally, a relationship between the transition to menopause and impaired sleep has been described, mediated by increased incidence in vasomotor symptoms and obstructive sleep apnea signs during the menopause. CONCLUSION: Further research is necessary to better characterize and manage nocturia in postmenopausal women.

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin®. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin® in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin®, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin® may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

18F-FDG micro-PET/CT for intra-operative margin assessment during breast-conserving surgery.

Rationale: Positive surgical margins for invasive breast cancer (BC) treated with breast-conserving surgery (BCS) are defined as ink on tumor. The rate of positive margins is approximately 20%, since a time- and cost-effective method for margin assessment is lacking. In this study, we investigated margin status by intra-operative imaging using high-resolution 18 F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) and X-ray computed tomography (CT).Methods: Twenty patients were enrolled and received 4 MBq/kg of FDG prior to surgery. Intra-operative imaging of the specimens was performed by the MOLECUBES ß-CUBE (PET) and X-CUBE (CT). Margin status was assessed by three surgeons and compared with an algorithm. The sensitivity and specificity were calculated by using histopathological assessment as a gold standard.Results: A region with high FDG uptake was visualized in all specimens. Automated analysis showed a sensitivity of 90%, a specificity of 60%, and an area under the curve (AUC) of 0.86 after ROC analysis. Margin assessment by the surgeons resulted in a mean sensitivity and specificity of 79% and 72%, respectively.Conclusions: This proof-of-concept study demonstrates that high-resolution FDG-PET/CT can facilitate intra-operative margin assessment during BCS. This technique achieves good sensitivity and specificity and may therefore reduce re-operation rates in the future.

Precision medicine and drug development in Alzheimer's disease: the importance of sexual dimorphism and patient stratification.

Neurodegenerative diseases (ND) are among the leading causes of disability and mortality. Considerable sex differences exist in the occurrence of the various manifestations leading to cognitive decline. Alzheimer's disease (AD) exhibits substantial sexual dimorphisms and disproportionately affects women. Women have a higher life expectancy compared to men and, consequently, have more lifespan to develop AD. The emerging precision medicine and pharmacology concepts - taking into account the individual genetic and biological variability relevant for disease risk, prevention, detection, diagnosis, and treatment - are expected to substantially enhance our knowledge and management of AD. Stratifying the affected individuals by sex and gender is an important basic step towards personalization of scientific research, drug development, and care. We hypothesize that sex and gender differences, extending from genetic to psychosocial domains, are highly relevant for the understanding of AD pathophysiology, and for the conceptualization of basic/translational research and for clinical therapy trial design.

External partial breast irradiation in prone position: how to improve accuracy?

INTRODUCTION: In view of the limited incremental benefit between whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) and omission of radiotherapy in favorable early-stage breast cancer (ESBC), APBI can only be justified if it combines adequate target coverage with the lowest achievable toxicity. Interobserver exercises demonstrated the difficulty of precise target delineation, especially in prone position; information on accuracy is even scarcer. We tested the impact of inserting an additional indicator clip, marking the depth of the tumor in the breast, and the added value of a preoperative CT in treatment position on precision and accuracy. MATERIAL AND METHODS: In 12 patients, tumor bed delineation was performed by four radiation oncologists, with CTVstandard (clinical target volume) based on standard delineation guidelines, CTVclip resulting from a 1-2-cm symmetrical expansion with the indicator clip as center and CTVclip_CT expanding from the midpoint between the indicator clip and preoperative gross tumor volume (GTV) as center. Precision was measured as the mean pairwise Jaccard index (JIpairs) between observers, accuracy as the mean overlap between GTV and respective CTVs. RESULTS: JIpairs was 0.38 for CTVstandard, 0.75 for CTVclip and 0.59 for CTVclip_CT. Overlap rate of GTV with CTVs was respectively 0.48, 0.67 and improved further to 0.88 for CTVclip_CT. High-dose coverage of GTV (D95 and D90) improved with an indicator clip, but the most optimal result was reached when preoperative CT was added. CONCLUSIONS: If EB-APBI in prone position is aimed for, an indicator clip intended to mark the depth of the tumor increases the probability of accurate target coverage, but cannot entirely replace the added value of a preoperative CT in treatment position. Avoiding the cost and effort of such CT implies a risk of missing the target, especially when small volumes are aimed for. Increasing target volumes to reduces this risk, questions the concept of APBI.

Resection of single metachronous liver metastases from breast cancer stage I-II yield excellent overall and disease-free survival. Single center experience and review of the literature.

PURPOSE: Improved survival after liver resection for breast cancer liver metastases (BCLM) has been proven; however, there is still controversy on predictive factors influencing outcomes. The analysis of factors related to primary and metastatic cancer eventually influencing long-term outcomes and a review of the literature are presented in this report. METHODS: Twenty-seven patients diagnosed with metachronous BCLM between 1996 and 2013 were retrospectively reviewed. Patients who had a minimum disease-free interval between primary tumor and liver metastasis of 12 months, no more than 3 liver lesions, no macroscopic extra-hepatic disease and in which systemic therapy showed a good response were included. RESULTS: Twenty-two patients (82%) were initially diagnosed with a stage I-II disease. Twelve patients presented with multiple liver metastases. The 5 years overall survival (OS) rate was 78%, while the 5 years disease-free survival (DFS) rate was 36%. Initial tumor stage III-IV at first diagnosis and number of metastases >1 was significantly associated with a shorter DFS at multivariate analysis (p = 0.03 and p = 0.04 respectively). Patients with multiple lesions had a median DFS of 15 months compared to 47 months in patients with a single lesion (p = 0.03). CONCLUSIONS: Resection of single BCLM from primary stage I-II cancer offers very good long-term survival rates and a low morbidity.

Need for recovery after work and associated risk factors in working menopausal women.

OBJECTIVES: To explore relationships between 'need for recovery' (NFR), a strong predictor of burnout, and menopause symptoms and to identify work-related factors that are associated with a high NFR in Belgian menopausal women. STUDY DESIGN: 760 menopausal women took part in a cross-sectional questionnaire study. NFR, presence of menopause symptoms, job type, age category, work activity, physical workload, psychosocial and physical work environment, balance of work and private life and the opportunity to discuss menopause at work were assessed. MAIN OUTCOME MEASURES: Uni- and multivariate logistic regression analyses were used to calculate the odds ratios for the presence of a high NFR. RESULTS: Of menopausal women currently experiencing menopause symptoms, 53.3 % reported problems while performing their work. The overall prevalence of a high NFR in menopausal women was 41.2 %. Women who experienced problems at work had the highest prevalence of a high NFR (61.1 %), and constituted a separate risk group for having a high NFR (OR 3.31 vs. never symptoms; 95%CI 1.72-6.38). The following factors were significantly associated with a high NFR: poor balance of work and private life (OR 7.89; 95%CI 4.32-14.39), physical workload (OR 1.17; 95%CI 1.08-1.28), discomfort from cognitive demands (OR 1.17; 95%CI 1.09-1.26), organizational justice (OR 0.86; 95%CI; 0.78-0.94), and social support from colleagues (OR 0.87; 95%CI 0.79-0.96). CONCLUSIONS: Maintaining a good balance of work and private life, reducing physical workload, addressing discomfort from cognitive work demands and assuring a fair work distribution are measures that require a culture where open and easy discussion about menopause is possible.

Comparison of speaking fundamental frequency between premenopausal women and postmenopausal women with and without hormone therapy.

OBJECTIVE: The purpose of this study was to investigate the speaking fundamental frequency (SFF) in pre- and postmenopausal women with and without hormone therapy (HT) and with low and high body mass index (BMI). PATIENTS AND METHODS: The SFF of premenopausal women with low BMI (n = 22) was compared with the SFF of premenopausal women with high BMI (n = 13), postmenopausal women with HT and low BMI (n = 35), postmenopausal women with HT and high BMI (n = 19), postmenopausal women without HT and with low BMI (n = 28) and postmenopausal women without HT and with high BMI (n = 12) using ANCOVA and post hoc tests. RESULTS: A significantly lower SFF of the voice was only found in postmenopausal women without HT and with a low BMI. CONCLUSION: The results of this study suggest that the menopause lowers the voice with approximately 14 Hz and that HT and adipose tissue (high BMI) might counteract the menopausal drop in SFF.

Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers.

BACKGROUND: Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. METHODS: We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. RESULTS: We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/ß-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. CONCLUSION: Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.

Does hormonal therapy affect the bladder or the kidney in postmenopausal women with and without nocturnal polyuria: Results of a pilot trial?

AIM: To observe the impact of hormonal treatment (HT) on voiding patterns and renal circadian rhythms in postmenopausal women with and without nocturnal polyuria (NP). MATERIAL AND METHODS: A prospective, observational study was executed at the menopause clinic of a tertiary hospital. HT was based on patients' choice and was in the form of either oral and transdermal oestrogen. Participants completed a 72-hour bladder diary, completed the ICIQ-FLUTS questionnaire, recorded a renal function profile and gave a blood sample. This set of tests was done before and after 3 months of HT. RESULTS: 32 postmenopausal women with a median age of 52.5 (49.3-56.0) years were enroled in this study. Three months of HT resulted in a significant decrease in fluid intake (p < 0.001) and daytime voiding frequency (p = 0.019). No impact on nocturnal parameters was observed. Observations drawn from the questionnaires did not differ between the baseline and three-month assessments. HT led to a disappearance of the circadian rhythm of the diuresis rate and sodium clearance in patients without NP, as no significant difference between daytime and night-time values was observed (diuresis rate p = 0.3; sodium clearance p = 0.08). In patients with NP at baseline, HT did not induce a circadian rhythm of the diuresis rate and sodium clearance (p = 0.2; p = 0.7). In contrast, free water clearance did change to a clear circadian rhythm (p = 0.02). CONCLUSION: HT led to a significant reduction in both fluid intake and daytime frequency. In women without NP, HT led to a disruption of the circadian rhythms of water and salt diuresis. In patients with NP, a limited normalisation of the circadian rhythm of free water clearance was observed after three months of HT. CLINICAL TRIAL REGISTRATION NUMBER FROM CLINICALTRIALS.GOV: NCT04891926.

Tumour characteristics of screen-detected and interval cancers in the Flemish Breast Cancer Screening Programme: A mammographic breast density study.

OBJECTIVE: The objective is to investigate tumour prognostic factors versus breast density in screen-detected cancers and interval cancers. The results may highlight the need for more personalised screening protocols based on breast density in organized screening programmes. STUDY DESIGN: A retrospective study was performed of tumour characteristics of screen-detected cancers (n=468) and interval cancers (n=515) of 983 women who participated in the Flemish Breast Cancer Screening Programme in 2009-2010. Breast density was obtained from the screening programme data. Information on nodal invasion and histological grading was taken from the Belgian Cancer Registry. Tumour size and proliferation and receptor expression status were retrieved from pathology reports. The differences in tumour characteristics between screen-detected and interval cancers as well as the variation in these variables with breast density in both groups were studied by logistic regression. RESULTS: A comparison of tumour characteristics between screen-detected cancers and interval cancers systematically showed features of more aggressive tumours in interval cancers: larger tumour size, nodal invasion, grade 3 tumours, and hormone receptor negative phenotype (p<0.05). The analysis of tumour characteristics versus breast density in screen-detected cancers showed higher numbers of aggressive grade 3 tumours in low-density breasts and of the luminal A subtype with good prognosis in high-density breasts (p<0.05). This analysis for interval cancers highlights a high proportion of the difficult-to-treat triple-negative subtype in low-density breasts compared with high-density breasts. In conclusion, the study data support arguments against changes in breast cancer screening programmes with prolongation of screening intervals in low-density breasts.

Reproducibility of repeated breathhold and impact of breathhold failure in whole breast and regional nodal irradiation in prone crawl position.

In whole breast and regional nodal irradiation (WB + RNI), breathhold increases organ at risk (OAR) sparing. WB + RNI is usually performed in supine position, because positioning materials obstruct beam paths in prone position. Recent advancements allow prone WB + RNI (pWB + RNI) with increased sparing of OARs compared to supine WB + RNI. We evaluate positional and dosimetrical impact of repeated breathhold (RBH) and failure to breathhold (FTBH) in pWB + RNI. Twenty left-sided breast cancer patients were scanned twice in breathhold (baseline and RBH) and once free breathing (i.e. FTBH). Positional impact was evaluated using overlap index (OI) and Dice similarity coefficient (DSC). Dosimetrical impact was assessed by beam transposition from the baseline plan. Mean OI and DSC ranges were 0.01-0.98 and 0.01-0.92 for FTBH, and 0.73-1 and 0.69-1 for RBH. Dosimetric impact of RBH was negligible. FTBH significantly decreased minimal dose to CTV WBI, level II and the internal mammary nodes, with adequate mean doses. FTBH significantly increased heart, LAD, left lung and esophagus dose. OI and DSC for RBH and FTBH show reproducible large ROI positions. Small ROIs show poor overlap. FTBH maintained adequate target coverage but increased heart, LAD, ipsilateral lung and esophagus dose. RBH is a robust technique in pWB + RNI. (Clinicaltrials.gov: NCT05179161, registered 05/01/2022).

Establishment of reference values for plasma neurofilament light based on healthy individuals aged 5-90 years.

The recent development of assays that accurately quantify neurofilament light, a neuronal cytoskeleton protein, in plasma has generated a vast literature supporting that it is a sensitive, dynamic, and robust biomarker of neuroaxonal damage. As a result, efforts are now made to introduce plasma neurofilament light into clinical routine practice, making it an easily accessible complement to its cerebrospinal fluid counterpart. An increasing literature supports the use of plasma neurofilament light in differentiating neurodegenerative diseases from their non-neurodegenerative mimics and suggests it is a valuable biomarker for the evaluation of the effect of putative disease-modifying treatments (e.g. in multiple sclerosis). More contexts of use will likely emerge over the coming years. However, to assist clinical interpretation of laboratory test values, it is crucial to establish normal reference intervals. In this study, we sought to derive reliable cut-offs by pooling quantified plasma neurofilament light in neurologically healthy participants (5-90 years) from eight cohorts. A strong relationship between age and plasma neurofilament light prompted us to define the following age-partitioned reference limits (upper 95th percentile in each age category): 5-17 years = 7 pg/mL; 18-50 years = 10 pg/mL; 51-60 years = 15 pg/mL; 61-70 years = 20 pg/mL; 70 + years = 35 pg/mL. The established reference limits across the lifespan will aid the introduction of plasma neurofilament light into clinical routine, and thereby contribute to diagnostics and disease-monitoring in neurological practice.

Safety of pre- or postoperative accelerated radiotherapy in 5 fractions: A randomized pilot trial.

OBJECTIVE: Neo-adjuvant radiotherapy (NART) for breast cancer has shown promising survival results in retrospective trials. However, there are some obstacles such as a chemotherapy delay, an increased overall treatment time (OTT) and the risk of increasing surgical morbidity. Accelerated radiotherapy (RT) in 5 fractions allows to deliver NART in a very short time span and minimizes the delay of surgery and chemotherapy. This trial investigates this NART schedule for safety, feasibility and OTT. MATERIAL AND METHODS: Twenty patients eligible for neo-adjuvant chemotherapy (NACT) and breast conserving surgery, were randomized between NART before NACT or NACT and postoperative RT. In both arms, RT treatment was given in 5 fractions to the whole breast with a simultaneously integrated boost (SIB) on the tumor(bed). Lymph node irradiation was given concomitantly in case of lymph node involvement. OTT was defined as the time from diagnosis to last surgery in the intervention group, while in the control group the time between diagnosis and last RT-fraction was used. In the intervention group NACT-delay was defined as time between diagnosis and start of chemotherapy. RESULTS: 20 patients were included, and 19 patients completed treatment. OTT was significantly shorter in the intervention group (mean 218 days, range 196-253) compared to the control group (mean 237, range 211-268, p = 0.001). The difference in mean duration from diagnosis to the first treatment was a non-significant 4 days longer (31 vs 27 days, p = 0.28), but the start of NACT after diagnosis was delayed by 21 days (48 vs 27 days, p < 0.001). NART did not result in additional surgery complications. CONCLUSION: This pilot trial is the first to report on accelerated NART in 5 fractions with SIB. NART before NACT resulted in a shorter OTT with good safety results.

Nasal resonance in middle-aged women: a multiparameter approach.

OBJECTIVES: Aging influences several speech characteristics in middle-aged women. However, the effect of aging on nasal resonance has not been widely investigated, and findings are contradictory. The purpose of this study was to investigate the effect of aging on nasal resonance by comparing young women (between 20 and 28 years of age) with middle-aged women (between 45 and 55 years of age). METHODS: Thirty-one middle-aged women with a mean age of 48 years participated in the subject group. The control group consisted of 22 young women with a mean age of 23 years. To investigate nasal resonance, we used a multiparameter approach by means of the Nasal Severity Index (NSI). Objective acoustic (nasal resonance scores of sounds and connected speech measured with the Nasometer) and aerodynamic measurements (maximum duration time of /s/, vital capacity, and mirror fogging test), as well as perceptual evaluations (Gutzmann /a/-i/test), were performed. RESULTS: The results of this study showed no differences in aerodynamic measurements and nasal resonance scores of connected speech and the sounds /i/, /u/, and /m/. Only the mean nasal resonance score of /a/ and the Gutzmann /a/ test were significantly different between the young and middle-aged women. The mean (+/- SD) NSI scores of the young women (12.93 +/- 17.9) and the middle-aged women (-1.49 +/- 14.4) both corresponded to normal nasal resonance. CONCLUSIONS: The results of this study indicate that both young and middle-aged women show a normal nasal resonance. Differences in objective and subjective measurements of nasal resonance were only found in isolated vowels, and not in connected speech.

Fezolinetant in the treatment of vasomotor symptoms associated with menopause.

Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS).Areas covered: This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS.Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.

Prolonged recombinant pregnancy hormone use in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: An early first full-time pregnancy substantially reduces the risk of developing breast cancer later in life. Extensive studies indicate that this protective effect is mediated by the pregnancy hormone human chorionic gonadotrophin (hCG). METHODS: In this proof-of-concept study 33 women with a BRCA mutation received recombinant-hCG (r-hCG). A 4-mm breast biopsy was obtained before (T1) and after 12 weeks of r-hCG injections (T2), as well as 6 months later (T3). The tissue was examined using RNA-sequencing methodology to determine if the 'high-risk' transcriptomic signature was converted to a 'low-risk' signature as in an early first full-time pregnancy. A stringent clinical safety monitoring was performed. RESULTS: The r-hCG administration was well tolerated in all participants. No clinically relevant changes were observed. In 25 women, the RNA quality was good for RNA sequencing in all three breast tissue biopsies. In response to the r-hCG, we observed 1907 differentially expressed genes (DEGs) (1032 up, 875 down) at T2 vs. T1 and 1065 DEGs (897 up, 168 down) at T3 vs. T1 in the group of women (n = 11) not using any hormonal contraceptives during the study. There was no response at T2 vs. T1 and a small number of DEGs, 260 (214 up, 46 down) at T3 vs. T1 in the group of 14 women using contraceptives. CONCLUSIONS: In summary, r-hCG has a remarkable effect on the gene expression profile of breast tissues from BRCA1/2 carriers who did not use any contraception. This opens an opportunity for a novel preventive strategy to reduce the incidence of breast cancer.