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IntroductionWe present findings from the International Collaborative Effusion database, a European Respiratory Society clinical research collaboration. Nonspecific pleuritis (NSP) is a broad term that describes chronic pleural inflammation. Various aetiologies lead to NSP, which poses a diagnostic challenge for clinicians. A significant proportion of patients with this finding eventually develop a malignant diagnosis.Methods12 sites across nine countries contributed anonymised data on 187 patients. 175 records were suitable for analysis.ResultsThe commonest aetiology for NSP was recorded as idiopathic (80 out of 175, 44%). This was followed by pleural infection (15%), benign asbestos disease (12%), malignancy (6%) and cardiac failure (6%). The malignant diagnoses were predominantly mesothelioma (six out of 175, 3.4%) and lung adenocarcinoma (four out of 175, 2.3%). The median time to malignant diagnosis was 12.2 months (range 0.8–32 months). There was a signal towards greater asbestos exposure in the malignant NSP group compared to the benign group (0.63versus0.27, p=0.07). Neither recurrence of effusion requiring further therapeutic intervention nor initial biopsy approach were associated with a false-negative biopsy. A computed tomography finding of a mass lesion was the only imaging feature to demonstrate a significant association (0.18versus0.01, p=0.02), although sonographic pleural thickening also suggested an association (0.27versus0.09, p=0.09).DiscussionThis is the first multicentre study of NSP and its associated outcomes. While some of our findings are reflected by the established body of literature, other findings have highlighted important areas for future research, not previously studied in NSP.

We report the full characterization of a new organic nonlinear optical (NLO) crystal for intense THz generation: PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). We discuss crystal growth and structural characteristics. We present the wavelength dependence of THz generation, the thickness dependence of the THz spectrum for PNPA crystals, and measure the efficiency. PNPA enables intense THz generation that surpasses NLO crystals DAST and OH-1, which have been the standard in organic high-field THz generators for several years., 11 pages, 7 figures

Land-use and land-cover change strongly affect biodiversity patterns and are assumed to be growing threats in the future. Particularly increasing urbanisation may affect species turnover and functional composition of biological communities. This study aimed to assess the characteristics of land-cover change in a medium-sized urban municipality from 2011 to 2018, and the effects of urbanisation on avian species- and functional diversity. The study was performed in Trondheim (Norway), using local land-cover maps and GBIF bird species occurrence records. GLMMs were used to model species turnover as a function of urbanisation, and the probability of species appearance and disappearance based on urbanisation and species traits. The extent of bird species turnover within a municipality-wide 500 × 500m2 grid was not predicted by a changes in developed area, but the probability of disappearance and appearance of bird species varied with urbanisation and bird functional traits. Species associated with urban- or open areas showed a decreasing probability of disappearing and an increasing probability of appearing with increasing amount of developed area within grid cells. Similarly, granivorous species showed a decreasing probability of disappearing. Species feeding above ground-level showed positive responses to changes in land-cover. The probability of both appearance and disappearance, thus species turnover, increased with increasing longevity. Most functional groups respond negatively to increasing urbanisation, indicating a potential impoverishment of local avifauna with future land-cover modifications. Considering planned future land-cover changes within the municipality, the local avian communities are in danger of homogenisation. The recommendations for local management are to minimise conversion of vulnerable habitats, such as wetlands and woodlands, in particular if these are converted to developed area.

Background and ObjectivesTo develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for identifying at-risk individuals who are candidates for early intervention with amyloid targeted treatments.MethodsWe used data from 4,134 cognitively normal individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. The sample was divided into training and test sets. A modified version of AutoScore, a machine learning–based software tool, was used to develop a scoring system using the training set. Three risk scores were developed using candidate predictors in various combinations from the following categories: demographics (age, sex, education, race, family history, body mass index, marital status, and ethnicity), subjective measures (Alzheimer's Disease Cooperative Study Activities of Daily Living–Prevention Instrument, Geriatric Depression Scale, and Memory Complaint Questionnaire), objective measures (free recall, Mini-Mental State Examination, immediate recall, digit symbol substitution, and delayed logical memory scores), andAPOE4status. Performance of the risk scores was evaluated in the independent test set.ResultsPARS model 1 included age, body mass index (BMI), and family history and had an area under the curve (AUC) of 0.60 (95% CI 0.57–0.64). PARS model 2 included free recall in addition to the PARS model 1 variables and had an AUC of 0.61 (0.58–0.64). PARS model 3, which consisted of age, BMI, andAPOE4information, had an AUC of 0.73 (0.70–0.76). PARS model 3 showed the highest, but still moderate, performance metrics in comparison with other models with sensitivity of 72.0% (67.6%–76.4%), specificity of 62.1% (58.8%–65.4%), accuracy of 65.3% (62.7%–68.0%), and positive predictive value of 48.1% (44.1%–52.1%).DiscussionPARS models are a set of simple and practical risk scores that may improve our ability to identify individuals more likely to be amyloid positive. The models can potentially be used to enrich trials and serve as a screening step in research settings. This approach can be followed by the use of additional variables for the development of improved risk scores.Classification of EvidenceThis study provides Class II evidence that in cognitively unimpaired individuals PARS models predict Aβ positivity with moderate accuracy.

Cervical intraepithelial neoplasia grade 2 (CIN 2) is an equivocal diagnosis with high interobserver variation. Owing to high regression rates of 50%, many countries recommend active surveillance of CIN 2, especially in women younger than age 25-30 years, where regression rates are even higher (ie, 60%). Additionally, excisional treatment is associated with increased risk of reproductive harm, particularly preterm birth. Active surveillance typically consists of semi-annual follow-up visits for up to 2 years, including colposcopy and either cytology, testing for human papillomavirus, or both. Excisional treatment is recommended for progression or persistent disease after 2 years. Because active surveillance in younger women is relatively new, knowledge on subsequent risk of cervical cancer is limited. Considering human papillomavirus latency, women undergoing active surveillance might be at higher risk of cervical cancer than women undergoing excisional treatment. Furthermore, there are limited data describing preferences of women for the management of CIN 2, and it is also unclear how active surveillance may affect planning for future pregnancy. In this context, biomarkers for risk stratification of CIN 2 into either high or low probability of progression would allow for targeted treatment. Currently, immunohistochemical staining for p16 is used to clarify the histologic diagnosis, but whether it or other biomarkers can be used for risk-stratification in clinical management of women with CIN 2 remains unknown. In conclusion, active surveillance of CIN 2 needs further investigation, including understanding the long-term cervical cancer risk and evaluation of markers that may enable risk stratification of CIN 2.

Ketogenic diets (KD) are very low-carbohydrate diets that promote nutritional ketosis and are widely used for weight loss, although concerns about potential adverse cardiovascular effects remain. In this study, we used apolipoprotein E deficient (ApoE-/-)mice to investigate the vascular impact and plasma metabolic signature of a very high-fat KD compared to a non-ketogenic high-fat diet (HFD). Plasma samples were collected after 4, 8, and 12 weeks on the experimental diets and used to quantify the major ketone body β-hydroxybutyrate (BHB), inflammatory cytokines (interleukin 6, IL-6; monocyte chemoattractant protein 1, MCP-1; and tumor necrosis factor α, TNF-α), and targeted metabolomic profiling by mass spectrometry. Moreover, aortic atherosclerotic lesions were quantified ex vivo by magnetic resonance imaging (MRI) on a 14-tesla system. The results showed that, relative to HFD mice, the KD mice had markedly higher levels of BHB and lower levels of cytokines, confirming the presence of ketosis that alleviated the well-established fat-induced systemic inflammation. Moreover, mice under nutritional ketosis displayed a distinct plasma amino acid profile evidencing a KD-induced alteration in protein metabolism. Significant changes in the plasma metabolome in KD mice included a decrease in lipophilic and increase in hydrophilic metabolites. Despite the higher fat content of the KD versus the HFD, KD mice presented significantly lower levels of several lipid metabolites, including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides. Consistent with the shift in energy metabolism toward fatty acid oxidation caused by the KD, the ratio of acylcarnitines to free carnitine was significantly higher in KD than in HFD mice., the aortic plaque burden was significantly lower in the KD versus the HFD group. In conclusion, nutritional ketosis induced by the KD was associated with specific metabolic changes and an atheroprotective phenotype versus the HFD.

Highly mutable infectious disease pathogens (hm-IDPs) such as HIV and influenza evolve faster than the human immune system can contain them, allowing them to circumvent traditional vaccination approaches and causing over one million deaths annually. Agent-based models can be used to simulate the complex interactions that occur between immune cells and hm-IDP-like proteins (antigens) during affinity maturation—the process by which antibodies evolve. Compared to existing experimental approaches, agent-based models offer a safe, low-cost, and rapid route to study the immune response to vaccines spanning a wide range of design variables. However, the highly stochastic nature of affinity maturation and vast sequence space of hm-IDPs render brute force searches intractable for exploring all pertinent vaccine design variables and the subset of immunization protocols encompassed therein. To address this challenge, we employed deep reinforcement learning to drive a recently developed agent-based model of affinity maturation to focus sampling on immunization protocols with greater potential to improve the chosen metrics of protection, namely the broadly neutralizing antibody (bnAb) titers or fraction of bnAbs produced. Using this approach, we were able to coarse-grain a wide range of vaccine design variables and explore the relevant design space. Our work offers new testable insights into how vaccines should be formulated to maximize protective immune responses to hm-IDPs and how they can be minimally tailored to account for major sources of heterogeneity in human immune responses and various socioeconomic factors. Our results indicate that the first 3 to 5 immunizations, depending on the metric of protection, should be specially tailored to achieve a robust protective immune response, but that beyond this point further immunizations require only subtle changes in formulation to sustain a durable bnAb response.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1–3, but also revealed how quickly viral escape can curtail effective options4, 5. With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including EvusheldTMand its constituent, cilgavimab4, 6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protectionin vivoagainst the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities.

Background Hemodialysis and infective endocarditis are both associated with poor patient outcome. However, despite high mortality rates for each disease entity, little attention is given to patients on hemodialysis who develop infective endocarditis. Purpose To examine patient characteristics, microbiological etiology, cardiac surgery, and outcome among patients on hemodialysis with infective endocarditis compared with patients with infective endocarditis without hemodialysis treatment. Methods With Danish nationwide registries, we identified patients with infective endocarditis between 2010–2018 and linked them to microbiological data from a nationwide microbiological registry with complete blood culture data. We included patients in the hemodialysis group if they received hemodialysis treatment within 6 months prior to their first-time infective endocarditis admission. Patients not meeting this criteria were put in the non-hemodialysis group. We used Kaplan-Meier estimates for difference in mortality and Cox regression for adjusted analysis. Results We included 4,106 patients with infective endocarditis of which 265 (6.5%) patients were also in hemodialysis treatment (66.8% men). Patients on hemodialysis were younger (median age 66 years [IQR=54.2–74.9] vs. 72.3 years [IQR=62.3–80.4]) and had a higher burden of comorbidities including hypertension (68.7 vs. 56.9%), diabetes (47.2% vs. 18.8%), and ischemic heart disease (41.1% vs. 32.2%) compared to patients without hemodialysis treatment, all p-values Conclusion Patients on hemodialysis with infective endocarditis are younger, sicker and have Staphylococcus aureus as causing agent more than twice as often as patients with infective endocarditis without hemodialysis treatment. This patient group have a higher mortality and by 5 years, 75% of patients in our hemodialysis group were dead. Funding Acknowledgement Type of funding sources: None.

High levels of dissolved SO4 in drinking water can adversely affect livestock performance. Some plant species may help to remove SO4 and cleanse drinking water, especially S-hyperaccumulators. However, little is known about the capacity of S-hyperaccumulators to grow in rangeland wetland environments. Here we measured plant properties, S concentration, and S mass of nine plant species. Plants were grown in a wetland environment on an artificial floating island (AFI) in a mesocosm supplied with high SO4 water (2 430−4 730 parts per million [PPM]) from a rangeland reservoir. Water properties were measured throughout the experiment. We also used our data and data from the literature to parameterize simulations and estimate the number of plants (per L) needed to reduce the SO4 concentration from 2 000 PPM to a recommended limit of 1 000 PPM. The average sulfur concentration of the nine species was 3.8 times greater than the average of 39 species from the literature. Among the nine species, Brassica napus L., B. napus var. pabularia (DC.) Rchb., and Brassica septiceps (L. H. Bailey) L. H. Bailey tended to have the greatest shoot S concentrations. The total S mass per plant was 5 times greater for B. septiceps (44 mg × plant−1) than B. juncea (L.) Czern. We found no other appreciable differences in total S mass among species. The simulations suggest that ≥ 1.9 plants × L−1 of B. septiceps or ≥ 0.6 plants × L−1 of B. oleracea L. would be needed to reduce the water's SO4 concentration from 2 000 PPM to the recommended limit. Given the small amount of S removed (per plant) relative to the vast amount of dissolved SO4 possible in rangeland water sources, planted AFIs are not likely to be a practical tool for reducing SO4 in livestock drinking water. Conversely, water treatment systems may be justified in some cases.

Dissolved solids can negatively impact livestock drinking water. To characterize dissolved solid concentrations in the northern Great Plains, we studied 45 water sources over 11 yr. Ca, F, Mg, Na, and total solids sometimes exceeded recommended levels but rarely reached levels empirically shown to negatively impact livestock. Fe often attained concentrations that reduce water consumption, which can reduce feed intake and weight gain. Excessive Fe was likeliest in creeks and reservoirs. SO4 sometimes reached concentrations that reduce weight gain but rarely reached concentrations causing health problems. Excessive SO4 was least likely in reservoirs. A safeguard against water quality problems is ensuring livestock can access multiple water source types (e.g., wells and reservoirs) so that they can use taste and smell to choose acceptable water. Where this is impossible, water quality monitoring is of greater importance. Inexpensive electrical conductivity meters roughly estimate water quality and can identify watering locations requiring more detailed monitoring.

In 2005, under the auspices of ESHRE, a group of international experts evaluated the existing best evidence and published the first European guideline on the management of endometriosis. This highly successful project was the first guideline by ESHRE and was adopted by many counties as their national standard. A second, fully-updated edition was presented in 2013. For the new ESHRE Endometriosis Guideline, published in February 2022, all available evidence for twelve chosen topics was gathered by a senior research specialist. Subgroups comprised of patient representatives and experts in healthcare, reproductive science and epidemiology evaluated the data according to GRADE criteria. Each subgroup wrote a chapter and formulated their recommendations which were then presented by a representative to the core group. There, a provisional document was generated and made available for stakeholder review. The resulting comments were taken into account and where relevant incorporated into the final guideline document for which approval was sought and gained from the ESHRE Executive Committee. 35 PICO (Patients, Interventions, Comparison, Outcome) and seven narrative questions were addressed resulting in 78 Research Recommendations were formulated. Where sufficient scientific evidence was lacking and the Guideline Development Group (GDG) was of the opinion that an important topic needed to be highlighted Good Clinical Practice Points where created based on experts’ experience. During the process of reviewing the literature it became apparent that large knowledge gaps of the best clinical approach to endometriosis exist. As a result, 30 research recommendations were also produced. One of the main differences to the 2013 version of the ESHRE guidelines is that laparoscopy is no longer the gold standard for endometriosis per se as there exist sufficient data to support the use of transvaginal ultrasound performed by an experienced operator or MRI can equally identify or rule out ovarian and most of deep endometriosis. However, it is recognised by the GDG that the required imaging standards are not ubiquitously available and for peritoneal disease both sensitivity and specificity using either imaging modalities are still poor. As opposed to the 2013 recommendation, the GDG does not anymore recommend an ultralong protocol for the women with rASRM stage III/IV endometriosis to improve IVF success rates. Furthermore, gonadotropin releasing hormone antagonists seem to be effective in the treatment of endometriosis-associate pain and, where available, could be considered as second-line treatment. Other changes were specific chapters on endometriosis in adolescents and in menopausal women as the GDG strongly felt that these groups are concerningly underrepresented in clinical care and research. Finally, a chapter focussing on the association of endometriosis with certain forms of cancer namely subgroups of ovarian cancer, breast and thyroid cancer was added to give both patients and clinicians a better insight into the current evidence of this complex topic. The GDG hope that the new ESHRE Endometriosis Guideline will improve the clinical management of a highly prevalent and heterogenous disease and that the freely-available patient-friendly version of the guideline empowers symptomatic and asymptomatic women to seek the best available advice, support and treatment.

Risk of complications following hernia repair is the key parameter to assess risk/benefit ratio of a technique. As mesh devices are permanent, their risks are life-long. Too many reports in the past assessed mesh safety prematurely after short follow-ups. We aimed to explore what length of follow up would reveal the full extent of complications. Time lapses between implantation and excision were analyzed in 460 cases of meshes excised for complications after hernia repair. Patterns of percentage growth and time lapses at 50th and 95th percentiles were used to compare groups of different hernia type, age, gender and reason for excision. The 50th and 95th case percentiles in the dataset were at 3.75 and 15.0 years between mesh implantation and excision. For hernia types, the longest time lapses were for groin hernias (4.0 and 16.11 years at 50th and 95th percentiles). The shortest were for umbilical hernias (2.16 and 9.68 years). Males had later excisions than females (4.11 and 16.1 vs. 2.47 and 9.79 years). Younger patients (

With the emergence of industry 4.0, the oil and gas (O&G) industry is now considering a range of digital technologies to enhance productivity, efficiency, and safety of their operations while minimizing capital and operating costs, health and environment risks, and variability in the O&G project life cycles. The deployment of emerging technologies allows O&G companies to construct digital twins (DT) of their assets. Considering DT adoption, the O&G industry is still at an early stage with implementations limited to isolated and selective applications instead of industry-wide implementation, limiting the benefits from DT implementation. To gain the full potential of DT and related technological adoption, a comprehensive understanding of DT technology, the current status of O&G-related DT research activities, and the opportunities and challenges associated with the deployment of DT in the O&G industry are of paramount importance. In order to develop this understanding, this paper presents a literature review of DT within the context of the O&G industry. The paper follows a systematic approach to select articles for the literature review. First, a keywords-based publication search was performed on the scientific databases such as Elsevier, IEEE Xplore, OnePetro, Scopus, and Springer. The filtered articles were then analyzed using online text analytic software (Voyant Tools) followed by a manual review of the abstract, introduction and conclusion sections to select the most relevant articles for our study. These articles and the industrial publications cited by them were thoroughly reviewed to present a comprehensive overview of DT technology and to identify current research status, opportunities and challenges of DT deployment in the O&G industry. From this literature review, it was found that asset integrity monitoring, project planning, and life cycle management are the key application areas of digital twin in the O&G industry while cyber security, lack of standardization, and uncertainty in scope and focus are the key challenges of DT deployment in the O&G industry. When considering the geographical distribution for the DT related research in the O&G industry, the United States (US) is the leading country, followed by Norway, United Kingdom (UK), Canada, China, Italy, Netherland, Brazil, Germany, and Saudi Arabia. The overall publication rate was less than ten articles (approximately) per year until 2017, and a significant increase occurred in 2018 and 2019. The number of journal publications was noticeably lower than the number of conference publications, and the majority of the publications presented theoretical concepts rather than the industrial implementations. Both these observations suggest that the DT implementation in the O&G industry is still at an early stage.

Background: Alcohol use disorders have been categorized as a ‘strongly modifiable’ risk factor for dementia. Objective: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain. Methods: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels. Results: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ– subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant. Conclusion: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ– individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.

We have improved the THz output and damage threshold of yellow organic THz generation crystals by fusing them to sapphire and using liquid crystals as index matching fluid to reduce reflective losses.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects individuals from all life stages, genders, and races/ethnicities. Accurate assessment of ADHD across different populations is essential as undiagnosed ADHD is associated with numerous costly negative public health outcomes and is complicated by high comorbidity and developmental change in symptoms over time. Predictive analysis suggests that best-practice evidence-based assessment of ADHD should include both ADHD-specific and broadband rating scales from multiple informants with consideration of IQ, academic achievement, and executive function when there are concerns about learning. For children under age 12, parent and teacher ratings should be averaged. For adolescents and adults, informant reports should be prioritized when self- and other-report are inconsistent. Future research should provide more stringent evaluation of the sensitivity of measures to treatment response and developmental change over time as well as further validate measures on historically understudied populations (i.e., adults, women, and racial/ethnic minorities).

Background Valve surgery guidelines for infective endocarditis (IE) are unchanged over decades and nationwide data about the use of valve surgery do not exist. Methods We included patients with first-time IE (1999–2018) using Danish nationwide registries. Proportions of valve surgery were reported for calendar periods (1999–2003, 2004–2008, 2009–2013, 2014–2018). Comparing calendar periods in multivariable analyses, we computed likelihoods of valve surgery with logistic regression and rates of 30 day postoperative mortality with Cox regression. Results We included 8804 patients with first-time IE; 1981 (22.5%) underwent surgery during admission, decreasing by calendar periods (N = 360 [24.4%], N = 483 [24.0%], N = 553 [23.5%], N = 585 [19.7%], P = P ≤ 0.001) and the proportion of males increased from 67.8% to 72.6% (P = 0.008) from 1999–2003 to 2014–2018. Compared with 1999–2003, associated likelihoods of valve surgery were: Odds ratio (OR) = 1.14 (95% CI: 0.96–1.35), OR = 1.20 (95% CI: 1.02–1.42), and OR = 1.10 (95% CI: 0.93–1.29) in 2004–2008, 2009–2013, and 2014–2018, respectively. 30 day postoperative mortalities were: 12.7%, 12.8%, 6.9%, and 9.7% by calendar periods. Compared with 1999–2003, associated mortality rates were: Hazard ratio (HR) = 0.96 (95% CI: 0.65–1.41), HR = 0.43 (95% CI: 0.28–0.67), and HR = 0.55 (95% CI 0.37–0.83) in 2004–2008, 2009–2013, and 2014–2018, respectively. Conclusions On a nationwide scale, 22.5% of patients with IE underwent valve surgery. Patient characteristics changed considerably and use of valve surgery decreased over time. The adjusted likelihood of valve surgery was similar between calendar periods with a trend towards an increase while rates of 30 day postoperative mortality decreased.

Cervical intraepithelial neoplasia grade 2 (CIN 2) is an equivocal diagnosis with high interobserver variation. Owing to high regression rates of 50%, many countries recommend active surveillance of CIN 2, especially in women younger than age 25-30 years, where regression rates are even higher (ie, 60%). Additionally, excisional treatment is associated with increased risk of reproductive harm, particularly preterm birth. Active surveillance typically consists of semi-annual follow-up visits for up to 2 years, including colposcopy and either cytology, testing for human papillomavirus, or both. Excisional treatment is recommended for progression or persistent disease after 2 years. Because active surveillance in younger women is relatively new, knowledge on subsequent risk of cervical cancer is limited. Considering human papillomavirus latency, women undergoing active surveillance might be at higher risk of cervical cancer than women undergoing excisional treatment. Furthermore, there are limited data describing preferences of women for the management of CIN 2, and it is also unclear how active surveillance may affect planning for future pregnancy. In this context, biomarkers for risk stratification of CIN 2 into either high or low probability of progression would allow for targeted treatment. Currently, immunohistochemical staining for p16 is used to clarify the histologic diagnosis, but whether it or other biomarkers can be used for risk-stratification in clinical management of women with CIN 2 remains unknown. In conclusion, active surveillance of CIN 2 needs further investigation, including understanding the long-term cervical cancer risk and evaluation of markers that may enable risk stratification of CIN 2.

Cognitive decline follows pathological changes including neurodegeneration on the Alzheimer's disease continuum. However, it is unclear which cognitive domains first become affected by neurodegeneration in amyloid-positive individuals and if sex or apolipoprotein (Data from 1233 cognitively unimpaired, amyloid-positive individuals 65 to 85 years of age were studied to assess the effect of hippocampal volume (HV) on cognition and to evaluate differences due to sex andLower HV was linked with worse performance on measures of memory (free recall, total recall, logical memory delayed recall, Mini-Mental State Examination [MMSE]), executive functioning (digit symbol substitution, DSS), and the Preclinical Alzheimer's Cognitive Composite (PACC). Among both women andDespite all cognitive measures being associated with HV, cognitive tests show differences in detecting early or late signs of neurodegeneration. Differences exist in association between cognition and neurodegeneration based on sex and

Grazing dormant forage under low-input heifer development strategies typically exposes cattle to low-quality forage. Protein supplementation while grazing dormant range can enhance heifer growth and reproductive performance. We examined resource utilization of heifers and the effects of dormant season grazing on residual vegetation characteristics under two supplementation management strategies. Approximately 100 weaned composite heifer calves were randomly selected and placed into one of two supplementation treatments in each of 2 yr, one receiving a free access 62% crude protein self-fed concentrate and the other receiving a daily hand-fed 20% crude protein cake. Grazing occurred from December (2015 and 2016) through March (2016 and 2017). Thirty transects were randomly located within each pasture for measuring vegetation quality and structure before and after grazing. Daily space use and behavior was evaluated for 21 individuals within each treatment using global positioning system (GPS) collars and resource utilization functions. Heifers supplemented with concentrated protein spent more time grazing per day than heifers supplemented with cake (6.92 ± 0.18, 6.24 ± 0.17 h). Relative use by heifers in the cake treatment was negatively related to horizontal distance from the supplement delivery site early to midwinter ( β ¯ ˆ = − 0.41 ± 0.16, − 0.53 ± 0.17). Both treatments selected grazing locations relative to standing biomass of perennial grasses ( β ¯ ˆ = 0.0005 ± 0.00004) and crude protein ( β ¯ ˆ = 0.12 ± 0.007). However, resource selection was highly variable among individuals for both supplementation treatments. We found no treatment effects on pre-post grazing differences in residual cover of litter, grass, forbs and shrubs (P > 0.24). However, the time period when grazing occurred had an effect on residual vegetation conditions (P

Proceedings of the National Academy of Sciences of the United States of America 116(7), 2551 - 2560 (2019). doi:10.1073/pnas.1812963116, Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS$^{G12C}$–SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS–SOS1 interaction with an IC$_{50}$ of 21 nM and is a valuable chemical probe for future investigations., Published by National Acad. of Sciences, Washington, DC

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.