Miracle-dz/UniFAR-FTUs huggingface dataset:
Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study

Abstract Context The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear. Objective This Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women. Methods As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio. Results Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10−3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10−13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10−11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers. Conclusion This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.
Association of Enzyme-Inducing Antiseizure Drug Use With Long-term Cardiovascular Disease.

Importance Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. Objective To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. Design, Setting, and Participants This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Exposures Receipt of 4 consecutive eiASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age ≥18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Main Outcomes and Measures Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Results Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. Conclusions and Relevance The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.
A novel hypothesis linking low‐grade ketonaemia to cardio‐renal benefits with sodium‐glucose cotransporter‐2 inhibitors

The cardio‐renal benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are well established. In 2016, we postulated that these benefits are attributable, in part, to the occurrence of chronic low‐grade ketonaemia and a shift in myocardial and renal fuel metabolism away from fat oxidation, which is energy inefficient, towards ketone oxidation, which is more energy efficient. This shift improves myocardial and renal function and can potentially translate into lower rates of progression to heart failure and end‐stage kidney disease in patients with and without diabetes. There is now evidence that, in addition to being an efficient fuel substrate, ketones also have antiinflammatory and antioxidative benefits on the heart and the kidney. In addition, ketones have positive effects on mitochondrial biogenesis and function, and on erythropoiesis, and thereby are potentially able to further ameliorate the proinflammatory and hypoxic milieu in those with heart and kidney failure, independent of hyperglycaemia. In the present review, we propose a novel hypothesis to link the pleiotropic effects of low‐grade ketonaemia to the cardio‐renal benefits seen with SGLT2 inhibitors.
Impact of donor telomere length on survival in patients undergoing matched sibling donor transplantation for aplastic anaemia

Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre‐transplant telomere length of patients and donors, measured by quantitative real‐time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26 years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft‐versus‐host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow‐up of 37 months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR) = 0·2, P = 0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five‐year overall survival was significantly better (94·9 ± 3·5% vs 65·4 ± 4·3%, P = 0·002) for donors with long (highest quartile, DTL‐HQ) versus short (lower three quartiles, DTL‐LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.
Behavioural generalism could facilitate co-existence of tropical and temperate fishes under climate change.

Coral-reef fishes are shifting their distributions poleward in response to human-mediated ocean warming, yet the consequences for recipient temperate fish communities remain poorly understood. Behavioural modification is often the first response of species to environmental change, but we know little about how this might shape the ongoing colonisation by tropical fishes of temperate-latitude ecosystems under climate change. In a global hotspot of ocean warming (southeast Australia), we quantified 14 behavioural traits of invading tropical and local co-occurring temperate fishes at 10 sites across a 730 km latitudinal gradient as a proxy of species behavioural niche space in different climate ranges (subtropical, warm-temperate, cold-temperate). We found that tropical fishes (4 species) modified their behavioural niches as well as increased their overall behavioural niche breadth in their novel temperate ranges where temperate species predominate, but maintained a moderate to high niche segregation with native temperate species across latitudinal range position. Temperate species (3 co-occurring species) also modified their niches, but in contrast to tropical species, experienced an increased niche breadth towards subtropical ranges. Alterations to feeding and shoaling behaviours contributed most to niche modifications in tropical and temperate species, while behaviours related to alertness and escape from potential threats contributed least. We here show that at warmer and colder range edges where community structures are being reshuffled due to climate change, behavioural generalism and niche modification are potential mechanisms adopted by tropical range extenders and native-temperate fishes to adjust to novel species interactions under climate change.
Sex and age differences in ICD-11 PTSD and complex PTSD: An analysis of four general population samples

Abstract Background Posttraumatic stress disorder (PTSD) is traditionally understood as a disorder that occurs more commonly in women than in men, and in younger age groups than in older age groups. The objective of this study was to determine if these patterns are also observed in relation to International Classification of Diseases (ICD-11) PTSD and complex PTSD (CPTSD). Methods Secondary data analysis was performed using data collected from three nationally representative samples from the Republic of Ireland (N = 1,020), the United States (N = 1,839), and Israel (N = 1,003), and one community sample from the United Kingdom (N = 1,051). Results Estimated prevalence rates of ICD-11 PTSD were higher in women than in men in each sample, and at a level consistent with existing data derived from Diagnostic and Statistics Manual of Mental Disorders (DSM)-based models of PTSD. Furthermore, rates of ICD-11 PTSD were generally lower in older age groups for men and women. For CPTSD, there was inconsistent evidence of sex and age differences, and some indication of a possible interaction between these two demographic variables. Conclusions Despite considerable revisions to PTSD in ICD-11, the same sex and age profile was observed to previous DSM-based models of PTSD. CPTSD, however, does not appear to show the same sex and age differences as PTSD. Theoretical models that seek to explain sex and age differences in trauma-related psychopathology may need to be reconsidered given the distinct effects for ICD-11 PTSD and CPTSD.
Transbronchial Lung Cryobiopsy in children

ABSTRACT Background Transbronchial Lung Cryobiopsy (TBLC) is a novel technique, available globally only in a limited number of centers. Since the data on the role of TBLCs amongst pediatric patients is limited, the aim was to evaluate its efficacy in diagnosing lung diseases amongst children. Methods The records of 28 pediatric patients were retrospectively reviewed from October 2016 till September 2018. The participants’ demographic information, procedural indications, sample adequacy, diagnostic utility, and the complications associated with this type of bronchoscopy apparatus were further assessed. Results Twenty-eight pediatric patients aged 22 months to 17 years underwent TBLC. From the 73 obtained biopsies, 97% had an adequate sampling size. The diagnostic yield of this method was 92.8%. The most common complication was mild bleeding. Transient hypoxemia and bronchospasm were observed in eleven and eight patients, respectively. Furthermore, most of them (78.6%) had uneventful post-procedure and recovery. Conclusions TBLC was a relatively safe and effective method with high accuracy and fewer complications in diagnosing and monitoring lung diseases in the selected children. However, more extensive multicentre trials are warranted to corroborate the potential benefits of this novel technique.
Increased Prevalence of Fractures in Congenital Adrenal Hyperplasia: A Swedish Population-based National Cohort Study

Abstract Context Low bone mineral density has been reported in individuals with congenital adrenal hyperplasia (CAH), but the prevalence of fractures is unclear. Objective To study the prevalence of fractures in CAH. Design, Setting, and Participants Patients with CAH (n = 714, all 21-hydroxylase deficiency) were compared with controls matched for sex and year and place of birth (n = 71 400). Data were derived by linking National Population-Based Registers. Main Outcome Measures Number and type of fractures. Results Mean age was 29.8 ± 18.4 years. Individuals with CAH had more fractures compared to controls [23.5% vs 16.1%, odds ratio (OR) 1.61, 95% CI 1.35-1.91], and this was found in both sexes (females: 19.6% vs 13.3%, OR 1.57, 95% CI 1.23-2.02; males: 28.7% vs 19.6%, OR 1.65, 95% CI 1.29-2.12). Fractures were significantly increased in patients born before the introduction of neonatal screening but not in those born afterwards. Any major fracture associated with osteoporosis (spine, forearm, hip, or shoulder) was increased in all individuals with CAH (9.8% vs 7.5%, OR 1.34, 95% CI 1.05-1.72). The highest prevalence of fractures was seen in SV phenotype and I172N genotype while nonclassic phenotype and I2 splice genotype did not show increased prevalence. A transport accident as a car occupant and fall on the same level were more common in patients with CAH, both sexes, than in controls. Conclusions Patients with CAH had an increased prevalence of both any fracture and fractures associated with osteoporosis (both sexes) but not for patients neonatally screened. We conclude that fracture risk assessment and glucocorticoid optimization should be performed regularly.
Insight into susceptibility genes associated with bipolar disorder: a systematic review.

OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
Supporting Undergraduate Biology Students’ Academic Success: Comparing Two Workshop Interventions

College students’ performance in introductory-level biology course work is an important predictor of ongoing persistence in the major. This study reports on a researcher–educator partnership that designed and compared two cocurricular workshops. Seventeen laboratory sections of an undergraduate biology course were randomly assigned to one of two educational interventions during the regularly scheduled lab class section after students had completed and received the results for the first exam. The baseline Metacognition intervention was an hourlong workshop focused on effective learning strategies and self-awareness in the learning process; the extended Metacognition plus Time Management (Metacognition+TM) intervention included the aforementioned workshop plus a second hourlong workshop on time management and procrastination. Based on three exams and self-report surveys administered before the intervention and at the end of the semester, students who participated in the Metacognition+TM intervention experienced greater increases in their exam scores and degree commitment than those in the baseline intervention. Additionally, group status moderated the effect of the intervention, as the Metacognition+TM intervention was especially effective in increasing use of time management tools by students from minoritized groups.
Exceedingly biocompatible and thin-layered reduced graphene oxide nanosheets and its application in co-delivery of curcumin and paclitaxel shows highly potent synergistic anticancer effects in A549 and MDA-MB-231 cells

Delivery of anti-cancer drugs using graphene and its derivatives: graphene oxide (GO) and reduced graphene oxide (RGO) has sparked major interest in this emerging field. The anti-cancer therapies often pose a limitation of insolubility, administration problems and cell-penetration ability. In addition, systemic toxicity caused by lack of selective targeting towards cancer cells and inefficient distribution limits its clinical applications. Graphene nanocomposite is a promising tool to address these drawbacks. Graphene is a flat monolayer of carbon atoms that holds many promising properties such as unparalleled thermal conductivity, remarkable electronic properties, and most intriguingly high planar surface and superlative mechanical strength, which are attractive in biotechnology applications. However the synthesis route for the production of GO or RGO often involves the use of harsh chemicals which jeopardize its further application as a drug delivery cargo. To overcome these limitations, a simple one-pot strategy was used to synthesize RGO nanosheets by utilizing an easily available over-the-counter medicinal and edible mushroom, Ganoderma lucidum. The produced RGO was readily dispersible in water and various solvents. The RGO was highly biocompatible towards colon (HT-29), brain (U87MG) and normal cells (MRC-5). By functionalization of RGO with an amphiphilic polymer, PF-127, a more stable RGO was produced, called GP. Curcumin (Cur) and Paclitaxel (Ptx) was then loaded onto the GP cargo, resulting in a nano-sized GP-Cur-Ptx sytem with the particle size of 140 nm. A remarkably high drug loading was also achieved with 678 wt. %, highest thus far, compared to any other Cur nanoformulations. Based on cell proliferation assay, the GP-Cur-Ptx is a synergistic treatment and is highly potent towards A549 (lung) and MDA-MB-231 (breast) cancer cells. These positive findings are further confirmed by increased reactive oxygen species (ROS); mitochondrial membrane potential (MMP) depletion; and cell apoptosis. The same treated with normal cells (MRC-5) shows that the system is biocompatible and cell-specific.
Reentry in Practice: Sexual Offending, Self-Narratives, and the Implications of Stigma in Norway

Reentering society after serving a prison sentence involves many challenges and particularly so for one of the most stigmatized groups in modern society: people who have sexually offended. While most research on their reentry has been conducted in countries with Sex Offender Registration and Notification (SORN) laws, this study used Interpretative Phenomenological Analysis (IPA) to qualitatively investigate the accounts and experiences of men released from prison after serving a sex offense conviction in Norway (n = 8). Results showed that despite less restrictive policies and a total absence of SORN laws, the social stigma linked to being convicted of such crimes severely affected the men. To some degree, they all experienced feelings of stress or anxiousness and they withdrew and isolated more. Their narratives highlight a need for increased social support and recognition from others in the reentry process. Subjective and societal consequences as well as practical implications are discussed.
Streptomyces clavuligerus: The Omics Era

Abstract The Streptomyces clavuligerus genome consists in a linear chromosome of about 6.7 Mb and four plasmids (pSCL1 to pSCL4), the latter one of 1.8 Mb. Deletion of pSCL4, results in viable mutants with high instability in the chromosome arms, which may lead to chromosome circularisation. Transcriptomic and proteomic studies comparing different mutants with the wild-type strain improved our knowledge on the biosynthesis and regulation of clavulanic acid, cephamycin C and holomycin. Additional knowledge has been obtained on the SARP-type CcaR activator and the network of connections with other regulators (Brp, AreB, AdpA, BldG, RelA) controlling ccaR expression. The transcriptional pattern of the cephamycin and clavulanic acid clusters is supported by the binding of CcaR to different promoters and confirmed that ClaR is a CcaR-dependent activator that controls the late steps of clavulanic biosynthesis. Metabolomic studies allowed the detection of new metabolites produced by S. clavuligerus such as naringenin, desferroxamines, several N-acyl tunicamycins, the terpenes carveol and cuminyl alcohol or bafilomycin J. Heterologous expression of S. clavuligerus terpene synthases resulted in the formation of no less than 15 different terpenes, although none of them was detected in S. clavuligerus culture broth. In summary, application of the Omic tools results in a better understanding of the molecular biology of S. clavuligerus, that allows the use of this strain as an industrial actinobacterial platform and helps to improve CA production.