Variation in antral follicle counts at different times in the menstrual cycle: does it matter?

Antral follicle count (AFC) variation was examined across the menstural cycle and its effect on clinical management assessed. In 79 women, AFC was documented in early (iAFC) and late follicular phase (sAFC). Absolute agreement between iAFC and sAFC and agreement for classification into categories of risk of extremes of ovarian response were examined. Ovarian stimulation protocols designed with iAFC and sAFC, and the predictive value of iAFC and sAFC for extremes of ovarian response, were compared in women undergoing ovarian stimulation. Significant differences were found between iAFC and sAFC (16 [IQR 9-24] versus 13 [IQR 7- 21]; P = 0.001), with moderate agreement for the classification into at risk of extremes of response (k = 0.525). Agreement for protocol selection based on either AFC (k = 0.750) and starting gonadotrophin dose was good (concordance correlation coefficient 0.970 [95% CI 0.951 to 0.982]). Predictive value for iAFC and sAFC was maintained for poor ovarian response and risk of ovarian hyperstimulation syndrome (OR 0.634 [0.427 to 0.920], 0.467 [0.233 to 0.935]) and (OR 1.049 [0.974 to 1.131], 1.140 [1.011 to 1.285]). Across the cycle, AFC varies but does not significantly affect ovarian stimulation protocol design and prediction of extreme ovarian response

Improving conventional prognosticators in diffuse large B cell lymphoma using marker ratios

Risk stratification for diffuse large B-cell lymphoma (DLBCL) is required as patients with disease may not be cured despite initial R-CHOP treatment. We investigated gene ratio tests to predict survival outcome of DLBCL patients based on the relationship between immune-effector and inhibitory (checkpoint) genes from nanoString™ nCounter in 158 paraffin-embedded DLBCL tissues. We assessed the predictive value of several possible gene ratios using a tree-based survival statistical model, and investigated the predictive value of those gene ratios in an independent R-CHOP treated cohorts of 233 patients. We showed that an immune ratio composed of CD4∗CD8∗:(CD163/CD68)∗PD-L1 was able to stratify overall survival better than single or combination of immune markers, distinguishing groups with disparate 4-year survivals (92% versus 47%). The immune ratio was independent of and added to the revised international prognostic index (R-IPI) and cell-of-origin (COO) and has potential implications for selection of patients for checkpoint-blockade within clinical trials

Treating symptomatic uterine fibroids with myomectomy: current practice and views of UK consultants

Background: The demand for uterus-sparing treatments is increasing as more women postpone childbirth to their 30–40s, when fibroids are more symptomatic. With an increasing choice of treatment options and changing care-provider profiles, now is an opportune time to survey current practices and opinions. Using a 25-stem questionnaire, a web-based survey was used to capture the practices and opinions of UK consultant gynecologists on the treatment of symptomatic fibroids, including the types of procedure most frequently used, methods used to reduce blood loss, and awareness and acceptability of treatment options, and to assess the impact of gender and experience of the treating gynecologist. Results: The response rate was 22%. Laparascopic myomectomy is used least frequently, with 80% of the respondents using GnRHa preoperatively to minimize blood loss and correct anemia, while vasopressin is most frequently used to reduce intraoperative blood loss. Female consultants operate significantly less frequently than males. Those with more than 10 years consultant experience are more likely to perform an open myomectomy compared to those with less than 10 years experience. Conclusions: Compared to a similar survey performed 10 years ago, surgical methods remain to be the most common treatments, but use of less invasive treatments such as UAE has increased. Consultants’ attitudes appear to be responding to the patient demand for less radical treatments. However, it is yet to be seen if the changing consultant demographics will keep up with this demand. The low response rate warrants cautious interpretation of the results, but they provide an interesting snapshot of current views and practices

Risk of osteoporotic fractures in menopausal women with common mental health diagnoses prescribed SSRIs/SNRIs: cohort and self-controlled case series analyses

Summary : In a population-based cohort study of menopausal women with common mental health diagnoses, SSRIs/SNRIs were associated with a 32% increased risk of osteoporotic fractures. The risk of osteoporotic fractures was particularly increased for longer periods of treatment with SSRIs/SNRIs (> 5 years) and in younger menopausal women (< 50 years old). Purpose: To investigate the association between selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and the risk of osteoporotic fractures (OF) in menopausal women with common mental health diagnoses (CMHD). Methods: We conducted the study with two designs (cohort and self-controlled case series [SCCS]), using the IQVIA Medical Research Database (IMRD) UK. The source population comprised women aged ≥ 50 years and women with a record indicating menopause (< 50 years). All women had a recorded CMHD. For the cohort analysis, the risk of OFs was estimated by comparing women prescribed SSRIs/SNRIs (exposed) to those not exposed. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CIs). For the SCCS, women acted as their own controls; periods of exposure to SSRIs/SNRIs were compared to periods of non-exposure using conditional Poisson regression to estimate incidence rate ratios (IRR) with 95% CIs. Results: We identified 292,848 women, of whom 35,222 experienced OFs within a median follow-up of 6.01 years. We found strong evidence of an association between SSRIs/SNRIs and the risk of OFs (adjusted HR = 1.32, 95% CI:1.29–1.35). Compared to periods of no exposure, SSRIs/SNRIs increased the risk of OFs during the first 30 days (IRR = 1.38, 95% CI:1.26–1.51), during the first 90 days (IRR = 1.58, 95% CI: 1.48–1.69), and the remaining exposure (IRR = 1.42, 95% CI:1.37–1.48). Conclusions: In a population of menopausal women with CMHDs, the prescribing of SSRIs/SNRIs antidepressants was associated with a higher risk of OFs. Careful assessment of osteoporosis risk needs to be considered when treating menopausal women with SSRIs/SNRIs antidepressants

Plasma cells arise from differentiation of clonal lymphocytes and secrete IgM in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is characterized by bone marrow infiltration with malignant lymphoplasmacytic cells (LPCs), a smaller population of plasma cells (PCs), and hypersecretion of IgM monoclonal protein. Here, we show that CD45low, CD38+, and CD138+ PCs and CD45high, CD38-, CD138-, CD19+, and CD20+ LPCs carry a heterozygous L265P mutation in the Toll-like receptor signaling adaptor MYD88. Both PCs and LPCs express the same auto-reactive IgHV sequences, suggesting a similar clonal origin and role for auto-antigens in WM cell survival. PCs are primarily responsible for IgM production even without substantial cell proliferation. When cultured in isolation, LPCs give rise to more differentiated PCs and secrete less IgM. Our analyses suggest that malignant PCs arise from the clonal LPC population, and are primarily responsible for IgM secretion in WM. Targeting malignant PCs may have therapeutic benefits in the treatment of WM and improve the duration of response and potentially, survival

The evolving perspective of menopause management in the United Kingdom

BACKGROUND: The use of menopausal hormone therapy (MHT) was significantly reduced following the publication of the Women\u27s Health Initiative study results and has remained low ever since. However, from 2015 onwards, the UK has seen a substantial increase in MHT prescribing compared to other European countries. OBJECTIVES: To evaluate the factors contributing to the shift in women\u27s and healthcare professionals\u27 (HCPs) perception of MHT in the United Kingdom and to provide learning points for other European countries. DESIGN: An exploratory, descriptive and qualitative study. METHODS: An interactive virtual panel discussion in which seven UK-based HCPs with a special interest in the menopause discussed the evolution of its management in the United Kingdom. RESULTS: In the last 8 years, there has been a substantial increase in MHT prescriptions in the United Kingdom due to improved menopause awareness and acceptance of MHT. Accessibility to accurate, scientific, information and guidance from respected institutions is one of the main drivers of this change. Social media has increased that reach with \u27influencers\u27 empowering women to seek help. Women are demanding access to menopause health care so that they can receive holistic and individualized treatment based on their clinical conditions and needs. Standardized education of HCPs is an essential pillar to provide appropriate and equitable care to menopausal women and to guarantee safe prescribing of MHT. Furthermore, up to date and factually correct menopausal education would benefit all the population. CONCLUSIONS: Publication of new scientific data reporting a more favourable benefit/risk ratio with MHT, production of national guidance and an increased awareness via social media have led to the significant rise in MHT prescribing and improvement of menopause care in the United Kingdom. The lessons learned may benefit other European countries

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

Could Perimenopausal Estrogen Prevent Breast Cancer? Exploring the Differential Effects of Estrogen-Only Versus Combined Hormone Replacement Therapy.

Breast cancer is the commonest cancer among women in the western world, accounting for up to 30% of all cancers in women. There is a long-standing controversy about the potential link to hormone replacement therapy (HRT), with large observational studies suggesting that HRT increases the risk, while the Women's Health Initiative (WHI), a prospective, randomized placebo-controlled trial, has reported several times over a period of 20 years that combined (estrogen and progestogen) HRT increases the risk, while estrogen-only HRT given to women who have had a prior hysterectomy, is associated with a significantly reduced risk of developing breast cancer. Evidence from the randomized trial shows a significant reduction in both incidence of and mortality from breast cancer in women who took estrogen replacement therapy; this message needs to be presented clearly and robustly so that it can help women with decision making when considering HRT for menopause

Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome.

The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. Mechanistically, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex and docking at Rab5+Rab7+ early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer

A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37–80), with a median of four (1–8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5–6.7) and 7.4 months (95% CI 6.4–10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6–13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4–39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics