The coexistence of diabetic retinopathy and diabetic nephropathy is associated with worse kidney outcomes.

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses. Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P = .001]. Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD.

Indications of Induction and Caesarean Sections Performed Using the Robson Classification in a University Hospital in Spain from 2010 to 2021.

Background: The Robson Ten Group Classification System (RTGCS) enables the assessment, monitoring, and comparison of caesarean section rates both within healthcare facilities and between them, and the indications of caesarean sections (CS) performed in a maternity ward. The aims of the present study were to conduct an analysis to assess the levels and distribution of birth from a descriptive approach by CS in La Ribera University Hospital (Spain) between 2010-2021 using the Robson classification; to describe the indications for the induction of labour and the causes of caesarean sections performed; and to examine the association between the induction of labour and CS birth. Methods: A retrospective study between 1 January 2010 and 31 December 2021. All eligible women were classified according to the RTGCS to determine the absolute and relative contribution by each group to the overall CS rate. The odds ratio (OR) of the variables of interest was estimated by logistic regression. In an analysis of the subgroups, the level of significance was adjusted using the Bonferroni method. Results: 20,578 women gave birth during the study period, 19% of them by CS. In 33% of births, induction was performed, and the most common cause was the premature rupture of membranes. Group 2 (nulliparous with induced labour/elective CS before labour) accounted for the largest contribution to the overall rate of CS (31.5%) and showed an upward trend from 23.2% to 39.7% in the time series, increasing the CS rate by 6.7%. The leading cause of CS was suspected fetal distress, followed by induction failure. Conclusions: In our study, Robson Group 2 was identified as the main contributor to the hospital's overall CS rate. Determining the causes of induction and CS in a population sample classified using the RTGCS enables the identification of the groups with the greatest deviation from the optimal rate of CS and the establishment of improvement plans to reduce the overall rate of caesarean sections in the maternity unit.

Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

Evaluating the impact of plain packaging among Canadian smokers: findings from the 2018 and 2020 ITC Smoking and Vaping Surveys.

BACKGROUND: In February 2020, Canada implemented plain packaging without any changes to the size and content of health warning labels (HWLs), which were last updated in 2012 (pictorial HWLs on 75% of the pack front and back). This pre-post evaluation study assessed the impact of plain packaging in Canada on: (1) pack appeal; (2) HWL effectiveness; and (3) support for plain packaging. Additionally, a quasi-experimental design was used to assess the Canadian results relative to two comparator countries: Australia, where plain packaging (with new larger HWLs) was implemented in 2012, and the United States (USA), where plain packaging has not been implemented and the same text warnings have appeared on cigarette packs since 1985. METHODS: Data are from adult smokers who participated in the 2018 and/or 2020 International Tobacco Control Smoking and Vaping Surveys in Canada (n=4600), Australia (n=1834) and the USA (n=3046). Online surveys were conducted before (February to July 2018) and after (February to June 2020) the implementation of plain packaging in Canada. Adjusted regression analyses were conducted on weighted data. RESULTS: Plain packaging was associated with a significant increase in the percentage of Canadian smokers who did not like the look of their cigarette pack (2018: 28.6% vs 2020: 44.7%, p<0.001), whereas no change in pack appeal was observed among smokers in Australia and the USA over the same period. Plain packaging was not associated with changes in HWL effectiveness in Canada. Support for plain packaging increased significantly among Canadian smokers (2018: 25.6% vs 2020: 33.7%, p<0.001). CONCLUSIONS: Plain packaging in Canada substantially reduced pack appeal and increased support for the policy among adult smokers; however, there was no increase in the effectiveness of Canada's 8-year-old HWLs. The impact of plain packaging on health warning effectiveness may depend on the design of the warnings and length of time since implementation.

Cell-based receptor discovery identifies host factors specifically targeted by the SARS CoV-2 spike.

Receptor-ligand interactions on the plasma membrane regulate cellular communication and play a key role in viral infection. Despite representing main targets for drug development, the characterization of these interactions remains challenging in part due to the dearth of optimal technologies. Here, we build a comprehensive library of human proteins engineered for controlled cell surface expression. Coupled to tetramer-based screening for increased binding avidity, we develop a high throughput cell-based platform that enables systematic interrogation of receptor-ligand interactomes. Using this technology, we characterize the cell surface proteins targeted by the receptor binding domain (RBD) of the SARS-CoV spike protein. Host factors that specifically bind to SARS CoV-2 but not SARS CoV RBD are identified, including proteins that are expressed in the nervous system or olfactory epithelium. Remarkably, our results show that Contactin-1, a previously unknown SARS CoV-2 spike-specific receptor that is upregulated in COVID-19 patients, significantly enhances ACE2-dependent pseudotyped virus infection. Starting from a versatile platform to characterize cell surface interactomes, this study uncovers host factors specifically targeted by SARS CoV-2, information that may help design improved therapeutic strategies against COVID-19.

Receptor Interactome Discovery with RDIMIS, a Membrane Protein Interaction Screen Using Recombinant Extracellular Vesicles.

Membrane protein interactions are challenging to identify because of the unique biophysical characteristics of both transmembrane proteins and membrane environments. The Receptor Display in Membranes Interaction Screen (RDIMIS) platform overcomes these challenges by screening transmembrane and membrane-proximal proteins in a membrane environment using recombinant extracellular vesicles (rEVs). The screen has been used to successfully identify interactions for difficult-to-study receptors in an unbiased manner. In this report, we detail how we generate rEVs, characterize the rEVs to ensure screen-readiness, and perform the full interaction screening, with emphasis on the criteria necessary to obtain clear, interpretable results. We also include support protocols for generating a screening library and validating screening results, as well as an alternate protocol for RDIMIS enabling the profiling of naturally occurring extracellular vesicles. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Generating and isolating extracellular vesicles from cells Basic Protocol 2: Characterizing recombinant extracellular vesicles Support Protocol 1: Preparing the receptor screening library Basic Protocol 3: Performing the Receptor Display in Membranes Interaction Screen (RDIMIS) Support Protocol 2: Validating RDIMIS results using microscopy Alternate Protocol: Detecting unlabeled endogenous vesicles.

Differences in cigarette smoking quit attempts and cessation between adults who did and did not take up nicotine vaping: Findings from the ITC four country smoking and vaping surveys.

INTRODUCTION: There is mixed evidence as to whether nicotine vaping products (NVPs) can help adults who smoke transition away from cigarettes. This study investigated if self-reported attempts to quit smoking and smoking cessation, over a period of either 18 or 24 months, differed between respondents who initiated nicotine vaping versus those who did not. Outcome comparisons were made between those who: (1) initiated vaping vs. those who did not; (2) initiated daily or non-daily vaping vs. those who did not; and (3) initiated daily or non-daily vaping between surveys and continued to vape at follow-up (daily or non-daily) vs. those who did not initiate vaping. METHODS: This cohort study included 3516 respondents from the ITC Four Country Smoking and Vaping Surveys (Australia, Canada, England, United Sates), recruited at Wave 1 (2016) or 2 (2018) and followed up at Wave 2 (18 months) and/or 3 (2020, 24 months). Adults who smoked daily at baseline and did not have a history of regular vaping were included. Initiation of vaping was defined as beginning to vape at least monthly between surveys. Respondents indicated whether they made an attempt to quit smoking between surveys. Smoking cessation was defined as those who self-reported no longer smoking cigarettes at follow-up. RESULTS: Relative to those who did not initiate vaping, initiation of any daily vaping between surveys was associated with a greater likelihood of smokers making a cigarette quit attempt (p < 0.001) and quitting smoking (p < 0.001). Among smokers who attempted to quit smoking, initiation of daily vaping was associated with a greater likelihood of being abstinent from smoking at follow-up (p = 0.001). Respondents who initiated vaping between surveys and were vaping daily at follow up were significantly more likely to have attempted to quit smoking (p < 0.001) and to have quit smoking (p < 0.001) than those who did not initiate vaping. Respondents who initiated non-daily vaping did not differ significantly from those who did not initiate vaping on any of the outcome measures. CONCLUSIONS: Daily NVP use was associated with increased attempts to quit smoking and abstinence from smoking cigarettes. These findings are consistent with the concept that complete cigarette substitution may be more likely to be achieved when smokers vape nicotine daily.

Structural basis for HCMV Pentamer receptor recognition and antibody neutralization.

Human cytomegalovirus (HCMV) represents the viral leading cause of congenital birth defects and uses the gH/gL/UL128-130-131A complex (Pentamer) to enter different cell types, including epithelial and endothelial cells. Upon infection, Pentamer elicits the most potent neutralizing response against HCMV, representing a key vaccine candidate. Despite its relevance, the structural basis for Pentamer receptor recognition and antibody neutralization is largely unknown. Here, we determine the structures of Pentamer bound to neuropilin 2 (NRP2) and a set of potent neutralizing antibodies against HCMV. Moreover, we identify thrombomodulin (THBD) as a functional HCMV receptor and determine the structures of the Pentamer-THBD complex. Unexpectedly, both NRP2 and THBD also promote dimerization of Pentamer. Our results provide a framework for understanding HCMV receptor engagement, cell entry, antibody neutralization, and outline strategies for antiviral therapies against HCMV.

CHAOS: síndrome de obstrucción congénita de las vías aéreas superiores / CHAOS: congenital high airway obstruction syndrome

Resumen El síndrome de obstrucción congénita de vías áreas superiores (CHAOS) es una condición que se caracteriza por la existencia de una obstrucción en las vías áreas altas en el feto, la cual puede ser parcial o completa. Comúnmente es una situación incompatible con la vida, por lo que su diagnóstico prenatal es importante considerando el pronóstico y los diferentes manejos prenatales y posnatales que existen. Presentamos un caso de CHAOS diagnosticado en la semana 21, con una breve revisión de la literatura sobre su diagnóstico, pronóstico y alternativas terapéuticas.

Abstract Congenital high airway obstruction syndrome (CHAOS) is a condition characterized by the existence of an obstruction of the fetal upper airways, which may be partial or complete. It is commonly incompatible with life, so its prenatal diagnosis is important due to the prognosis and the recently described pre and postnatal management options. We present a case of CHAOS in a pregnancy of 21 weeks with a brief review of the current literature about its diagnosis, prognosis and therapeutic alternatives.

Responses to potential nicotine vaping product flavor restrictions among regular vapers using non-tobacco flavors: Findings from the 2020 ITC Smoking and Vaping Survey in Canada, England and the United States.

INTRODUCTION: Some jurisdictions have implemented nicotine vaping product (NVP) flavor restrictions because of concerns about rising adolescent use. However, little is known how these restrictions may impact adult vapers. This study describes the level of support and predictive behavioral responses to a hypothetical NVP ban on non-tobacco flavors among regular adult vapers who only use flavors that would be banned. METHODS: Data came from 851 regular vapers (all current or ex-smokers) participating in the 2020 ITC Four Country Smoking and Vaping Survey in Canada, England, and the United States (US). A random sample of respondents in each country received and completed the questions about flavor bans: (1) do you support or oppose a ban on all non-tobacco flavors; and (2) what would you do if all flavors were banned, with the exception of tobacco in the US, and tobacco and menthol in Canada and England. Those who used tobacco-flavored or unflavored NVPs were excluded from all analyses, and additionally, vapers of menthol flavor in Canada and England were excluded from Aim 2. RESULTS: Overall, 53.6% of vapers were strongly opposed to flavor bans, 28.2% were opposed, 9.3% were in support, 3.6% were in strong support, and 5.2% did not know. Predicted behavioral responses were: 28.8% would continue vaping an available flavor, 28.3% would find a way to get their banned flavor(s), 17.1% would stop vaping and smoke instead, 12.9% said that they would stop vaping and not smoke, and 12.9% do not know what they would do. Responses to a potential flavor ban largely varied by smoking and vaping status, and by the level of support of a flavor restriction policy. CONCLUSIONS: At this time, it is not clear what net population-level consequences would occur if non-tobacco flavored NVPs were prohibited. While a majority of vapers in this study opposed this policy, and many vapers would not be willing to switch to available flavors, there was considerable variability in predicted behavioral responses.

The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology.

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.

A membrane protein display platform for receptor interactome discovery.

Cell surface receptors are critical for cell signaling and constitute a quarter of all human genes. Despite their importance and abundance, receptor interaction networks remain understudied because of difficulties associated with maintaining membrane proteins in their native conformation and their typically weak interactions. To overcome these challenges, we developed an extracellular vesicle-based method for membrane protein display that enables purification-free and high-throughput detection of receptor-ligand interactions in membranes. We demonstrate that this platform is broadly applicable to a variety of membrane proteins, enabling enhanced detection of extracellular interactions over a wide range of binding affinities. We were able to recapitulate and expand the interactome for prominent members of the B7 family of immunoregulatory proteins such as PD-L1/CD274 and B7-H3/CD276. Moreover, when applied to the orphan cancer-associated fibroblast protein, LRRC15, we identified a membrane-dependent interaction with the tumor stroma marker TEM1/CD248. Furthermore, this platform enabled profiling of cellular receptors for target-expressing as well as endogenous extracellular vesicles. Overall, this study presents a sensitive and easy to use screening platform that bypasses membrane protein purification and enables characterization of interactomes for any cell surface-expressed target of interest in its native state.

Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1.

Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.

Smokers' cognitive and behavioural reactions during the early phase of the COVID-19 pandemic: Findings from the 2020 ITC Four Country Smoking and Vaping Survey.

INTRODUCTION: COVID-19 is primarily a respiratory illness, and smoking adversely impacts the respiratory and immune systems; this confluence may therefore incentivize smokers to quit. The present study, conducted in four high-income countries during the first global wave of COVID-19, examined the association between COVID-19 and: (1) thoughts about quitting smoking; (2) changes in smoking (quit attempt, reduced or increased smoking, or no change); and (3) factors related to a positive change (making a quit attempt or reducing smoking) based on an adapted framework of the Health Belief Model. METHODS: This cross-sectional study included 6870 adult smokers participating in the Wave 3 (2020) ITC Four Country Smoking and Vaping Survey conducted in Australia, Canada, England, and United States (US). These four countries had varying responses to the pandemic by governments and public health, ranging from advising voluntary social distancing to implementing national and subnational staged lockdowns. Considering these varying responses, and the differences in the number of confirmed cases and deaths (greatest in England and the US and lowest in Australia), smoking behaviours related to COVID-19 may have differed between countries. Other factors that may be related to changes in smoking because of COVID-19 were also explored (e.g., sociodemographics, nicotine dependence, perceptions about personal and general risks of smoking on COVID-19). Regression analyses were conducted on weighted data. RESULTS: Overall, 46.7% of smokers reported thinking about quitting because of COVID-19, which differed by country (p<0.001): England highest (50.9%) and Australia lowest (37.6%). Thinking about quitting smoking because of COVID-19 was more frequent among: females, ethnic minorities, those with financial stress, current vapers, less dependent smokers (non-daily and fewer cigarettes smoked/day), those with greater concern about personal susceptibility of infection, and those who believe COVID-19 is more severe for smokers. Smoking behaviour changes due to COVID-19 were: 1.1% attempted to quit, 14.2% reduced smoking, and 14.6% increased smoking (70.2% reported no change). Positive behaviour change (tried to quit/reduced smoking) was reported by 15.5% of smokers, which differed by country (p = 0.02), where Australia had significantly lower rates than the other three countries. A positive behavioural smoking change was more likely among smokers with: lower dependence, greater concern about personal susceptibility to infection, and believing that COVID-19 is more severe for smokers. CONCLUSIONS: Though nearly half of smokers reported thinking about quitting because of COVID-19, the vast majority did not change their smoking behaviour. Smokers were more likely to try and quit or reduce their smoking if they had greater concern about susceptibility and severity of COVID-19 related to smoking. Smokers in Australia were least likely to reduce or try to quit smoking, which could be related to the significantly lower impact of COVID-19 during the early phase of the pandemic relative to the other countries.

Self-Reported Quit Aids and Assistance Used By Smokers At Their Most Recent Quit Attempt: Findings from the 2020 International Tobacco Control Four Country Smoking and Vaping Survey.

INTRODUCTION: This study retrospectively describes smoking cessation aids, cessation services, and other types of assistance used by current and ex-smokers at their last quit attempt in four high-income countries. AIMS AND METHODS: Data are from the Wave 3 (2020) International Tobacco Control Four Country Smoking and Vaping Survey in Australia, Canada, England, and the United States (US). Eligible respondents were daily smokers or past-daily recent ex-smokers who made a quit attempt/quit smoking in the last 24-months, resulting in 3614 respondents. Self-reported quit aids/assistance included: nicotine vaping products (NVPs), nicotine replacement therapy (NRT), other pharmacological therapies (OPT: varenicline/bupropion/cytisine), tobacco (noncombustible: heated tobacco product/smokeless tobacco), cessation services (quitline/counseling/doctor), other cessation support (e.g., mobile apps/website/pamphlets, etc.), or no aid. RESULTS: Among all respondents, at last quit attempt, 28.8% used NRT, 28.0% used an NVP, 12.0% used OPT, 7.8% used a cessation service, 1.7% used a tobacco product, 16.5% other cessation support, and 38.6% used no aid/assistance. Slightly more than half of all smokers and ex-smokers (57.2%) reported using any type of pharmacotherapy (NRT or OPT) and/or an NVP, half-used NRT and/or an NVP (49.9%), and 38.4% used any type of pharmacotherapy (NRT and/or OPT). A quarter of smokers/ex-smokers used a combination of aids. NVPs and NRT were the most prevalent types of cessation aids used in all four countries; however, NRT was more commonly used in Australia relative to NVPs, and in England, NVPs were more commonly used than NRT. The use of NVPs or NRT was more evenly distributed in Canada and the US. CONCLUSIONS: It appears that many smokers are still trying to quit unassisted, rather than utilizing cessation aids or other forms of assistance. Of those who did use assistance, NRT and NVPs were the most common method, which appears to suggest that nicotine substitution is important for smokers when trying to quit smoking. IMPLICATIONS: Clinical practice guidelines in a number of countries state that the most effective smoking cessation method is a combination of pharmacotherapy and face-to-face behavioral support by a health professional. Most quit attempts however are made unassisted, particularly without the use of government-approved cessation medications. This study found that about two in five daily smokers used approved cessation medications (nicotine replacement therapy (NRT) or other approved pharmacotherapies, such as varenicline). Notably, nicotine substitution in the form of either NRT and nicotine vaping products (NVPs) were the most common method of cessation assistance (used by one in two respondents), but the proportion using NRT and/or NVPs varied by country. Few smokers who attempted to quit utilized cessation services such as stop-smoking programs/counseling or quitlines, despite that these types of support are effective in helping smokers manage withdrawals and cravings. Primary healthcare professionals should ask their patients about smoking and offer them evidence-based treatment, as well as be prepared to provide smokers with a referral to trained cessation counselors, particularly when it comes to tailoring intensive treatment programs for regular daily smokers. Additionally, healthcare providers should be prepared to discuss the use of NVPs, particularly if smokers are seeking advice about NVPs, wanting to try/or already using an NVP to quit smoking, have failed repeatedly to quit with other cessation methods, and/or if they do not want to give up tobacco/nicotine use completely.

Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit.

Dysfunction of embryo transport causes ectopic pregnancy which affects approximately 2% of conceptions in the US and Europe, and is the most common cause of pregnancy-related death in the first trimester. Embryo transit involves a valve-like tubal-locking phenomenon that temporarily arrests oocytes at the ampullary-isthmic junction (AIJ) where fertilisation occurs, but the mechanisms involved are unknown. Here we show that female mice lacking the orphan adhesion G-protein coupled receptor Adgrd1 are sterile because they do not relieve the AIJ restraining mechanism, inappropriately retaining embryos within the oviduct. Adgrd1 is expressed on the oviductal epithelium and the post-ovulatory attenuation of tubal fluid flow is dysregulated in Adgrd1-deficient mice. Using a large-scale extracellular protein interaction screen, we identified Plxdc2 as an activating ligand for Adgrd1 displayed on cumulus cells. Our findings demonstrate that regulating oviductal fluid flow by Adgrd1 controls embryo transit and we present a model where embryo arrest at the AIJ is due to the balance of abovarial ciliary action and the force of adovarial tubal fluid flow, and in wild-type oviducts, fluid flow is gradually attenuated through Adgrd1 activation to enable embryo release. Our findings provide important insights into the molecular mechanisms involved in embryo transport in mice.

Structures of HCMV Trimer reveal the basis for receptor recognition and cell entry.

Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind to platelet-derived growth factor receptor alpha (PDGFRα) and transforming growth factor beta receptor 3 (TGFßR3) to gain entry into multiple cell types. This complex is targeted by potent neutralizing antibodies and represents an important candidate for therapeutics against HCMV. Here, we determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFßR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFßR3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFRα interaction has an inhibitory effect on PDGFRα signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.

Changes in Smoking and Vaping over 18 Months among Smokers and Recent Ex-Smokers: Longitudinal Findings from the 2016 and 2018 ITC Four Country Smoking and Vaping Surveys.

This descriptive study of smokers (smoked at least monthly) and recent ex-smokers (quit for ≤2 years) examined transitions over an 18 month period in their smoking and vaping behaviors. Data are from Waves 1 (W1: 2016) and 2 (W2: 2018) of the ITC Four Country Smoking and Vaping Survey, a cohort study of adult (≥18+) smokers, concurrent users (smoke and vape), and recent ex-smokers from Australia, Canada, England, and the United States (US). Respondents (N = 5016) were classified according to their smoking and vaping status, which resulted in eight subgroups: (1) exclusive daily smokers (2) exclusive non-daily smokers; (3-6) concurrent users (subdivided into four groups by each combination of daily/non-daily smoking and daily/non-daily vaping); (7) ex-smokers who vape; (8) ex-smokers not vaping. The analyses focused first on describing changes between groups from W1 to W2. Second, transition outcomes were assessed based on changes in smoking and vaping between W1 and W2. Transitions focused on smoking were: no change in smoking (continued smoking at the same frequency); decreased smoking; increased smoking; discontinued smoking; relapsed (ex-smokers at W1 who were smoking at W2). Transitions focused on vaping were: initiated vaping; switched from smoking to vaping. Overall, this study found that the vast majority of smokers were smoking 18 months later. Non-daily smokers were more likely than daily smokers to have discontinued smoking (p < 0.0001) and to have switched to exclusive vaping (p = 0.034). Exclusive non-daily smokers were more likely than exclusive daily smokers to have initiated vaping (p = 0.04). Among all W1 daily smokers, there were no differences in discontinued smoking between daily smokers who vaped (concurrent users) and exclusive daily smokers; however, concurrent users were more likely than exclusive daily smokers to have decreased to non-daily smoking (p < 0.001) or to have switched to vaping by W2 (p < 0.001). Among all W1 non-daily smokers, there were no significant differences in increased smoking or discontinued smoking between concurrent users or exclusive smokers. Most ex-smokers remained abstinent from smoking, and there was no difference in relapse back to smoking between those who vaped and those who did not.

Risk factors for non-diabetic renal disease in diabetic patients.

BACKGROUND: Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal biopsy findings in patients with diabetes. METHODS: Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to 2014. RESULTS: In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 ± 12.8 years, creatinine was 2.8 ± 2.2 mg/dL and proteinuria 2.7 (interquartile range: 1.2-5.4) g/24 h. About 39.5% (n = 329) of patients had DN, 49.6% (n = 413) NDRD and 10.8% (n = 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n = 87, 9.3%). In the multivariate logistic regression analysis, older age [odds ratio (OR) = 1.03, 95% CI: 1.02-1.05, P < 0.001], microhaematuria (OR = 1.51, 95% CI: 1.03-2.21, P = 0.033) and absence of diabetic retinopathy (DR) (OR = 0.28, 95% CI: 0.19-0.42, P < 0.001) were independently associated with NDRD. Kaplan-Meier analysis showed that patients with DN or mixed forms presented worse renal prognosis than NDRD (P < 0.001) and higher mortality (P = 0.029). In multivariate Cox analyses, older age (P < 0.001), higher serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P = 0.007) and DN (P < 0.001) were independent risk factors for renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P = 0.002), higher creatinine (P = 0.01) and DN (P = 0.015) were independent risk factors for mortality. CONCLUSIONS: The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD. These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and subsequently treatment and prognosis.

The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Clinical Outcome.

Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays. Our study reveals a map of cell-type-specific interactions and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss of function for tumor-associated mutations. Furthermore, investigation of the IgSF interactome in a large cohort of cancer patients identifies interacting protein signatures associated with clinical outcome. The IgSF interactome represents an important resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.