Deep learning assessment of senescence-associated nuclear morphologies in mammary tissue from healthy female donors to predict future risk of breast cancer: a retrospective cohort study.

BACKGROUND: Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumour-promoting microenvironmental mechanism that secretes proinflammatory paracrine factors. With most work done in non-human models and the heterogeneous nature of senescence, the precise role of senescent cells in the development of cancer in humans is not well understood. Furthermore, more than 1 million non-malignant breast biopsies are taken every year that could be a major resource for risk stratification. We aimed to explore the clinical relevance for breast cancer development of markers of senescence in mammary tissue from healthy female donors. METHODS: In this retrospective cohort study, we applied single-cell deep learning senescence predictors, based on nuclear morphology, to histological images of haematoxylin and eosin-stained breast biopsy samples from healthy female donors at the Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (Indianapolis, IN, USA). All KTB participants (aged ≥18 years) who underwent core biopsies for research purposes between 2009 and 2019 were eligible for the study. Senescence was predicted in the epithelial (terminal duct lobular units [TDLUs] and non-TDLU epithelium), stromal, and adipose tissue compartments using validated models, previously trained on cells induced to senescence by ionising radiation (IR), replicative exhaustion (or replicative senescence; RS), or antimycin A, atazanavir-ritonavir, and doxorubicin (AAD) exposures. To benchmark our senescence-based cancer prediction results, we generated 5-year Gail scores-the current clinical gold standard for breast cancer risk prediction-for participants aged 35 years and older on the basis of characteristics at the time of tissue donation. The primary outcome was estimated odds of breast cancer via logistic modelling for each tissue compartment based on predicted senescence scores in cases (participants who had been diagnosed with breast cancer as of data cutoff, July 31, 2022) and controls (those who had not been diagnosed with breast cancer). FINDINGS: 4382 female donors (median age at donation 45 years [IQR 34-57]) were eligible for the study. As of data cutoff (median follow-up of 10 years [7-11]), 86 (2·0%) had developed breast cancer a mean of 4·8 years (SD 2·84) after date of donation and 4296 (98·0%) had not received a breast cancer diagnosis. Among the 86 cases, we found significant differences in adipose-specific IR and AAD senescence prediction scores compared with controls. Risk analysis showed that individuals in the upper half (above the median) of scores for the adipose tissue IR model had higher odds of developing breast cancer (odds ratio [OR] 1·71 [95% CI 1·10-2·68]; p=0·019), whereas the adipose AAD model revealed a reduced odds of developing breast cancer (OR 0·57 [0·36-0·88]; p=0·013). For the other tissue compartments and the RS model, no significant associations were found (except for stromal tissue via the IR model, had higher odds of developing breast cancer [OR 1·59, 1·03-2·49]). Individuals with both of the adipose risk factors had an OR of 3·32 (1·68-7·03; p=0·0009). Participants with 5-year Gail scores above the median had an OR for development of cancer of 2·33 (1·46-3·82; p=0·0012) compared with those with scores below the median. When combining Gail scores with our adipose AAD risk model, we found that individuals with both of these predictors had an OR of 4·70 (2·29-10·90; p<0·0001). When combining the Gail score with our adipose IR model, we found that individuals with both predictors had an OR of 3·45 (1·77-7·24; p=0·0002). INTERPRETATION: Assessment of senescence-associated nuclear morphologies with deep learning allows prediction of future cancer risk from normal breast biopsy samples. The combination of multiple models improved prediction of future breast cancer compared with the current clinical benchmark, the Gail model. Our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. FUNDING: Novo Nordisk Foundation, Danish Cancer Society, and the US National Institutes of Health.

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.

Decreased Extracellular Vesicle Vasorin in Severe Preeclampsia Plasma Mediates Endothelial Dysfunction.

Background: Preeclampsia (PE) is a serious pregnancy complication affecting 5-8% of pregnancies globally. It is a leading cause of maternal and neonatal morbidity and mortality. Despite its prevalence, the underlying mechanisms of PE remain unclear. This study aimed to determine the potential role of vasorin (VASN) in PE pathogenesis by investigating its levels in extracellular vesicles (EV) and its effects on vascular function. Methods & Results: We conducted unbiased proteomics on urine-derived EV from severe PE (sPE) and normotensive pregnant women (NTP), identifying differential protein abundances. Out of one hundred and twenty proteins with ≥ ±1.5-fold regulation at P<0.05 between sPE and NTP, we focused on Vasorin (VASN), which is downregulated in sPE in urinary EV, in plasma EV and in the placenta and is a known regulator of vascular function. We generated EV with high VASN content from both human and murine placenta explants (Plex EV), which recapitulated disease-state-dependent effects on vascular function observed when treating murine aorta rings (MAR) or human aortic endothelial cells (HAEC) with murine or human plasma-derived EV. In normal murine pregnancy, VASN increases with gestational age (GA), and VASN is decreased in plasma EV, in placenta tissue and in Plex EV after intravenous administration of adenovirus encoding short FMS-like tyrosine kinase 1 (sFLT-1), a murine model of PE (murine-PE). VASN is decreased in plasma EV, in placenta tissue and in EV isolated from conditioned media collected from placenta explants (Plex EV) in patients with sPE as compared to NTP. Human sPE and murine-PE plasma EV and Plex EV impair migration, tube formation, and induces apoptosis in human aortic endothelial cells (HAEC) and inhibit acetylcholine-induced vasorelaxation in murine vascular rings (MAR). VASN over-expression counteracts the effects of sPE EV treatment in HAEC and MAR. RNA sequencing revealed that over-expression or knock down of VASN in HAEC results in contrasting effects on transcript levels of hundreds of genes associated with vasculogenesis, endothelial cell proliferation, migration and apoptosis. Conclusions: The data suggest that VASN, delivered to the endothelium via EV, regulates vascular function and that the loss of EV VASN may be one of the mechanistic drivers of PE. CLINICAL PERSPECTIVE: What is NewVASN in circulating plasma EV in sPE is reduced compared with VASN content in plasma EV of gestational age-matched pregnant women.VASN is encapsulated and transported in EV and plays a pro-angiogenic role during pregnancy.VASN should be explored both for its pro-angiogenic mechanistic role and as a novel biomarker and potential predictive diagnostic marker for the onset and severity of PE.What Are the Clinical Implications?VASN plays a role in maintaining vascular health and the normal adaptive cardiovascular response in pregnancy. A decrease of VASN is observed in sPE patients contributing to cardiovascular maladaptation.Strategies to boost diminished VASN levels and/or to pharmacologically manipulate mechanisms downstream of VASN may be explored for potential therapeutic benefit in PE.The decrease in EV-associated VASN could potentially be used as a (predictive) biomarker for PE.

Trends in Salmonella Infantis human illness incidence and chicken carcass prevalence in the United States; 1996-2019.

The incidence of human illness due to Salmonella Infantis reported to Foodborne Diseases Active Surveillance Network and the prevalence of Infantis on chicken carcasses reported by the United States Department of Agriculture Food Safety and Inspection Service have increased significantly in the past decade. However, the trends do not appear coincident, as would be expected if the increased prevalence in chicken led to the increase in the incidence of human illness. Salmonella Infantis incidence and prevalence trends are analyzed using penalized B-spline methods for generalized additive regression models. The association between the two time series is analyzed using time-lagged rank-order cross-correlation. Geographic variations in reported incidence and trends are also explored. The increase in human incidence of Salmonella Infantis began circa 2011. The increase in chicken carcass prevalence began circa 2015. A 4-year lag on chicken carcass prevalence maximizes the rank-order cross-correlation with the incidence of illness. While chicken consumption undoubtedly contributes to the incidence of human illness due to Salmonella Infantis, the initial increase in reported illness was likely due to one or more other transmission pathways. Other potential transmission pathways include non-chicken foodborne, waterborne, person-to-person, animal contact, and environmental.

Understanding current antenatal Hepatitis C testing and care in maternity services in England.

OBJECTIVES: Universal opt-out antenatal screening for Hepatitis C virus (HCV) is not currently recommened and it is recommended that maternity services offer risk-based testing. We aimed to investigate antenatal HCV testing and adherence to testing guidance. METHODS: A cross-sectional survey was circulated to maternity service providers between November-December 2020 which included testing policy, training for healthcare staff, and management of women found to be HCV positive. Descriptive data are presented. RESULTS: A total of 75 questionnaires were returned, representing 48 % of English maternity service providers. 87 % of providers reported offering antenatal HCV risk-based testing. Risk factors used to identify pregnant women for testing varied. Less than 15 % of respondents considered women that were ever homeless or with history of incarceraton or from higher HCV prevalence areas as high risk. CONCLUSIONS: Current antenatal HCV testing practices are inadequate and HCV infection likely goes undiagnosed in pregnancy, especially among vulnerable population groups. In the absence of universal antenatal screening, re-framing antenatal HCV risk-based testing and management as a quality improvement initiative and developing HCV specific pathway guidance for maternity units is required.

Assessment of salivary cadmium levels and breast density in the Marin Women's Study.

BACKGROUND: We aimed to determine if salivary cadmium (Cd) levels had any association with breast density, hoping to establish a less invasive cost-effective method of stratifying Cd burden as an environmental breast cancer risk factor. METHODS: Salivary Cd levels were quantified from the Marin Women's Study, a Marin County, California population composite. Volumetric compositional breast density (BDsxa ) data were measured by single x-ray absorptiometry techniques. Digital screening mammography was performed by the San Francisco Mammography Registry. Radiologists reviewed mammograms and assigned a Breast Imaging-Reporting and Data System score. Early morning salivary Cd samples were assayed. Association analyses were then performed. RESULTS: Cd was quantifiable in over 90% of saliva samples (mean = 55.7 pg/L, SD = 29). Women with higher saliva Cd levels had a non-significant odds ratio of 1.34 with BI-RAD scores (3 or 4) (95% CI 0.75-2.39, p = 0.329). Cd levels were higher in current smokers (mean = 61.4 pg/L, SD = 34.8) than former smokers or non-smokers. These results were non-significant. Pilot data revealed that higher age and higher BMI were associated with higher BI-RAD scores (p < 0.001). CONCLUSION: Salivary Cd is a viable quantification source in large epidemiologic studies. Association analyses between Cd levels and breast density may provide additional information for breast cancer risk assessment, risk reduction plans, and future research directions. Further work is needed to demonstrate a more robust testing protocol before the extent of its usefulness can be established.

Trends in reported illness due to poultry- and nonpoultry associated Salmonella serotypes; United States 1996-2019.

Retrospective review is a key to designing effective food safety measures. Despite the reported reduction of Salmonella prevalence in poultry products, there has not been a concomitant reduction of the overall incidence of Salmonella illnesses reported to the US Foodborne Diseases Active Surveillance Network (FoodNet) since 1996. However, there have been significant annual trends among Salmonella serotypes. This analysis examines trends in the reported incidence of illness due to poultry- and nonpoultry associated Salmonella serotypes. Overall, the findings indicate declining trends in illness due to the poultry-associated serotypes and increasing trends in illness due to Salmonella serotypes not associated with poultry.

Chronic hepatitis C elimination prison initiative: HCV-intensive test and treat, a whole prisoner population HCV test-and-treat program in England.

Background and Aim: Prison residents are at high risk for hepatitis C virus (HCV) infection. HCV test-and-treat initiatives within prisons provide an opportunity to engage with prison residents and achieve HCV micro-elimination. The aim of the prison HCV-intensive test and treat initiative was to screen over 95% of all prison residents for HCV infection within a defined number of days determined by the size of the prison population and to initiate treatment within 7-14 days of a positive HCV RNA diagnosis. Methods: An HCV-intensive test and treat toolkit was developed based on learnings from pilot HCV-intensive test and treat events. From January 2020 to September 2021, 13 HCV-intensive test and treat events took place at prisons in England selected based on high levels of reception blood-borne virus testing and good access to peers from The Hepatitis C Trust. Results: Among a total of 8487 residents, 8139 (95.9%) underwent testing for HCV. Across the 13 prisons included, HCV antibody and RNA prevalence was 8.2% and 1.5%, respectively. The treatment initiation rate among HCV RNA-positive individuals (n = 124) was 79.0%. Conclusion: The HCV-intensive test and treat initiative presented here provides a feasible and rapid test-and-treat process to achieve HCV elimination within individual prisons. The HCV-intensive test and treat toolkit can be adapted for rapid HCV testing and treatment events at other prisons in the United Kingdom and worldwide.

Simultaneous separation and detection of nine kynurenine pathway metabolites by reversed-phase liquid chromatography-mass spectrometry: Quantitation of inflammation in human cerebrospinal fluid and plasma.

BACKGROUND: The kynurenine pathway (KP) generates eight tryptophan (TRP) metabolites collectively called kynurenines, which have gained enormous interest in clinical research. The importance of KP for different disease states calls for developing a low-cost and high-throughput chromatography-mass spectrometry method to evaluate the potential of different kynurenines. Simultaneous separation of TRP and its eight metabolites is challenging because they have substantial polarity differences (log P = -2.5 to +1.3). RESULTS: A low-cost, reversed-phase LC-MS/MS method based on polarity partitioning was established to simultaneously separate and quantitate all nine kynurenine pathway metabolites (KPMs) in a single run for the first time in the open literature. Based on stationary phase screening and ternary mobile phase optimization strategy, high polarity KPMs were retained while medium and low polarity KPMs were eluted in a shorter time. After method validation, we demonstrated the applicability of this LC/MS/MS method by quantitative measurement of all nine KPM in cerebrospinal fluid (CSF) and plasma among two groups of human subjects diagnosed with depression. Furthermore, we measured the differential KPMs in these two groups of low and high inflammation and correlated the results with CRP or TNF-α markers for depression. SIGNIFICANCE: Our proposed LC-MS/MS provides a new metabolite assay that can be easily applied in various clinical applications to simultaneously quantify multiple biomarkers in KP dysfunction.

Evidence for some antimicrobial properties of English churchyard lichens.

The emergence of multidrug-resistant bacteria has driven the need for novel antibiotics. Our investigations have focussed on lichens as they naturally produce a wide range of unique and very effective defence chemicals. The aim of this study was to evaluate some of the antimicrobial properties of ten common British churchyard lichens. The lichen material was sampled from ten species, namely Caloplaca flavescens, Diploicia canescens, Cladonia fimbriata, Psilolechia lucida, Lecanora campestris subsp. Campestris, Lecanora sulphurea, Pertusaria amara f.amara, Lepraria incana, Porpidia tuberculosa and Xanthoria calcicola. Crude acetone extracts of these lichens were tested against six bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonela typhimurium, Listeria monocytogenes and Lactobacillus acidophilus ) and two fungi (Trichophyton interdigitale and Aspergillus flavus) by the disc-diffusion susceptibility test method. Extracts of Diploicia canescens, Psilolechia lucida, Lecanora sulphurea, Pertusaria amara and Lepraria incana showed clear inhibition of the Gram-positive bacteria tested (S. aureus, L. monocytogenes, L. plantarum). Diploicia canescens, Pertusaria amara and Lepraria incana extracts also inhibited the dermatophyte fungi tested. The Lepraria incana sample tested here was the only extract that showed activity against any of the Gram-negative bacteria tested; it showed inhibition of Pseudomnas aeruginosa. Overall, our results showed that crude extracts of Diploicia canescens and Pertusaria amara had the most potent antimicrobial activity of all the extracts tested. Our results are in general agreement with published findings elsewhere. The activity of the Porpidia tuberculosa margin sample being different from that of the main colony material was an interesting and new finding reported here for the first time.

Breast cancer risk based on a deep learning predictor of senescent cells in normal tissue.

Background: The ability to predict future risk of cancer development in non-malignant biopsies is poor. Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumor-promoting microenvironmental mechanism that secretes pro-inflammatory paracrine factors. With most work done in non-human models and the heterogenous nature of senescence the precise role of senescent cells in the development of cancer in humans is not well understood. Further, more than one million non-malignant breast biopsies are taken every year that could be a major source of risk-stratification for women. Methods: We applied single cell deep learning senescence predictors based on nuclear morphology to histological images of 4,411 H&E-stained breast biopsies from healthy female donors. Senescence was predicted in the epithelial, stromal, and adipocyte compartments using predictor models trained on cells induced to senescence by ionizing radiation (IR), replicative exhaustion (RS), or antimycin A, Atv/R and doxorubicin (AAD) exposures. To benchmark our senescence-based prediction results we generated 5-year Gail scores, the current clinical gold standard for breast cancer risk prediction. Findings: We found significant differences in adipocyte-specific IR and AAD senescence prediction for the 86 out of 4,411 healthy women who developed breast cancer an average 4.8 years after study entry. Risk models demonstrated that individuals in the upper median of scores for the adipocyte IR model had a higher risk (OR=1.71 [1.10-2.68], p=0.019), while the adipocyte AAD model revealed a reduced risk (OR=0.57 [0.36-0.88], p=0.013). Individuals with both adipocyte risk factors had an OR of 3.32 ([1.68-7.03], p<0.001). Alone, 5-year Gail scores yielded an OR of 2.70 ([1.22-6.54], p=0.019). When combining Gail scores with our adipocyte AAD risk model, we found that individuals with both of these risk predictors had an OR of 4.70 ([2.29-10.90], p<0.001). Interpretation: Assessment of senescence with deep learning allows considerable prediction of future cancer risk from non-malignant breast biopsies, something that was previously impossible to do. Furthermore, our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. Funding: This study was funded by the Novo Nordisk Foundation (#NNF17OC0027812), and by the National Institutes of Health (NIH) Common Fund SenNet program (U54AG075932).

Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE).

BACKGROUND: Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors. METHODS: We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses. RESULTS: Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×1012 vp day 1; 6×1012 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3-4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8+ T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity. CONCLUSIONS: Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing. TRIAL REGISTRATION NUMBER: NCT02636036.

A common IGF1R gene variant predicts later life breast cancer risk in women with preeclampsia.

PURPOSE: Preeclampsia has been inconsistently associated with altered later life risk of cancer. This study utilizes the Nurses' Health Study 2 (NHS2) to determine if the future risk of breast and non-breast cancers in women who experience preeclampsia is modified by carrying a protective variant of rs2016347, a functional insulin-like growth factor receptor-1 (IGF1R) single nucleotide polymorphism. METHODS: This retrospective cohort study completed within the NHS2 evaluated participants enrolled in 1989 and followed them through 2015, with a study population of 86,751 after exclusions. Cox proportional hazards models both with and without the impact of rs2016347 genotype were used to assess the risk of invasive breast cancer, hormone receptor-positive (HR+) breast cancer, and non-breast cancers. RESULTS: Women with preeclampsia had no change in risk of all breast, HR+ breast, or non-breast cancers when not considering genotype. However, women carrying at least one T allele of rs2016347 had a lower risk of HR+ breast cancer, HR 0.67, 95% CI: 0.47-0.97, P = 0.04, with interaction term P = 0.06. For non-breast cancers as a group, women carrying a T allele had an HR 0.76, 95% CI: 0.53-1.08, P = 0.12, with interaction term P = 0.26. CONCLUSIONS: This retrospective cohort study found that women with preeclampsia who carry a T allele of IGF1R rs2016347 had a reduced future risk of developing HR+ breast cancer, and a reduced but not statistically significant decreased risk of non-breast cancers suggesting a possible role for the IGF-1 axis in the development of cancer in these women.

Securing wider EU commitment to the elimination of hepatitis C virus.

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes-from the municipality level to the EU level-were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call-to-Action' statement supported by all the major relevant European associations in the field.

Sugammadex versus neostigmine for routine reversal of neuromuscular blockade and the effect on perioperative efficiency.

Sugammadex produces recovery from neuromuscular blockade more rapidly and reliably than neostigmine. We sought to determine if sugammadex is associated with improved perioperative efficiency when compared to traditional neuromuscular blockade reversal with neostigmine, potentially offsetting the higher medication cost. This retrospective analysis involved patients receiving either neostigmine or sugammadex for reversal of neuromuscular blockade at a single academic tertiary care hospital. The final propensity-matched groups consisted of 4060 in each group (neostigmine or sugammadex). The primary outcome measured was total time in the operating room. Secondary outcomes included specific measures of perioperative efficiency as well as postoperative pulmonary failure. The average operating room time for patients was 169.59 [1.27] minutes for neostigmine and 157.06 [1.33] minutes for sugammadex (P < 0.001). The difference was primarily accounted for by shorter surgical times (121.45 [1.18] vs 109.62 [1.22] minutes, P < 0.011). Sugammadex was also associated with a shorter post-anesthesia care unit length of stay (102.47 [1.04] vs 98.67 [1.02] minutes, P < 0.001). For 8120 patients, sugammadex use was associated with shorter operating room and surgical durations as well as shorter post-anesthesia care unit stay. The favorable pharmacodynamic profile of sugammadex may improve surgical and perioperative efficiency and offset higher medication cost.

Sulfur Cycling as a Viable Metabolism under Simulated Noachian/Hesperian Chemistries.

Water present on the surface of early Mars (>3.0 Ga) may have been habitable. Characterising analogue environments and investigating the aspects of their microbiome best suited for growth under simulated martian chemical conditions is key to understanding potential habitability. Experiments were conducted to investigate the viability of microbes from a Mars analogue environment, Colour Peak Springs (Axel Heiberg Island, Canadian High Arctic), under simulated martian chemistries. The fluid was designed to emulate waters thought to be typical of the late Noachian, in combination with regolith simulant material based on two distinct martian geologies. These experiments were performed with a microbial community from Colour Peak Springs sediment. The impact on the microbes was assessed by cell counting and 16S rRNA gene amplicon sequencing. Changes in fluid chemistries were tested using ICP-OES. Both chemistries were shown to be habitable, with growth in both chemistries. Microbial communities exhibited distinct growth dynamics and taxonomic composition, comprised of sulfur-cycling bacteria, represented by either sulfate-reducing or sulfur-oxidising bacteria, and additional heterotrophic halophiles. Our data support the identification of Colour Peak Springs as an analogue for former martian environments, with a specific subsection of the biota able to survive under more accurate proxies for martian chemistries.

Reduced cardiovascular risks in women with endometriosis or polycystic ovary syndrome carrying a common functional IGF1R variant.

STUDY QUESTION: Is the increased future cardiovascular risk seen in women with endometriosis or polycystic ovary syndrome (PCOS) mitigated by functional insulin-like growth factor-1 receptor (IGF1R) single-nucleotide polymorphism (SNP) rs2016347 as previously shown in women with hypertensive disorders of pregnancy? SUMMARY ANSWER: This cohort study found that women with endometriosis or PCOS who carry a T allele of IGF1R SNP rs2016347 had a reduced future risk of developing cardiovascular disease (CVD) and associated risk factors, with risk reduction dependent on cohort era. WHAT IS KNOWN ALREADY: Women with endometriosis or PCOS have been shown to have an increased future risk of CVD and associated risk factors with limited predictive ability. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study took place in the Nurses' Health Study 2 (NHS2), which enrolled 116 430 participants in 1989 who were followed through 2015. The study population was analyzed in its entirety, and subdivided into entry (pre-1989) and after entry (post-1989) exposure cohorts. All NHS2 participants were eligible for inclusion in the study, 9599 (8.2%) were excluded for missing covariates. PARTICIPANTS/MATERIALS, SETTING, METHODS: The NHS2 enrolled female registered nurses from 14 different states who ranged in age from 25 to 42 years at study entry. Data were collected from entry and biennial questionnaires, and analysis conducted from November 2020 to June 2021. Cox proportional hazard models were used to assess risk of CVD, hypertension (HTN), hypercholesterolemia (HC) and type 2 diabetes, both with and without genotyping for rs2016347. MAIN RESULTS AND THE ROLE OF CHANCE: While women without endometriosis or PCOS, as a whole, demonstrated no impact of genotype on risk in either cohort, women with endometriosis carrying a T allele had a lower risk of CVD (hazard ratio (HR), 0.48; 95% CI, 0.27-0.86, P = 0.02) and HTN (HR, 0.80; 95% CI, 0.66-0.97, P = 0.03) in the pre-1989 cohort, while those in the post-1989 cohort had a decrease in risk for HC (HR, 0.76; 95% CI, 0.62-0.94, P = 0.01). Women with PCOS in the post-1989 cohort showed a significant protective impact of the T allele on HTN (HR, 0.44; 95% CI, 0.27-0.73, P = 0.002) and HC (HR, 0.62; 95% CI, 0.40-0.95, P = 0.03). LIMITATIONS, REASONS FOR CAUTION: Data on specific endometriosis lesion locations or disease stage, as well as on PCOS phenotypes were lacking. In addition, data on systemic medical treatments beyond the use of oral contraceptives were missing, and these treatments may have confounded the results. WIDER IMPLICATIONS OF THE FINDINGS: These findings implicate systemic dysregulation of the insulin-like growth factor-1 axis in the development of HTN, HC and clinical CVD in endometriosis and PCOS, suggesting a common underlying pathogenetic mechanism. STUDY FUNDING/COMPETING INTEREST(S): The NHS2 infrastructure for questionnaire data collection was supported by National Institute of Health (NIH) grant U01CA176726. This work was also supported in part by NIH and National Cancer Institute grant U24CA210990; as well, research effort and publication costs were supported by the Elizabeth MA Stevens donor funds provided to the Buck Institute for Research on Aging. The authors declare they have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Extracellular Vesicles From Women With Severe Preeclampsia Impair Vascular Endothelial Function.

BACKGROUND: Preeclampsia (PE) manifesting as hypertension and organ injury is mediated by vascular dysfunction. In biological fluids, extracellular vesicles (EVs) containing microRNA (miRNA), protein, and other cargo released from the placenta may serve as carriers to propagate injury, altering the functional phenotype of endothelial cells. PE has been consistently correlated with increased levels of placenta-derived EVs (pEVs) in maternal circulation. However, whether pEVs impaired endothelial cell function remains to be determined. In this study, we hypothesize that pEVs from pregnant women with severe PE (sPE) impair endothelial function through altered cell signaling. METHODS: We obtained plasma samples from women with sPE (n = 14) and normotensive pregnant women (n = 15) for the isolation of EVs. The total number of EV and pEV contribution was determined by quantifying immunoreactive EV-cluster of designation 63 (CD63) and placental alkaline phosphatase (PLAP) as placenta-specific markers, respectively. Vascular endothelial functional assays were determined by cell migration, electric cell-substrate impedance sensing in human aortic endothelial cells (HAECs), and wire myography in isolated blood vessels, preincubated with EVs from normotensive and sPE women. RESULTS: Plasma EV and pEV levels were increased in sPE when compared to normotensive without a significant size distribution difference in sPE (108.8 ± 30.2 nm) and normotensive-EVs (101.3 ± 20.3 nm). Impaired endothelial repair and proliferation, reduced endothelial barrier function, reduced endothelial-dependent vasorelaxation, and decreased nitrite level indicate that sPE-EVs induced vascular endothelial dysfunction. Moreover, sPE-EVs significantly downregulated endothelial nitric oxide synthase (eNOS and p-eNOS) when compared to normotensive-EV. CONCLUSIONS: EVs from sPE women impair endothelial-dependent vascular functions in vitro.