From intramural ectopic pregnancy to hysterectomy: A case report.

An intramural ectopic pregnancy is one of the rarest types of ectopic pregnancy, and due to the scarcity of reported cases there are no clear guidelines regarding diagnosis and management of the condition. We report a case of a non-viable intramural ectopic pregnancy managed with intravenous methotrexate, in a patient with no previous pregnancies but a history of uterine cornual cyst excision. The patient subsequently developed a uterine arteriovenous malformation, which was embolised. Following this, she had two pregnancies, one culminating in an elective caesarean section at term, and the other a medical termination of pregnancy at 19 weeks of gestation. As a result of post-traumatic stress disorder attributed to this complicated history, the patient requested a hysterectomy. This case demonstrates the complexity of the management of intramural ectopic pregnancy and highlights the impacts the condition can have on a patient's physical and mental health.

The potential for Scotch Malt Whisky flavour diversification by yeast.

Scotch Whisky, a product of high importance to Scotland, has gained global approval for its distinctive qualities derived from the traditional production process, which is defined in law. However, ongoing research continuously enhances Scotch Whisky production and is fostering a diversification of flavour profiles. To be classified as Scotch Whisky, the final spirit needs to retain the aroma and taste of 'Scotch'. While each production step contributes significantly to whisky flavour-from malt preparation and mashing to fermentation, distillation, and maturation-the impact of yeast during fermentation is crucially important. Not only does the yeast convert the sugar to alcohol, it also produces important volatile compounds, e.g. esters and higher alcohols, that contribute to the final flavour profile of whisky. The yeast chosen for whisky fermentations can significantly influence whisky flavour, so the yeast strain employed is of high importance. This review explores the role of yeast in Scotch Whisky production and its influence on flavour diversification. Furthermore, an extensive examination of nonconventional yeasts employed in brewing and winemaking is undertaken to assess their potential suitability for adoption as Scotch Whisky yeast strains, followed by a review of methods for evaluating new yeast strains.

Introduction of the day case total laparoscopic hysterectomy (TLH) protocol.

BACKGROUND: Traditionally total laparoscopic hysterectomy (TLH) patients are admitted for 1-2 days post-operatively. Day case TLH has been proven to be feasible and safe in other countries; however, this tertiary Queensland hospital is one of the first Australian institutions to introduce a day case TLH protocol. AIM: To pilot the implementation of our day case TLH protocol assessing the feasibility, safety and patient satisfaction of same-day discharge. MATERIALS AND METHODS: A retrospective audit of the implementation of our day case TLH protocol at a tertiary Queensland hospital was conducted. Primary outcome was length of post-operative hospital stay. Secondary outcomes included perioperative complications and post-operative re-presentation rates. Patient satisfaction was assessed through a patient questionnaire. RESULTS: Seventy-seven patients were included in the study. There were 94.81% patients who went home on the same day. Their average length of post-operative hospital stay was 7.72 (SD ± 3.36) hours. Of the patients who did achieve same-day discharge, the average length of stay was 7.05 (SD ±1.46) hours. There were no significant differences in perioperative complications or re-presentation rates compared to previously published literature. Patients reported they were extremely satisfied with day case TLH. CONCLUSION: The implementation of our day case TLH protocol is feasible, safe and well received by patients in our tertiary Australian hospital. These results can have multimodal effects in healthcare: decrease in hospital costs by reducing length of stay and overnight admissions, improved theatre efficiency and patient flow, while maintaining patient safety and satisfaction.

NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24.

Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical drug discovery timelines. The recently developed NMR molecular replacement (NMR2) method dramatically reduces the time needed to generate ligand-protein complex structures using published structures (apo or holo) of the target protein and treating all observed NOEs as ambiguous restraints, bypassing the laborious process of obtaining sequence-specific resonance assignments for the protein target. We apply this method to two therapeutic targets, the bromodomain of TRIM24 and the second bromodomain of BRD4. We show that the NMR2 methodology can guide SBDD by rationalizing the observed SAR. We also demonstrate that new types of restraints and selective methyl labeling have the potential to dramatically reduce "time to structure" and extend the method to targets beyond the reach of traditional NMR structure elucidation.

Patient experiences of conservative treatment for early stage endometrial cancer and endometrial hyperplasia with atypia using levonorgestrel intrauterine device: A qualitative study.

OBJECTIVE: The aim of the study was to obtain an in-depth understanding of the experience of women who received non-surgical treatment for endometrial adenocarcinoma (EAC) or endometrial hyperplasia with atypia (EHA). Enhanced understanding of women's experiences of non-surgical treatment is essential to inform counselling of the growing number of patients in this field. METHODS: Individual semi-structured interviews were conducted with 21 women who received conservative (non-surgical hormonal) treatment for early stage EAC or EHA using the levonorgestrel intrauterine device (LNG-IUD) as part of the feMMe trial (NCT01686126). All interviews were audiotaped and transcribed verbatim prior to content analysis. RESULTS: Of the 21 women interviewed, ten received conservative treatment for early stage EAC and 11 received conservative treatment for EHA. Five overarching themes were identified: i) extensive information and support needs (e.g. understanding of how the LNG-IUD treatment worked); ii) gratitude for treatment choice and non-surgical options (e.g. avoidance of potential risks associated with surgery); iii) onco-fertility (e.g. desire to maintain reproductive potential); iv) patient experience of overweight and obesity related to EAC development (e.g. history of trauma and disordered eating, multiple unsuccessful weight loss attempts); and v) patient experience of treatment options and actual non-surgical treatment (e.g. desire for early referral to counselling services). CONCLUSIONS: This qualitative investigation enabled novel insights into the treatment preferences and decision-making process of women with newly diagnosed EHA and EAC when offered non-surgical treatment options. These insights facilitate the development of pragmatic guidance and decision support tools that could be tested in future clinical trials.

Experimental Whisky Fermentations: Influence of Wort Pretreatments.

In addition to ethanol yield, the production of flavour congeners during fermentation is a major consideration for Scotch whisky producers. Experimental whisky fermentations can provide useful information to the industry, and this is the focus of this paper. This study investigated the impact of wort pretreatments (boiled, autoclaved, filtered) on fermentation performance and flavour development in Scotch whisky distillates as an alternative to freezing wort for storage. Our study showed that no significant sensorial differences were detected in low wines (first distillates), while the chemical compositions showed clear changes in increased levels of esters and higher alcohols in boiled and autoclaved wort. In contrast, filtered wort comprised overall lower levels of congeners. Regarding alcohol yield, all three pretreatments resulted in decreased yields. In practice, the pretreatment of wort prior to fermentation requires additional process operations, while freezing requires large storage units. The pretreatments adopted in this study significantly influence the composition of the malt wort used for experimental whisky fermentations, and this results in a poorer fermentation performance compared with untreated wort. We recommend the use of fresh or frozen wort as the best options for small-scale fermentation trials.

hSSB2 (NABP1) is required for the recruitment of RPA during the cellular response to DNA UV damage.

Maintenance of genomic stability is critical to prevent diseases such as cancer. As such, eukaryotic cells have multiple pathways to efficiently detect, signal and repair DNA damage. One common form of exogenous DNA damage comes from ultraviolet B (UVB) radiation. UVB generates cyclobutane pyrimidine dimers (CPD) that must be rapidly detected and repaired to maintain the genetic code. The nucleotide excision repair (NER) pathway is the main repair system for this type of DNA damage. Here, we determined the role of the human Single-Stranded DNA Binding protein 2, hSSB2, in the response to UVB exposure. We demonstrate that hSSB2 levels increase in vitro and in vivo after UVB irradiation and that hSSB2 rapidly binds to chromatin. Depletion of hSSB2 results in significantly decreased Replication Protein A (RPA32) phosphorylation and impaired RPA32 localisation to the site of UV-induced DNA damage. Delayed recruitment of NER protein Xeroderma Pigmentosum group C (XPC) was also observed, leading to increased cellular sensitivity to UVB. Finally, hSSB2 was shown to have affinity for single-strand DNA containing a single CPD and for duplex DNA with a two-base mismatch mimicking a CPD moiety. Altogether our data demonstrate that hSSB2 is involved in the cellular response to UV exposure.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Regional Variation in Epidermal Susceptibility to UV-Induced Carcinogenesis Reflects Proliferative Activity of Epidermal Progenitors.

To better understand the influence of ultraviolet (UV) irradiation on the initial steps of skin carcinogenesis, we examine patches of labeled keratinocytes as a proxy for clones in the interfollicular epidermis (IFE) and measure their size variation upon UVB irradiation. Multicolor lineage tracing reveals that in chronically irradiated skin, patches near hair follicles (HFs) increase in size, whereas those far from follicles do not change. This is explained by proliferation of basal epidermal cells within 60 µm of HF openings. Upon interruption of UVB, patch size near HFs regresses significantly. These anatomical differences in proliferative behavior have significant consequences for the cell of origin of basal cell carcinomas (BCCs). Indeed, a UV-inducible murine BCC model shows that BCC patches are more frequent, larger, and more invasive near HFs. These findings have major implications for the prevention of field cancerization in the epidermis.

Investigating women with postmenopausal bleeding: The utility of endometrial thickness in transvaginal ultrasound.

BACKGROUND: Australian clinical guidelines recommend further investigation in females with postmenopausal bleeding (PMB) and endometrial thickness (ET) of ≥4 mm on transvaginal ultrasound (TVUS). However, the literature indicates that an ET of ≥3 mm as an upper limit is a more sensitive predictor of endometrial malignancy (EM) in females with PMB. AIMS: To assess whether Australian guidelines for PMB with an upper limit of 4 mm ET on ultrasound investigation, is sensitive enough for malignancy detection. MATERIAL AND METHODS: A retrospective study was performed on tissue results in PMB presentations to the Gold Coast Hospital and Health Service between 2011 and 2015. RESULTS: Twenty point nine percent of women with PMB had a malignancy. With an upper limit of 4 mm in ET on ultrasound, malignancy was present in 22% of participants. [Correction added on 10 July 2020, after first online publication: percentage of women with PMB that had a malignancy has been amended to twenty point nine percent.] CONCLUSIONS: A limit of 3 mm for ET in PMB, along with office endometrial biopsy, should be considered to ensure timely diagnoses.

The Third International Symposium on Fungal Stress - ISFUS.

Stress is a normal part of life for fungi, which can survive in environments considered inhospitable or hostile for other organisms. Due to the ability of fungi to respond to, survive in, and transform the environment, even under severe stresses, many researchers are exploring the mechanisms that enable fungi to adapt to stress. The International Symposium on Fungal Stress (ISFUS) brings together leading scientists from around the world who research fungal stress. This article discusses presentations given at the third ISFUS, held in São José dos Campos, São Paulo, Brazil in 2019, thereby summarizing the state-of-the-art knowledge on fungal stress, a field that includes microbiology, agriculture, ecology, biotechnology, medicine, and astrobiology.

Mitigating stress in industrial yeasts.

The yeast, Saccharomyces cerevisiae, is the premier fungal cell factory exploited in industrial biotechnology. In particular, ethanol production by yeast fermentation represents the world's foremost biotechnological process, with beverage and fuel ethanol contributing significantly to many countries economic and energy sustainability. During industrial fermentation processes, yeast cells are subjected to several physical, chemical and biological stress factors that can detrimentally affect ethanol yields and overall production efficiency. These stresses include ethanol toxicity, osmostress, nutrient starvation, pH and temperature shock, as well as biotic stress due to contaminating microorganisms. Several cell physiological and genetic approaches to mitigate yeast stress during industrial fermentations can be undertaken, and such approaches will be discussed with reference to stress mitigation in yeasts employed in Brazilian bioethanol processes. This article will highlight the importance of furthering our understanding of key aspects of yeast stress physiology and the beneficial impact this can have more generally on enhancing industrial fungal bioprocesses.

Murine dorsal hair type is genetically determined by polymorphisms in candidate genes that influence BMP and WNT signalling.

Mouse dorsal coat hair types, guard, awl, auchene and zigzag, develop in three consecutive waves. To date, it is unclear if these hair types are determined genetically through expression of specific factors or can change based on their mesenchymal environment. We undertook a novel approach to this question by studying individual hair type in 67 Collaborative Cross (CC) mouse lines and found significant variation in the proportion of each type between strains. Variation in the proportion of zigzag, awl and auchene, but not guard hair, was largely due to germline genetic variation. We utilised this variation to map a quantitative trait locus (QTL) on chromosome 12 that appears to influence a decision point switch controlling the propensity for either second (awl and auchene) or third wave (zigzag) hairs to develop. This locus contains two strong candidates, Sostdc1 and Twist1, each of which carry several ENCODE regulatory variants, specific to the causal allele, that can influence gene expression, are expressed in the developing hair follicle, and have been previously reported to be involved in regulating human and murine hair behaviour, but not hair subtype determination. Both of these genes are likely to play a part in hair type determination via regulation of BMP and/or WNT signalling.

Advances in yeast alcoholic fermentations for the production of bioethanol, beer and wine.

Yeasts have a long-standing relationship with humankind that has widened in recent years to encompass production of diverse foods, beverages, fuels and medicines. Here, key advances in the field of yeast fermentation applied to alcohol production, which represents the predominant product of industrial biotechnology, will be presented. More specifically, we have selected industries focused in producing bioethanol, beer and wine. In these bioprocesses, yeasts from the genus Saccharomyces are still the main players, with Saccharomyces cerevisiae recognized as the preeminent industrial ethanologen. However, the growing demand for new products has opened the door to diverse yeasts, including non-Saccharomyces strains. Furthermore, the development of synthetic media that successfully simulate industrial fermentation medium will be discussed along with a general overview of yeast fermentation modeling.

Data for life cycle assessment of legume biorefining for alcohol.

Benchmarking the environmental sustainability of alcohol produced from legume starch against alcohol produced from cereal grains requires considering of crop production, nutrient cycling and use of protein-rich co-products via life cycle assessment. This article describes the mass balance flows behind the life cycle inventories for gin produced from wheat and peas (Pisum sativum L.) in an associated article summarising the environmental footprints of wheat- and pea-gin [1], and also presents detailed supplementary results. Activity data were collected from interviews with actors along the entire gin value chain including a distillery manager and ingredient and packaging suppliers. Important fertiliser and animal-feed substitution effects of co-product use were derived using detailed information and models on nutrient flows and animal feed composition, along with linear optimisation modelling. Secondary data on environmental burdens of specific materials and processes were obtained from the Ecoinvent v3.4 life cycle assessment database. This article provides a basis for further quantitative evaluation of the environmental sustainability of legume-alcohol value chains.

Just the tonic! Legume biorefining for alcohol has the potential to reduce Europe's protein deficit and mitigate climate change.

Industrialised agriculture is heavily reliant upon synthetic nitrogen fertilisers and imported protein feeds, posing environmental and food security challenges. Increasing the cultivation of leguminous crops that biologically fix nitrogen and provide high protein feed and food could help to address these challenges. We report on the innovative use of an important leguminous crop, pea (Pisum sativum L.), as a source of starch for alcohol (gin) production, yielding protein-rich animal feed as a co-product. We undertook life cycle assessment (LCA) to compare the environmental footprint of 1 L of packaged gin produced from either 1.43 kg of wheat grain or 2.42 kg of peas via fermentation and distillation into neutral spirit. Allocated environmental footprints for pea-gin were smaller than for wheat-gin across 12 of 14 environmental impact categories considered. Global warming, resource depletion, human toxicity, acidification and terrestrial eutrophication footprints were, respectively, 12%, 15%, 15%, 48% and 68% smaller, but direct land occupation was 112% greater, for pea-gin versus wheat-gin. Expansion of LCA boundaries indicated that co-products arising from the production of 1 L of wheat- or pea-gin could substitute up to 0.33 or 0.66 kg soybean animal feed, respectively, mitigating considerable greenhouse gas emissions associated with land clearing, cultivation, processing and transport of such feed. For pea-gin, this mitigation effect exceeds emissions from gin production and packaging, so that each L of bottled pea gin avoids 2.2 kg CO2 eq. There is great potential to scale the use of legume starches in production of alcoholic beverages and biofuels, reducing dependence on Latin American soybean associated with deforestation and offering considerable global mitigation potential in terms of climate change and nutrient leakage - estimated at circa 439 Tg CO2 eq. and 8.45 Tg N eq. annually.

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma.

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the 'usual suspects' by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.

Keratinocyte Cytokine Networks Associated with Human Melanocytic Nevus Development.

Melanocytes can group together in nevi, commonly thought to form because of intrinsic somatic mutations involving MAPK pathway activation. However, the role of the microenvironment, in particular keratinocytes, in nevogenesis is rarely studied. Melanocytes proliferate during the hair follicle growth phase and in some basal cell carcinomas, allowing us to construct keratinocyte gene expression clusters correlated with melanocyte activation. We asked whether such correlations are evident in the more subtle context of regulation of melanocyte behavior in normal skin. We considered genes which, when mutated in keratinocytes in mice, lead to nevogenesis. Across the human GTEx normal skin database, their expression was correlated with that of keratinocyte cytokines KITLG, HGF, FGF2, EDN1, and melanocyte markers. These cytokines have pleiotropic effects on melanocyte-specific and pigmentation genes and also influence mast cell gene expression. We show five classes of keratinocyte genes that, via germline genetic variation, influence melanocyte activity. These include genes involved in SHH signaling, structural keratins, ribosomal biogenesis, and stem cell governance. In agreement with the finding of KITLG linked to nevogenesis in human genome-wide association studies, we provide evidence that specific keratinocyte cytokines are components of networks that may drive or exacerbate nevus development.