Exploring the knowledge, attitudes, and perceptions of women of reproductive age towards fertility and elective oocyte cryopreservation for age-related fertility decline in the UK: a cross-sectional survey.

STUDY QUESTION: What are the knowledge, perceptions and attitudes towards fertility and elective oocyte cryopreservation (OC) for age-related fertility decline (ARFD) in women in the UK? SUMMARY ANSWER: Awareness of OC for ARFD has reportedly improved compared to studies carried out almost a decade ago, but inconsistencies in knowledge remain regarding the rate of miscarriage amongst specific age groups, the financial costs and optimal age to undergo OC for ARFD. WHAT IS KNOWN ALREADY: The age of first-time motherhood has increased amongst western societies, with many women of reproductive age underestimating the impact of age on fertility. Further understanding of women's awareness of their fertility, the options available to preserve it and the barriers for seeking treatment earlier are required in order to prevent the risk of involuntary childlessness. STUDY DESIGN, SIZE, DURATION: A hyperlink to a cross-sectional survey was posted on social media (Instagram) between 25 February 2021 and 11 March 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women from the general population aged 18-50 years were invited to complete the survey. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 5482 women fulfilled the inclusion criteria and completed the survey. The mean age of participants was 35.0 years (SD 10.25; range 16-52). Three quarters (74.1%; n = 4055) disagreed or strongly disagreed they felt well informed regarding the options available to preserve their fertility, in case of a health-related problem or ARFD. The majority overestimated the risk of miscarriage in women aged ≥30 years old, with 14.5% correctly answering 20%, but underestimated the risks in women ≥40, as 20.1% correctly answered 40-50%. Three quarters (73.2%; n = 4007) reported an awareness of OC for ARFD and 65.8% (n = 3605) reported that they would consider undergoing the procedure. The number of women who considered OC for ARFD across age groups were as follows: 18-25 (8.3%; n = 300), 26-30 (35.8%; n = 1289), 31-35 (45.9%; n = 1654), 36-40 (9.6%; n = 347), 41-45 (0.3%; n = 13), and 46-50 (0.1%; n = 2). The majority of women (81.3%; n = 4443) underestimated the cost of a single cycle of OC for ARFD (<£5000). Furthermore, 10.4% (n = 566) believed a single cycle would be adequate enough to retrieve sufficient oocytes for cryopreservation. Approximately 11.0% (n = 599) believed OC for ARFD may pose significant health risks and affect future fertility. Less than half agreed or strongly agreed that the lack of awareness regarding OC for ARFD has impacted the likelihood of pursuing this method of fertility preservation further (41.4%; n = 2259). LIMITATIONS, REASONS FOR CAUTION: Results from cross-sectional studies are limited as interpretations made are merely associations and not of causal relationships. The online nature of participant recruitment is subject to selection bias, considering women with access to social media are often from higher socioeconomic and education backgrounds, thus limiting generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: Further education regarding the financial costs and optimal age to undergo elective OC to increase the chances of successful livebirth are required. Clinicians should encourage earlier fertility counselling to ensure that OC is deemed a preventative measure of ARFD, rather than an ultimate recourse to saving declining fertility. STUDY FUNDING/COMPETING INTEREST(S): No funding was required for this article. There are no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Intraprostatic Cancer Recurrence following Radical Radiotherapy on Transperineal Template Mapping Biopsy: Implications for Focal Ablative Salvage Therapy.

PURPOSE: Men in whom external beam radiotherapy fails are usually placed on delayed hormone therapy. Some of these men have localized recurrence that might be suitable for further local therapy. We describe patterns of recurrence and suitability for focal ablative therapy in those undergoing transperineal template prostate mapping biopsies. MATERIALS AND METHODS: The study included 145 consecutive patients (December 2007 to May 2014) referred with suspicion of recurrence due to rising prostate specific antigen after external beam radiotherapy or brachytherapy who underwent transperineal template prostate mapping biopsies. Suitability for focal ablative therapy required the cancer to be unifocal or unilateral, or bilateral/multifocal with 1 dominant index lesion and secondary lesions with Gleason score 3+3=6 with no more than 3 mm cancer core involvement. RESULTS: Mean patient age was 70.7 (SD 5.8) years. Median prostate specific antigen at time of transperineal template prostate mapping biopsy was 4.5 ng/ml (IQR 2.5-7.7). Overall 75.9% (110) were suitable for a form of focal salvage treatment, 40.7% (59) were suitable for quadrant ablation, 14.5% (21) hemiablation, 14.5% (21) bilateral focal ablation and 6.2% (9) for index lesion ablation. CONCLUSIONS: Three-quarters of patients who have localized radiorecurrent prostate cancer may be suitable for focal ablative therapy to the prostate based on transperineal template prostate mapping biopsies.

Target highlights in CASP13: Experimental target structures through the eyes of their authors.

The functional and biological significance of selected CASP13 targets are described by the authors of the structures. The structural biologists discuss the most interesting structural features of the target proteins and assess whether these features were correctly reproduced in the predictions submitted to the CASP13 experiment.

Ultrafast Self-Induced X-Ray Transparency and Loss of Magnetic Diffraction.

Using ultrafast ≃2.5 fs and ≃25 fs self-amplified spontaneous emission pulses of increasing intensity and a novel experimental scheme, we report the concurrent increase of stimulated emission in the forward direction and loss of out-of-beam diffraction contrast for a Co/Pd multilayer sample. The experimental results are quantitatively accounted for by a statistical description of the pulses in conjunction with the optical Bloch equations. The dependence of the stimulated sample response on the incident intensity, coherence time, and energy jitter of the employed pulses reveals the importance of increased control of x-ray free electron laser radiation.

Color Vision Impairment Differentiates Alzheimer Dementia From Dementia With Lewy Bodies.

OBJECTIVE: Dementia with Lewy bodies (DLB) is frequently misdiagnosed for Alzheimer dementia (AD), especially in its earlier stages. We characterized color vision impairment (CVI) in patients with DLB versus patients with AD to determine its usefulness in improving accuracy of early diagnosis. METHODS: We retrospectively reviewed charts of patients with AD, DLB, and patients with mild cognitive impairment suspected to be in the prodromal phase of DLB (pro-DLB) or prodromal phase of AD (pro-AD). All patients underwent an online 15-hue color vision arrangement test. RESULTS: Fifty-two patients were included in this study with a median age of 77 years, of which 44% were female. No significant differences in gender, age, or Montreal Cognitive Assessment existed among patients with AD (n = 15), pro-AD (n = 5), pro-DLB (n = 8), and DLB (n = 24). Of the 52 patients, 4 (2 AD, 1 DLB, and 1 pro-AD) had CVI history from a young age and were excluded from final analyses. New-onset CVI prevalence differed significantly based on diagnosis: patients with pro-AD (20%), patients with AD (15%), patients with pro-DLB (38%), and patients with DLB (78%, P < .001). In a stepwise multivariate logistic regression analysis to determine factors associated with CVI, "diagnosis type" as a binary variable (DLB or pro-DLB vs AD or pro-AD) was the only variable retained in the model (odds ratio = 9.8 [95% CI: 2.3-42.1], P < .001). CONCLUSIONS: Color vision impairment in patients with DLB showed a prevalence similar to the core features of DLB (∼80%) and can be supportive to a diagnosis of DLB versus AD. Pending prospective confirmation of our findings, simple online color vision testing could be incorporated into multivariate diagnostic tools to possibly improve accuracy of early diagnosis of DLB.

Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA for precision medicine.

Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study.

Oceanic protists with different forms of acquired phototrophy display contrasting biogeographies and abundance.

This first comprehensive analysis of the global biogeography of marine protistan plankton with acquired phototrophy shows these mixotrophic organisms to be ubiquitous and abundant; however, their biogeography differs markedly between different functional groups. These mixotrophs, lacking a constitutive capacity for photosynthesis (i.e. non-constitutive mixotrophs, NCMs), acquire their phototrophic potential through either integration of prey-plastids or through endosymbiotic associations with photosynthetic microbes. Analysis of field data reveals that 40-60% of plankton traditionally labelled as (non-phototrophic) microzooplankton are actually NCMs, employing acquired phototrophy in addition to phagotrophy. Specialist NCMs acquire chloroplasts or endosymbionts from specific prey, while generalist NCMs obtain chloroplasts from a variety of prey. These contrasting functional types of NCMs exhibit distinct seasonal and spatial global distribution patterns. Mixotrophs reliant on 'stolen' chloroplasts, controlled by prey diversity and abundance, dominate in high-biomass areas. Mixotrophs harbouring intact symbionts are present in all waters and dominate particularly in oligotrophic open ocean systems. The contrasting temporal and spatial patterns of distribution of different mixotroph functional types across the oceanic provinces, as revealed in this study, challenges traditional interpretations of marine food web structures. Mixotrophs with acquired phototrophy (NCMs) warrant greater recognition in marine research.

In-vivo quantitative assessment of the therapeutic response in a mouse model of collagen-induced arthritis using 18 F-fluorodeoxyglucose positron emission tomography.

Mouse collagen-induced arthritis (CIA) is the most commonly used animal model to investigate underlying pathogenesis of autoimmune arthritis and to demonstrate the therapeutic efficacy of novel drugs in autoimmune arthritis. The conventional read-outs of CIA are clinical score and histopathology, which have several limitations, including (i) subjected to observer bias; and (ii) longitudinal therapeutic efficacy of a new drug cannot be determined. Thus, a robust, non-invasive, in-vivo drug screening tool is currently an unmet need. Here we have assessed the utility of 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG) as an in-vivo screening tool for anti-inflammatory drugs using the mouse CIA model. The radiotracer 18 F-FDG and a PET scanner were employed to monitor CIA disease activity before and after murine anti-tumour necrosis factor (TNF)-α antibody (CNTO5048) therapy in the mouse CIA model. Radiotracer concentration was derived from PET images for individual limb joints and on a per-limb basis, and Spearman's correlation coefficient (ρ) was determined with clinical score and histology of the affected limbs. CNTO5048 improved arthritis efficiently, as evidenced by clinical score and histopathology. PET showed an increased uptake of 18 F-FDG with the progression of the disease and a significant decrease in the post-treatment group. 18 F-FDG uptake patterns showed a strong correlation with clinical score (ρ = 0·71, P < 0·05) and histopathology (ρ = 0·76, P < 0·05). This study demonstrates the potential of 18 F-FDG PET as a tool for in-vivo drug screening for inflammatory arthritis and to monitor the therapeutic effects in a longitudinal setting.

RNA interference in mosquito: understanding immune responses, double-stranded RNA delivery systems and potential applications in vector control.

RNA interference (RNAi) refers to the process of post-transcriptional silencing of cellular mRNA by the application of double-stranded RNA (dsRNA). RNAi strategies have been widely employed to regulate gene expression in plants and animals including insects. With the availability of the full genome sequences of major vector mosquitoes, RNAi has been increasingly used to conduct genetic studies of human pathogens in mosquito vectors and to study the evolution of insecticide resistance in mosquitoes. This review summarizes the recent progress in our understanding of mosquito-pathogen interactions using RNAi and various methods of dsRNA delivery in mosquitoes at different stages. We also discuss potential applications of this technology to develop novel tools for vector control.

Ambiguity in a masculine world: Being a BRCA1/2 mutation carrier and a man with prostate cancer.

OBJECTIVE: Increased risk of prostate cancer (PCa) is observed in men with BRCA1/BRCA2 mutations. Sex and gender are key determinants of health and disease although unequal care exists between the sexes. Stereotypical male attitudes are shown to lead to poor health outcomes. METHODS: Men with BRCA1/2 mutations and diagnosed with PCa were identified and invited to participate in a qualitative interview study. Data were analysed using a framework approach. "Masculinity theory" was used to report the impact of having both a BRCA1/2 mutation and PCa. RESULTS: Eleven of 15 eligible men were interviewed. The umbrella concept of "Ambiguity in a Masculine World" was evident. Men's responses often matched those of women in a genetic context. Men's BRCA experience was described, as "on the back burner" but "a bonus" enabling familial detection and early diagnosis of PCa. Embodiment of PCa took precedence as men revealed stereotypical "ideal" masculine responses such as stoicism and control while creating new "masculinities" when faced with the vicissitudes of having 2 gendered conditions. CONCLUSION: Health workers are urged to take a reflexive approach, void of masculine ideals, a belief in which obfuscates men's experience. Research is required regarding men's support needs in the name of equality of care.

Lag structure in resting-state fMRI.

The discovery that spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals contain information about the functional organization of the brain has caused a paradigm shift in neuroimaging. It is now well established that intrinsic brain activity is organized into spatially segregated resting-state networks (RSNs). Less is known regarding how spatially segregated networks are integrated by the propagation of intrinsic activity over time. To explore this question, we examined the latency structure of spontaneous fluctuations in the fMRI BOLD signal. Our data reveal that intrinsic activity propagates through and across networks on a timescale of ∼1 s. Variations in the latency structure of this activity resulting from sensory state manipulation (eyes open vs. closed), antecedent motor task (button press) performance, and time of day (morning vs. evening) suggest that BOLD signal lags reflect neuronal processes rather than hemodynamic delay. Our results emphasize the importance of the temporal structure of the brain's spontaneous activity.

Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum.

The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUC∞) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation.

The Dufour's gland and the cuticle in the social wasp Ropalidia marginata contain the same hydrocarbons in similar proportions.

Queens in many social insects are known to maintain their status through chemicals (pheromones) and cuticular hydrocarbons and have been the focus of many investigations that have looked at the chemicals involved in queen signaling. In the primitively eusocial wasp Ropalidia marginata Lepeletier (Hymenoptera: Vespidae), the Dufour's gland has been shown to be involved in queen signaling, and Dufour's gland hydrocarbons have been found to be correlated with fertility. Hence, this study analyzed the cuticle of R. marginata along with the Dufour's gland in order to compare their hydrocarbon profiles. The results show that the Dufour's gland and cuticle contained the same set of hydrocarbons in similar proportions (for the majority of compounds). Patterns pertaining to fertility signaling present in cuticular hydrocarbons were also similar to those present in the Dufour's gland hydrocarbons. Furthermore, the haemolymph contained the same hydrocarbons as found in the Dufour's gland and cuticle in similar proportions, thereby providing an explanation as to why the hydrocarbon profiles of the Dufour's gland and cuticle are correlated.

Characterization of comorbid factors in hip fracture related in-hospital mortality.

It is important to delineate factors which influence in-hospital mortality rates following a hip fracture. The current study aimed to identify the nature and frequency of comorbidities prevalent in this patient cohort. A retrospective chart review of cases of in-patient mortality following admission for a hip fracture was performed. These cases (n=127) were characterized for comorbidities, complications, medical status indicators, and other contributory factors. Cardiovascular 104 (81.9%), respiratory 66 (52.0%), genitourinary 41 (32.3%), psychiatric 41 (32.3%), vascular 40 (31.5%), and gastrointestinal 40 (31.5%), are the physiological systems, most commonly associated with comorbidity amongst hip fracture patients who succumb to in-hospital mortality. Renal failure, pneumonia, sepsis, myocardial infarction, congestive cardiac failure (CCF), respiratory failure, and Clostridium difficile infection are conditions which are associated with postoperative complications leading to in-patient mortality. Analysis of medical status indicators illustrated an inverse correlation between ASA scores and postoperative survival time, in this cohort-of hip fracture patients (R2 = 0.9485).

IL-17 and IL-17R: an auspicious therapeutic target for psoriatic disease.

The continuous discovery of new T cell subpopulations in human autoimmune diseases is making the immunopathological network more complex. Th17 cells are one such newly identified subset of T cells, characterized by the production of signature cytokine IL-17. In last few years, several studies have strongly established the regulatory role of Th17 cells and its signature cytokine IL-17 in autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. Psoriasis and PsA are immune mediated hyperproliferative diseases, affecting skin and joint respectively. Before the discovery of Th17 cells, psoriasis and psoriatic diseases were thought to be chiefly Th1 mediated diseases; later on IL-17 knockout animal studies as well as human experimental data indicate the crucial role of Th17 cells and its signature cytokine IL-17 in the pathogenesis of these diseases. In vitro human studies have shown the abundance of Th17 cells in the psoriatic plaques. Subsequently our research group has extended this observation in psoriatic arthritis and found the abundance of CD4+IL-17+ T cells in the synovial fluid and majority of these T cells are of memory phenotype (CD4RO+CD45RA-CD11a+). In addition, we showed the significant presence of functional IL-17 receptor in synovial fibroblast of psoriatic arthritis patients. Considering the strong association of IL-17 and psoriatic disease, IL-17 targeted therapy have shown promises in preclinical and clinical trials. In this review article, we have discussed the pathogenic role of IL-17 in psoriatic disease and summarized the therapeutic efficacy and safety profile of different anti IL-17 therapy as an anti-psoriatic agent.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Measurement of the damping of the nuclear shell effect in the doubly magic 208Pb region.

The damping of the nuclear shell effect with excitation energy has been measured through an analysis of the neutron spectra following the triton transfer in the (7)Li induced reaction on (205)Tl. The measured neutron spectra demonstrate the expected large shell correction energy for the nuclei in the vicinity of doubly magic (208)Pb and a small value around (184)W. A quantitative extraction of the allowed values of the damping parameter γ, along with those for the asymptotic nuclear level density parameter ã, has been made for the first time.

Electromagnetic transition from the 4+ to 2+ resonance in 8Be measured via the radiative capture in 4He + 4He.

An earlier measurement on the 4+ to 2+ radiative transition in 8Be provided the first electromagnetic signature of its dumbbell-like shape. However, the large uncertainty in the measured cross section does not allow a stringent test of nuclear structure models. This Letter reports a more elaborate and precise measurement for this transition, via the radiative capture in the 4He + 4He reaction, improving the accuracy by about a factor of 3. Ab initio calculations of the radiative transition strength with improved three-nucleon forces are also presented. The experimental results are compared with the predictions of the alpha cluster model and ab initio calculations.