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Abstract Krill are vital as food for many marine animals but also impacted by global warming. To learn how they and other zooplankton may adapt to a warmer world we studied local adaptation in the widespread Northern krill (Meganyctiphanes norvegica). We assemble and characterize its large genome and compare genome-scale variation among 74 specimens from the colder Atlantic Ocean and warmer Mediterranean Sea. The 19 Gb genome likely evolved through proliferation of retrotransposons, now targeted for inactivation by extensive DNA methylation, and contains many duplicated genes associated with molting and vision. Analysis of 760 million SNPs indicates extensive homogenizing gene-flow among populations. Nevertheless, we detect signatures of adaptive divergence across hundreds of genes, implicated in photoreception, circadian regulation, reproduction and thermal tolerance, indicating polygenic adaptation to light and temperature. The top gene candidate for ecological adaptation was nrf-6, a lipid transporter with a Mediterranean variant that may contribute to early spring reproduction. Such variation could become increasingly important for fitness in Atlantic stocks. Our study underscores the widespread but uneven distribution of adaptive variation, necessitating characterization of genetic variation among natural zooplankton populations to understand their adaptive potential, predict risks and support ocean conservation in the face of climate change.

Introduction: The aim of this study was to assess whether the choice between double embryo transfer (DET) and single embryo transfer (SET) in healthy women of advanced maternal age (AMA) was associated with an increased risk of adverse outcomes. Materials and Methods: Healthy women aged 39?40 years who achieved live birth after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment between 2009 and 2020 at Karolinska University Hospital, Stockholm in Sweden, were included in this prospective, single-center cohort study. Results: A total of 310 women, who underwent IVF/ICSI treatments and achieved live births, were included in our analysis. Within this cohort, 78% of the women received SET, while 22% received DET. Nulliparity was common in both the SET (62.7%) and DET (85.3%) groups. Fresh embryo transfers were more prevalent in the DET group (91.2%) than in the SET group (31.1%). The rate of pregnancy-induced hypertension was higher in the SET group (8.3%) compared to the DET group (1.5%, p?=?0.048). Furthermore, the DET group had a significantly higher rate of twin pregnancies (13.2%) compared to the SET group (0.4%). No statistically significant differences were observed in composite obstetric and perinatal complications between the SET and DET groups across all model estimates following different adjustments. Clinical Trial Registration number: ClinicalTrials.gov NTC04602962. Conclusions: While DET was more common in nulliparous women and associated with a higher rate of twin pregnancies, our analysis did not reveal significant differences in adverse outcomes between the SET and DET groups after comprehensive adjustments. Our study suggests that in the absence of co-morbidities, meticulous patient selection coupled with comprehensive maternal care can potentially mitigate potential DET-associated risks in women of AMA.

Abstract In the past few years, the unifying frameworks of 4-dimensional Chern-Simons theory and affine Gaudin models have allowed for the systematic construction of a large family of integrable σ-models. These models depend on the data of a Riemann surface C (here of genus 0 or 1) and of a meromorphic 1-form ω on C, which encodes the geometry of their spectral parameter and the analytic structure of their Lax connection. The main subject of this paper is the renormalisation of these theories and in particular two conjectures describing their 1-loop RG-flow in terms of the 1-form ω. These conjectures were put forward in [1] and [2] and were proven in a variety of cases. After extending the proposal of [1] to the elliptic setup (with C of genus 1), we establish the equivalence of these two conjectures and discuss some of their applications. Moreover, we check their veracity on an explicit example, namely an integrable elliptic deformation of the Principal Chiral Model on $${{\text{SL}}}_{\mathbb{R}}\left(N\right)$$ .

Abstract We introduce a new elliptic integrable σ-model in the form of a two-parameter deformation of the Principal Chiral Model on the group SLℝ(N), generalising a construction of Cherednik for N = 2 (up to reality conditions). We exhibit the Lax connection and R $$ \mathcal{R} $$ -matrix of this theory, which depend meromorphically on a spectral parameter valued in the torus. Furthermore, we explain the origin of this model from an equivariant semi-holomorphic 4-dimensional Chern-Simons theory on the torus. This approach opens the way for the construction of a large class of elliptic integrable σ-models, with the deformed Principal Chiral Model as the simplest example.

IntroductionThe mechanisms leading to ovarian primordial follicle depletion following gonadotoxic chemotherapy with cyclophosphamide and other cytotoxic drugs are currently understood through two main explanatory theories: apoptosis and over-activation. Discrepancies between the findings of different studies investigating these mechanisms do not allow to reach a firm conclusion. The heterogeneity of cell types in ovaries and their different degrees of sensitivity to damage, cell-cell interactions, periodical follicle profile differences, model age-dependent differences, and differences of exposure durations of tested drugs may partially explain the discrepancies among studies.MethodsThis study used intact prepubertal mice ovaries in culture as study model, in which most follicles are primordial follicles. Histological and transcriptional analyses of ovaries exposed to the active metabolite of cyclophosphamide 4-hydroperoxycyclophosphamide (4-HC) were carried out via a time-course experiment at 8, 24, 48, and 72 h.Results4-HC treated ovaries showed a significant decrease in primordial follicle density at 24 h, along with active DNA damage (TUNEL) and overexpressed apoptosis signals (cleaved-poly ADP ribose polymerase in immunohistochemistry and western blotting). Meanwhile 4-HC treatment significantly up-regulated H2ax, Casp 6, Casp 8, Noxa, and Bax in ovaries, and up-regulated Puma in primordial follicles (FISH).DiscussionOur results indicated that cyclophosphamide-induced acute ovarian primordial follicle depletion was mainly related to apoptotic pathways. No evidence of follicle activation was found, neither through changes in the expression of related genes to follicle activation nor in the density of growing follicles. Further validation at protein level in 4-HC-treated prepubertal mice ovaries at 24 h confirmed these observations.

Abstract The decarbonization of the power generation and transport sector encourage the analysis of connection of distributed energy resources (DER), such as electric vehicles (EVs), to the electrical system, as well as the evaluation of their impact on smart cities. A better understanding of the negative impacts on the power systems will lead to propose mitigation measures and eventually revolutionize the way distributed generation works. This paper aims at modelling and evaluating the impact of EVs on a real distribution network. The energy system chosen operates at 60 Hz, 34.5 kV (medium voltage) and 0.208 kV (low voltage) and it is simulated using PSCAD/EMTDC. To reproduce realistic user consumption profiles, dynamic load profiles based on EV owners behaviour have been simulated. The vehicle‐to‐grid (V2G) technology is modelled to mitigate the impacts of high penetration of EVs by supporting the network from undervoltage. The results show the importance of active management in modern power systems, especially considering the increase in DER penetration expected for the coming years. This work shows the benefits of implementing V2G technology while highlighting the challenges involved in a real case.

Background Anaemia is commonly caused by iron deficiency and screened by haemoglobin (Hb) concentration in blood. There is a scarcity of longitudinal data on the relationship between maternal Hb levels during pregnancy and neurodevelopment in children. Objective To measure the relationship of maternal Hb concentrations during pregnancy on early child development. Methods This prospective cohort study included 1,720 mother-child dyads in rural Bangladesh. Maternal Hb concentrations were measured at 14 and 30 weeks of gestation. The child’s Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 18 months of age were measured using Bayley Scales of Infant and Toddler Development (BSID-II). Data on socio-demographic characteristics, anthropometrics, mothers’ IQ and children’s home stimulation were also collected. Bivariate and multivariable-adjusted linear regression analyses were used to explore associations of maternal Hb with child development. Results Mean Hb concentrations at 14 and 30 weeks of gestation were 116.6 g/L (±12.7) and 114.7 g/L (±12.7), respectively. Mean MDI and PDI scores among 18-month-old children were 78.9 (±12.4) and 93.8 (±13.7), respectively. Maternal 14-week Hb concentration was correlated with PDI (r = 0.06; p

Summary: Background: Despite progress in managing cancer in children, adolescents, and young adults (CAYAs), persistent complications may impact their quality of life. This study covers the morbidity and mortality, among CAYAs, with the aim to investigate the influence of socioeconomic factors on outcomes. Methods: This retrospective matched cohort study included the entire Swedish population of individuals under 25 with cancer 1958–2021. The population was identified from the Cancer Register, and controls were paired 1:5 based on age, sex, and residence. Multiple registers provided data on morbidity, mortality, and demographics. Findings: This survey covering 63 years, identified 65,173 CAYAs and matched controls, a total of 378,108 individuals (74% females). CAYAs exhibited a 3.04-times higher risk for subsequent cancer (Odds ratio (OR) 95% confidence interval (CI) 2.92–3.17, p

The internal variability of European summer temperatures has been linked to various mechanisms on seasonal to sub- and multi-decadal timescales. We find that sub-decadal timescales dominate summer temperature variability over large parts of the continent and determine mechanisms controlling extremely warm summers on sub-decadal timescales. We show that the sub-decadal warm phases of bandpass-filtered European summer temperatures, hereinafter referred to as extremely warm European summers, are related to a strengthening of the North Atlantic Ocean subtropical gyre, an increase in meridional heat transport, and an accumulation of ocean heat content in the North Atlantic several years prior to the extreme summer. This ocean warming affects the ocean–atmosphere heat fluxes, leading to a weakening and northward displacement of the jet stream and increased probability of occurrence of high-pressure systems over Scandinavia. Thus, our findings link the occurrence of extremely warm European summers to the accumulation of heat in the North Atlantic Ocean and provide the potential to improve the predictability of extremely warm summers several years ahead, which is of great societal interest.

Abstract Polar ecosystems are experiencing amongst the most rapid rates of regional warming on Earth. Here, we discuss ‘omics’ approaches to investigate polar biodiversity, including the current state of the art, future perspectives and recommendations. We propose a community road map to generate and more fully exploit multi-omics data from polar organisms. These data are needed for the comprehensive evaluation of polar biodiversity and to reveal how life evolved and adapted to permanently cold environments with extreme seasonality. We argue that concerted action is required to mitigate the impact of warming on polar ecosystems via conservation efforts, to sustainably manage these unique habitats and their ecosystem services, and for the sustainable bioprospecting of novel genes and compounds for societal gain.

Sugar beet molasses is a low-value byproduct from the sugar industry. It contains significant amounts of sucrose (approx. 50% (w/w)), which can be used for many different applications, for example, as feedstock for the production of fuel (as ethanol) and biobased chemicals such as 5-hydoxymethyl furfural (HMF). To produce platform chemicals, sucrose is hydrolyzed into its monomeric C6 sugars: glucose and fructose. When comparing the hydrolysis rates of molasses with a pure sucrose solution, the specific reaction rate is much slower (Qp/x,60min = 93 and 70 gprod L−1 h−1 gcell−1 for pure sucrose and crude molasses, respectively) at the same sucrose concentration (300 g/L) and process conditions. To clarify why molasses inhibits the enzymatic hydrolysis rate, the influence of its viscosity and inorganic and organic composition was investigated. Also, the effects of molasses and treated molasses on pure enzymes, invertase (from Saccharomyces cerevisiae, 0.05 mg/mL), compared with hydrolysis using whole cells of Baker’s yeast (3 mg/mL), were tested. The results indicate an inhibitory effect of potassium (Qp/x,60min = 76 gprod L−1 h−1 gcell−1), generally at high salt concentrations (Qp/x,60min = 67 gprod L−1 h−1 gcell−1), which could be correlated to the solution’s high salt concentrations and possibly the synergistic effects of different ions when applying concentrations that were four times that in the molasses. Also, the viscosity and sucrose purity seem to have an effect, where pure sucrose solutions and thick juice from the sugar mill yielded higher hydrolysis rates (Qp/x,60min = 97 gprod L−1 h−1 gcell−1) than molasses-type solutions with a higher viscosity (Qp/x,60min = 70–74 gprod L−1 h−1 gcell−1). Attempting to further understand the effects of different components on the invertase activity, an in silico investigation was performed, indicating that high salt concentrations affected the binding of sucrose to the active site of the enzyme, which can result in a lower reaction rate. This knowledge is important for future scale-up of the hydrolysis process, since reduced hydrolysis rates require larger volumes to provide a certain productivity, requiring larger process equipment and thereby higher investment costs.

Summary: Background: Worldwide, an increasing number of women with cancer are receiving Gonadotropin Releasing Hormone agonist (GnRHa) co-treatment during chemotherapy aiming at ovarian protection. There is divergence among guidelines, and some have recommended GnRHa co-treatment for women with breast cancer, however, the effect of GnRHa on future fertility is uncertain. Methods: In this population-based cohort study we included all women diagnosed with cancer at ages 15–45 between July 2005 and March 2017 in Sweden, identified in the Swedish Cancer Register. Exposure to GnRHa co-treatment was captured using the Prescribed Drug Register. Post-cancer childbirth, extracted from the Medical Birth Register, was the main outcome. Secondary outcomes included childbirths achieved through natural conception (NC), infertility diagnosis and cancer mortality. For each outcome, adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using delayed-entry Cox models, stratified by age and cancer site. Findings: Among 24,922 women diagnosed with cancer, 1.5% had GnRHa co-treatment. Breast cancer diagnoses were found in 80.2% of GnRHa exposed women and the GnRHa exposure was not associated with higher rates of childbirth (aHR 1.23, 95% CI 0.80–1.89), or NC childbirth (aHR 1.02, 95% CI 0.62–1.67), whereas the rate of infertility was significantly higher (aHR 2.42, 95% CI 1.44–4.08). In women with lymphoma and other cancers, GnRHa exposure was not associated with higher rates of childbirth, NC childbirth or infertility. GnRHa exposure was not associated with higher cancer mortality for any cancer type. Interpretation: We did not find evidence of improved or maintained fertility, estimated as childbirth rates post-cancer, in women who received GnRHa during cancer treatment. Funding: This study was financed by research grants from The Swedish Cancer Society (CAN 2017/704; 190249Pj, 200170F), The Swedish Research Council (Dnr 2019-00446), the Nordic Cancer Union NCU (Grant 2017), The Swedish Childhood Cancer Fund (KP2016-0031), Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963).

Summary: Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2−9 disrupt its secondary structure and charge properties, impeding phase separation. Maps−/− pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. MapsΔ2–9/Δ2–9 male mice expressing MAPS protein lacking aa 2–9 phenocopy Maps−/− mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.

Background Gonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical studies investigating a beneficial effect of GnRHa cotreatment on ovarian function have been small, retrospective and uncontrolled. Unblinded randomised studies on women with breast cancer have suggested a beneficial effect, but results are mixed with lack of evidence of improvement in markers of ovarian reserve. Unblinded randomised studies of women with lymphoma have not shown any benefit regarding fertility markers after long-term follow-up and no placebo-controlled study has been conducted so far. The aim of this study is to investigate if administration of GnRHa during cancer treatment can preserve fertility in young female cancer patients in a double-blind, placebo-controlled clinical trial.Methods and analysis A prospective, randomised, double-blinded, placebo-controlled, phase III study including 300 subjects with breast cancer. In addition, 200 subjects with lymphoma, acute leukemias and sarcomas will be recruited. Women aged 14–42 will be randomised 1:1 to treatment with GnRHa (triptorelin) or placebo for the duration of their gonadotoxic chemotherapy. Follow-up until 5 years from end of treatment (EoT). The primary endpoint will be change in anti-Müllerian hormone (AMH) recovery at follow-up 12 months after EoT, relative to AMH levels at EoT, comparing the GnRHa group and the placebo group in women with breast cancer.Ethics and dissemination This study is designed in accordance with the principles of Good Clinical Practice (ICH-GCP E6 (R2)), local regulations (ie, European Directive 2001/20/EC) and the ethical principles of the Declaration of Helsinki. Within 6 months of study completion, the results will be analysed and the study results shall be reported in the EudraCT database.Study registration The National Institutional review board in Sweden dnr:2021–03379, approval date 12 October 2021 (approved amendments 12 June 2022, dnr:2022-02924-02 and 13 December 2022, dnr:2022-05565-02). The Swedish Medical Product Agency 19 January 2022, Dnr:5.1-2021-98927 (approved amendment 4 February 2022). Manufacturing authorisation for authorised medicinal products approved 6 December 2021, Dnr:6.2.1-2020-079580. Stockholm Medical Biobank approved 22 June 2022, RBC dnr:202 253.Trial registration number NCT05328258; EudraCT number:2020-004780-71.

PurposeToday, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium.MethodsThe Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process.ResultsThis interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity.ConclusionThe goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Abstract Single‐model initial‐condition large ensembles are powerful tools to quantify the forced response, internal climate variability, and their evolution under global warming. Here, we present the CMIP6 version of the Max Planck Institute Grand Ensemble (MPI‐GE CMIP6) with currently 30 realizations for the historical period and five emission scenarios. The power of MPI‐GE CMIP6 goes beyond its predecessor ensemble MPI‐GE by providing high‐frequency output, the full range of emission scenarios including the highly policy‐relevant low emission scenarios SSP1‐1.9 and SSP1‐2.6, and the opportunity to compare the ensemble to complementary high‐resolution simulations. First, we describe MPI‐GE CMIP6, evaluate it with observations and reanalyzes and compare it to MPI‐GE. Then, we demonstrate with six application examples how to use the power of the ensemble to better quantify and understand present and future climate extremes, to inform about uncertainty in approaching Paris Agreement global warming limits, and to combine large ensembles and artificial intelligence. For instance, MPI‐GE CMIP6 allows us to show that the recently observed Siberian and Pacific North American heatwaves would only avoid reaching 1–2 years return periods in 2071–2100 with low emission scenarios, that recently observed European precipitation extremes are captured only by complementary high‐resolution simulations, and that 3‐hourly output projects a decreasing activity of storms in mid‐latitude oceans. Further, the ensemble is ideal for estimates of probabilities of crossing global warming limits and the irreducible uncertainty introduced by internal variability, and is sufficiently large to be used for infilling surface temperature observations with artificial intelligence.

Optically pure lactic acid (LA) is needed in PLA (poly-lactic acid) production to build a crystalline structure with a higher melting point of the biopolymer than that of the racemic mixture. Lignocellulosic biomass can be used as raw material for LA production, in a non-food biorefinery concept. In the present study, genetically engineered P. acidilactici ZP26 was cultivated in a simultaneous saccharification and fermentation (SSF) process using steam pretreated softwood solids as a carbon source to produce optically pure D-LA. Given the low concentrations of identifiable inhibitory compounds from sugar and lignin degradation, the fermentation rate was expected to follow the rate of enzymatic hydrolysis. However, added pretreated solids (7% on weight (w/w) of water-insoluble solids [WIS]) significantly and immediately affected the process performance, which resulted in a long lag phase (more than 40 h) before the onset of the exponential phase of the fermentation. This unexpected delay was also observed without the addition of enzymes in the SSF and in a model fermentation with glucose and pretreated solids without added enzymes. Experiments showed that it was possible to overcome the extended lag phase in the presence of pretreated softwood solids by allowing the microorganism to initiate its exponential phase in synthetic medium, and subsequently adding the softwood solids and enzymatic blend to proceed to an SSF with D-LA production.

Abstract Background With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. Methods The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. Results Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60–40.90) vs 83.5 (23.9) p

Lignocellulosic biomass represents the most abundant renewable carbon source on earth and is already used for energy and biofuel production. The pivotal step in the conversion process involving lignocellulosic biomass is pretreatment, which aims to disrupt the lignocellulose matrix. For effective pretreatment, a comprehensive understanding of the intricate structure of lignocellulose and its compositional properties during component disintegration and subsequent conversion is essential. The presence of lignin-carbohydrate complexes and covalent interactions between them within the lignocellulosic matrix confers a distinctively labile nature to hemicellulose. Meanwhile, the recalcitrant characteristics of lignin pose challenges in the fractionation process, particularly during delignification. Delignification is a critical step that directly impacts the purity of lignin and facilitates the breakdown of bonds involving lignin and lignin-carbohydrate complexes surrounding cellulose. This article discusses a two-step fractionation approach for efficient lignin extraction, providing viable paths for lignin-based valorization described in the literature. This approach allows for the creation of individual process streams for each component, tailored to extract their corresponding compounds.

High-intensity interval training (HIIT) and hyperbaric oxygen therapy (HBOT) induce reactive oxygen species (ROS) formation and have immunomodulatory effects. The lack of readily available biomarkers for assessing the dose–response relationship is a challenge in the clinical use of HBOT, motivating this feasibility study to evaluate the methods and variability. The overall hypothesis was that a short session of hyperbaric oxygen (HBO2) would have measurable effects on immune cells in the same physiological range as shown in HIIT; and that the individual response to these interventions can be monitored in venous blood and/or peripheral blood mononuclear cells (PBMCs). Ten healthy volunteers performed two interventions; a 28 min HIIT session and 28 min HBO2 in a crossover design. We evaluated bulk RNA sequencing data from PBMCs, with a separate analysis of mRNA and microRNA. Blood gases, peripheral venous oxygen saturation (SpvO2), and ROS levels were measured in peripheral venous blood. We observed an overlap in the gene expression changes in 166 genes in response to HIIT and HBO2, mostly involved in hypoxic or inflammatory pathways. Both interventions were followed by downregulation of several NF-κB signaling genes in response to both HBO2 and HIIT, while several interferon α/γ signaling genes were upregulated. Only 12 microRNA were significantly changed in HBO2 and 6 in HIIT, without overlap between interventions. ROS levels were elevated in blood at 30 min and 60 min compared to the baseline during HIIT, but not during/after HBO2. In conclusion, HBOT changed the gene expression in a number of pathways measurable in PBMC. The correlation of these changes with the dose and individual response to treatment warrants further investigation.

BackgroundIn Scandinavian countries, programs for fertility preservation (FP) are offered free of charge at tertiary-care university hospitals to all patients facing infertility risks due to malignant diagnoses or benign conditions. In this prospective study we aimed to investigate trends and outcomes of FP indicated by a diagnosis of Turner syndrome.MethodsProspective cohort study of patients with Turner karyotype receiving fertility preservation counselling at the Karolinska University Hospital between 1 January 1999 and 31 December 2021.ResultsThe cohort included 100 women and girls that received counselling, whereof 27% were prepubertal girls, 59% were adolescents and 14% of adult age. Before 2006 all patients were referred for fertility counselling at the time of Turner diagnosis. Based on updated guidelines, mainly patients who showed signs of puberty were referred after 2006. As a result, spontaneous menarche was more common in the later period. In total, 39% of the cohort had monosomal karyotype (45X), 20% had 45X/46XX or 45X/47XXX mosaicisms and 36% had an X-chromosomal structural anomaly. Ovarian tissue cryopreservation was planned for 73% of all patients, and oocyte cryopreservation following gonadotropin stimulation was planned for 10% of the patients. Follicles were present in 25% of all biopsies analyzed. Adolescents were more likely to have follicles present (30%) than prepubertal girls (16%) or adult women (17%). The ten patients that underwent gonadotropin stimulation for oocyte cryopreservation underwent a total of 15 cycles and eight patients successfully preserved oocytes. In total, 26% of the cohort has undergone fertility treatment or expressed further interest in fertility preservation. Six women have given birth using donated oocytes and three following spontaneous conception. Two women have undergone re-transplantation of cryopreserved ovarian tissue, without regaining ovarian function, and none of the women that have cryopreserved oocytes has returned to use them.ConclusionFertility counselling for girls with Turner syndrome should ideally be offered at onset of spontaneous puberty to improve the chances of fertility preservation. Since the girls and women in this cohort are still young, the return rate and utilization of the preserved tissue and oocytes is expected to increase with time.Clinical Trial RegistrationClinicalTrials.gov, identifier NTC04602962.

BackgroundDuring the COVID-19 pandemic, changes in working life occurred, even in Sweden, where there was no general lockdown. The aim of this study was to examine how the COVID-19 pandemic was perceived as affecting the hindering and enabling factors among young employees with CMD to remain at or return to work, here as investigated from the perspective of young employees and managers.Material and methodsA qualitative design was applied with semistructured interviews with 23 managers and 25 young employees (20-29 years old). The interviews were recorded and transcribed verbatim, and the parts of the interviews related to the aim of this article were analysed using conventional content analysis.ResultsThe hindering factors were changed working conditions, decreased well-being when spending more time at home, and uncertainty. The enabling factors were decreased demands, increased balance, and well-functioning work processes. For managers it is important to be aware of warning signals indicating blurred boundaries between work and private life, to create and maintain well-functioning communication, and leave room for recovery.ConclusionThe hindering and enabling factors can be described as two sides of the same coin. Changes in the working conditions during the pandemic led to difficulties for both young employees and managers when the margins of maneuver were insufficient.

The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients.Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

Introduction Long COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL.Methods and analysis A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board.Ethics and dissemination The trial is approved by the Swedish National Institutional Review Board (2021–02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access.Trial registration number NCT04842448.

Abstract Background A growing number of medical schools have individual scholarly projects as a component of their curricula. The fact that all students, and not only those with research interests, have to carry out a project puts high demands on the projects and their supervision. Evidence is lacking for how to produce scholarly projects with satisfactory outcomes. This study aimed to explore the observations of faculty teachers regarding factors that predict the educational outcomes of medical students’ scholarly projects. Methods Two focus group interviews were held with seven of the 16 faculty coordinators who were external reviewers of students’ research projects. The audio-recorded interview transcripts were analyzed using qualitative content analysis. We employed a constant comparative approach to create categories firmly grounded in the participants’ experiences. A successful project was defined as coordinators’ perception that the stated learning outcomes were achieved, in terms of students’ ability to demonstrate a scientific attitude. Results Five categories emerged from the data: Supervision, Project setup, Student characteristics, Curriculum structure, and Institutional guidance. The supervisors’ experience and availability to students were mentioned as key factors for successful outcomes. Further, a clear aim and adaptation to the time frame were stated to be project-related factors that were also supervisors’ responsibilities. Important student-related factors were skills related to scientific writing, taking ownership of and managing the projects, and making use of feedback. Finally, the course requirements, support, and control accomplished by faculty coordinators played important roles. Conclusions Contributing factors to achievement of the learning outcomes were supervisors’ commitment and experience, and the projects being suitable for the time frame and having a clearly stated research question. Furthermore, the students’ prowess at scientific writing, adequate handling of feedback, and ability to assume ownership of the project contributed to the final outcome, as did adherence to curricular instructions.

The conversion of rice hulls into fermentable saccharides was explored through steam pretreatment employing 2.5% SO2. The interaction between temperature and time was assessed by means of the response surface method to achieve optimum contents of C6-sugars in water-insoluble solids (WIS) and C5-sugars in the liquor. Pretreatment carried out at 218 °C for 2.3 min released liquor containing 55.4 g/L of sugars (29.1 g/L of xylose). In parallel, the WIS was subjected to enzymatic saccharification using different solid and enzyme loads via an experimental design: assays using 22.0% WIS and 20.0 filter paper units (FPU)/g led to 90.6 g/L of glucose, corresponding to a yield of 86.4% and an overall yield of 72.4%. The data reported are the highest ever found for such raw material, making it attractive to compete with conventional lignocellulosic biomass.

The commercial production of bioethanol from lignocellulosic biomass such as wheat straw requires utilizing a microorganism that can withstand all the stressors encountered in the process while fermenting all the sugars in the biomass. Therefore, it is essential to develop tools for monitoring and controlling the cellular fitness during both cell propagation and sugar fermentation to ethanol. In the present study, on-line flow cytometry was adopted to assess the response of the biosensor TRX2p-yEGFP for redox imbalance in an industrial xylose-fermenting strain of Saccharomyces cerevisiae during cell propagation and the following fermentation of wheat-straw hydrolysate. Rapid and transient induction of the sensor was recorded upon exposure to furfural and wheat straw hydrolysate containing up to 3.8 g/L furfural. During the fermentation step, the induction rate of the sensor was also found to correlate to the initial ethanol production rate, highlighting the relevance of redox monitoring and the potential of the presented tool to assess the ethanol production rate in hydrolysates. Three different propagation strategies were also compared, and it was confirmed that pre-exposure to hydrolysate during propagation remains the most efficient method for high ethanol productivity in the following wheat-straw hydrolysate fermentations.

Fertility counseling should be offered to all individuals of young reproductive age early in the patient’s trajectory following a cancer diagnosis. Systemic cancer treatment and radiotherapy often have an inherent gonadotoxic effect with the potential to induce permanent infertility and premature ovarian failure. For the best chances to preserve a patient’s fertility potential and to improve future quality of life, fertility preservation methods should be applied before cancer treatment initiation, thus multidisciplinary team-work and timely referral to reproductive medicine centers specialized in fertility preservation is recommended. We aim to review the current clinical possibilities for fertility preservation and summarize how infertility, as a late effect of gonadotoxic treatment, affects the growing population of young female cancer survivors.

We describe a screen for cellular response to drugs that makes use of haploid embryonic stem cells. We generated ten libraries of mutants with piggyBac gene trap transposon integrations, totalling approximately 100,000 mutant clones. Random barcode sequences were inserted into the transposon vector to allow the number of cells bearing each insertion to be measured by amplifying and sequencing the barcodes. These barcodes were associated with their integration sites by inverse PCR. We exposed these libraries to commonly used cancer drugs and profiled changes in barcode abundance by Ion Torrent sequencing in order to identify mutations that conferred sensitivity. Drugs tested included conventional chemotherapeutics as well as targeted inhibitors of topoisomerases, poly(ADP-ribose) polymerase (PARP), Hsp90 and WEE1.