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BACKGROUND Exception from informed consent (EFIC) enables the enrollment of research subjects with emergent conditions to clinical trials without prior consent. EFIC study approval requires community consultation and public disclosure. We hypothesized that the integration of social media with targeted emails and in-person outreach is an effective community consultation strategy. METHODS We utilized social media with targeted emails and in-person outreach for the community consultation of the ACCESS cardiac arrest trial. Study advertisements were disseminated using Facebook and Instagram, and targeted emails were sent to emergency medicine, prehospital, and cardiology providers. We also interviewed at-risk individuals with cardiac conditions, their caretakers, and patient advocacy groups. Participants were asked to complete a survey about their opinions about the study. RESULTS We collected 559 surveys over an 8-week period, and 70.5% of the surveys were obtained using social media. The median (IQR) age of survey respondents was 44 (33-57) years; 89.9% were White and 60.1% were women. A total of 91.3% believed ACCESS was an important study. Compared to the in-person group, more from social media (81.8% vs. 63.3%, p

OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N = 1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia–2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes—including psychotropics used in usual care—should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

Few African American men graduating from medical school find a home as a provider in obstetrics and gynecology. This is a story of mentorship at every level of the medical pipeline and should serve as a primer on how to help future leaders from diverse backgrounds.

Sara is a siphovirus with a linear 17,362bp genome containing 25 genes. Birdfeeder is a podovirus with a circularly permuted 53,897bp genome containing 52 genes. Sara and Birdfeeder were isolated from environmental samples in Plattsburgh, NY, USA and Forest Hill, MD, USA, respectively, using Microbacterium foliorum NRRL B-24224.

Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.

Cathepsin S (CatS) and proteinase-activated receptor (PAR)-2 are involved in the remodelling of vascular walls and neointima formation as well as in alloantigen presentation and T-cell priming. Therefore, we hypothesized that CatS/PAR-2 inhibition/deficiency would attenuate chronic allograft vasculopathy.Heterotopic aortic murine transplantation was performed from C57BL/6 J donors to C57BL/6 J recipients (syngeneic control group), Balb/c to C57BL/6 J without treatment (allogenic control group), Balb/c to C57BL/6 J with twice daily oral CatS inhibitor (allogenic treatment group) and Balb/c to Par2-/- C57BL/6 J (allogenic knockout group). The recipients were sacrificed on day 28 and the grafts were harvested for histological analysis and RT-qPCR.After 28 days, mice of the allogenic control group exhibited significant neointima formation and massive CD8 T-cell infiltration into the neointima while the syngeneic control group showed negligible allograft vasculopathy. The mRNA expression level of CatS in allografts was 5-fold of those in syngeneic grafts. Neointima formation and therefore intima/media-ratio were significantly decreased in the treatment and knockout group in comparison to the allogenic control group. Mice in treatment group also displayed significantly fewer CD8 T cells in the neointima compared with allogeneic controls. Additionally, treatment with the CatS inhibitor and PAR2-deficiency decreased mRNA-levels of interleukins and cytokines.In conclusion, our data indicate that inhibiting CatS and PAR-2 deficiency led to a marked reduction of neointima formation and associated inflammation in a murine heterotopic model for allograft vasculopathy.

Period life expectancy is defined as the average number of additional years someone of a given age would live if current age-specific mortality rates were to stay the same for the remainder of their life. It is one of the world's most widely used population health metrics to summarize, compare and rank the mortality situation of countries, forming the basis for various public health, life insurance and retirement policies (Luy et al., 2020). This is because a country's life expectancy reflects, among other things, its existing socio-economic conditions and the quality of its public health and healthcare infrastructure (Ho & Hendi, 2018). Although immigration and emigration events are routinely factored into estimates of life expectancy, the potential impact of the unique – and typically low mortality – of international migrants (Aldridge et al., 2018; Shor & Roelfs, 2021) on national life expectancy has received little attention. A handful of studies have so far been limited to Australia (Page et al., 2007) and the United States (US) (Hendi & Ho, 2021; Mehta et al., 2016; Preston & Elo, 2014). In the context of rising shares of migrants in many countries (United Nations, 2019), alongside their “ageing in place” (Ciobanu et al., 2017), the extent to which the mortality of international migrants affects national population health demands attention.Here, we aim to understand whether and how the mortality of international migrants affect the estimation and comparison of national life expectancy in four Nordic countries. Denmark, Finland, Norway and Sweden are all high-income countries in the latest stage of health transition. They have a long tradition of collaboration with shared features of social policy and universal welfare (Knudsen et al., 2019). Despite this, health inequality gaps remain large in the region relative to countries with less developed welfare systems (Mackenbach et al., 2016). International migration has been the major driving force behind population growth in the Nordic region in the past few decades. All four countries have experienced large increases in their absolute and relative numbers of migrants, alongside a transformation in migrant inflows from principally intra-Nordic flows to flows from all over the world (Karlsdottir et al., 2018). In recent years, life expectancy gains have slowed within the region; national life expectancies have also converged, although men and women in Denmark and men in Finland continue to lag some way behind Norway and Sweden (Knudsen et al., 2019).

Background: Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. Methods and Results: We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Conclusions: Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.

As COVID-19 vaccination becomes widely available and administered globally, there have been several reports of side effects attributed to the vaccine. This report highlights a patient who developed stroke 2 days following the administration of the COVID-19 vaccine, although its association remains uncertain. A man in his late 30s developed acute neurological symptoms 2 days after receiving the booster dose of the BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine. History and neurological examination suggested a posterior circulation stroke, which was confirmed by MRI, as a right-sided posterior inferior cerebellar artery stroke. Full workup did not suggest other causes of the stroke. Due to the patient’s age and well-controlled risk factors, it was presumed to be a rare adverse effect of the vaccine. Medical management with aspirin, statin therapy and rehabilitation led to the improvement of symptoms and enabled ongoing restoration of function. Further cases of stroke following administration of COVID-19 vaccine have been documented in the literature, but the association is yet to be established.

The rapidly expanding literature on the related subjects of geodiversity, geosites and their place in understanding and conserving our geoheritage has produced several proposed protocols for defining and valuing key sites and landscapes. Distinctions between geosites as well-defined features of our geological heritage and geodiversity sites as landscapes or geomorphosites have been proposed, while many subdivisions of the criteria for geosite recognition are also recognised. This paper uses two areas in central Africa to illustrate the realities of many landscapes, termed geosystems in this study. Largely Quaternary and present-day dynamic geosystems are considered as essential components of geodiversity and equally aspects of our geoheritage. To understand these geosystems requires detailed fieldwork including their relationships to ecology, rural land use and sensitivity to environmental change.

Loneliness is associated with increased morbidity and mortality. Deeper understanding of neurobiological mechanisms underlying loneliness is needed to identify potential intervention targets. We did not find any systematic review of neurobiology of loneliness. Using MEDLINE and PsycINFO online databases, we conducted a search for peer-reviewed publications examining loneliness and neurobiology. We identified 41 studies (n = 16,771 participants) that had employed various methods including computer tomography (CT), structural magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and post-mortem brain tissue RNA analysis or pathological analysis. Our synthesis of the published findings shows abnormal structure (gray matter volume or white matter integrity) and/or activity (response to pleasant versus stressful images in social versus nonsocial contexts) in the prefrontal cortex (especially medial and dorsolateral), insula (particularly anterior), amygdala, hippocampus, and posterior superior temporal cortex. The findings related to ventral striatum and cerebellum were mixed. fMRI studies reported links between loneliness and differential activation of attentional networks, visual networks, and default mode network. Loneliness was also related to biological markers associated with Alzheimer's disease (e.g., amyloid and tau burden). Although the published investigations have limitations, this review suggests relationships of loneliness with altered structure and function in specific brain regions and networks. We found a notable overlap in the regions involved in loneliness and compassion, the two personality traits that are inversely correlated in previous studies. We have offered recommendations for future research studies of neurobiology of loneliness.

Introduction The two week wait (2ww) colorectal referral pathway was introduced to expedite referrals where cancer is suspected, facilitating prompt diagnosis +/− intervention. Older frail patients are referred via this 2ww pathway even when invasive testing and intervention may not be appropriate. These patients may benefit more from holistic assessment than a universally surgical approach. A Colorectal and Geriatric Medicine (CGM) 2ww referral clinic was piloted, delivered by an urgent referral colorectal specialist nurse and an advanced clinical practitioner in geriatric medicine. Method Patients >65 years with a Clinical Frailty Scale (CFS) score of 5 or more at referral were directed to the CGM clinic. A telephone consultation was undertaken, incorporating both 2ww assessment and aspects of comprehensive geriatric assessment. Results 42-patients were reviewed in the clinic. Mean age was 86.1 years and mean CFS 6. 12-patients underwent CT, and 2 CT virtual colonoscopy. No patients underwent endoscopic investigation and 28-patients declined any investigation. Of those who underwent investigation, no cancers were identified. 1 patient was referred on for endosocpic mucosal resection of polyps. 5-patients had severe diverticular disease, which accounted for their symptoms. Medication recommendations were made for 30-patients, some of which led to symptom cessation. Onward referrals were made to a community geriatrician, diabetes and continence teams, and palliative care specialists. 9-patients were identified as meeting criteria for advance care planning. This was commenced during the consultation and communicated back to the referring clinician for further action. Conclusion Older, frail patients are often not able, nor wish to undergo, invasive investigations but should not be disadvantaged or delayed in their pathway. Further work is needed to determine the most appropriate referral pathway for this group of patients. Holistic assessment that leads to improvement in symptoms and future planning may not be achievable through a solely surgical assessment.

Introduction The prevalence and complications of biliary disease increase with age. We describe the prevalence of frailty in older patients hospitalised with benign biliary and pancreatic disease and establish its association with mortality and duration of hospital stay. Methods Prospective observational cohort study of patients aged 75 years and over admitted with a diagnosis of acute biliary disease to a surgical hospital unit between 17/09/2014 and 20/03/2017. Clinical Frailty Scale (CFS) score was recorded on admission. Results We included 200 patients with a median age of 82 (75–99), 60% females, 89% lived in their homes, 154 (77%) were independent for personal and 99 (49.5%) for instrumental ADLs, 95% mobilised independently, 17.5% had memory impairment and 8% low mood. Acute cholecystitis was the most common diagnosis (43%) followed by acute cholangitis (36%) and acute pancreatitis (21%). 99 patients were non-frail (NF = CFS 1–4) and 101 were frail (F = CFS ≥5). 104 patients received medical treatment only. Surgery was more common in non-frail (F 2% vs. NF 11%), percutaneous drainage more frequently carried out in frail patients (15% vs. NF 5%) and endoscopic cholangiopancreatography (ERCP) was similar in both groups (F 32%vs. NF 31%). Frailty was associated with worse clinical outcomes in F vs. NF: functional deconditioning (34% vs. 11%), increased care level (19% vs 3%), length of stay (12 vs. 7 days), 90-day (8% vs. 3%) and 1 year-mortality (48% vs. 24%). Conclusion Half of patients in our cohort of older adults hospitalised with acute biliary disease were frail. Higher scores of frailty are associated with increased mortality. Compared with non-frail patients, individuals living with frailty were less likely to undergo surgical treatment, spent longer in hospital and were less likely to remain alive at 12 months after hospital discharge.

The multidimensional structure of spatial ability remains a debated issue. However, the developmental trajectories of spatial skills have yet to be investigated as a source of evidence within this debate. We tested the intrinsic versus extrinsic and static versus dynamic dimensions of the Uttal et al. (2013, Psychol. Bull., 139, 352) typology in relation to spatial development. Participants (N = 184) aged 6-11 completed spatial tasks chosen to measure these spatial dimensions. The results indicated that the developmental trajectories of intrinsic versus extrinsic skills differed significantly. Intrinsic skills improved more between 6 and 8 years, and 7 and 8 years, than extrinsic skills. Extrinsic skills increased more between 8 and 10 years than intrinsic skills. The trajectories of static versus dynamic skills did not differ significantly. The findings support the intrinsic versus extrinsic, but not the static versus dynamic dimension, of the Uttal et al. (2013, Psychol. Bull., 139, 352) typology.

Objectives:Wisdom is a personality trait comprising seven components: self-reflection, pro-social behaviors, emotional regulation, acceptance of diverse perspectives, decisiveness, social advising, and spirituality. Wisdom, a potentially modifiable trait, is strongly associated with well-being. We have published a validated 28-item San Diego Wisdom Scale, the SD-WISE-28. Brief scales are necessary for use in large population-based studies and in clinical practice. The present study aimed to create an abbreviated 7-item version of the SD-WISE.Method:Participants included 2093 people, aged 20-82 years, recruited and surveyed through the online crowdsourcing platform Amazon Mechanical Turk. The participants’ mean age was 46 years, with 55% women. Participants completed the SD-WISE-28 as well as validation scales for various positive and negative constructs. Psychometric analyses (factor analysis and item response theory) were used to select one item from each of the seven SD-WISE-28 subscales.Results:We selected a combination of items that produced acceptable unidimensional model fit and good reliability (ω = 0.74). Item statistics suggested that all seven items were strong indicators of wisdom, although the association was weakest for spirituality. Analyses indicated that the 28-item and 7-item SD-WISE are both very highly correlated (r = 0.92) and produce a nearly identical pattern of correlations with demographic and validity variables.Conclusion:The SD-WISE-7, and its derived Jeste-Thomas Wisdom Index (JTWI) score, balances reliability and brevity for research applications.

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder and accounts for 5-10% of all cases of kidney failure. 50% of ADPKD patients reach kidney failure by the age of 58 years requiring dialysis or transplantation. Nephrectomy is performed in up to 20% of patients due to compressive symptoms, renal-related complications or in preparation for kidney transplantation. However, due to the large kidney size in ADPKD nephrectomy can come with a considerable burden. Here we evaluate our institution’s experience of laparoscopic nephrectomy (LN) as an alternative to standard-procedure nephrectomy for ADPKD patients.Materials and Methods: We report the results of the first 12 consecutive laparoscopic cystnephrectomies from 08/2020 to 08/2021 in our institution. Intra- and postoperative parameters were collected and analyzed. Health related quality of life (HRQoL) was assessed using the SF36 questionnaire.Results: Median age of patients was 60 years (±8,1a). Mean preoperative kidney volume measured by volumetric analyzes in abdominal CT scan was 3795ml (range 1255-8253ml). Mean operative time was 158min (range 85-227min). Mean postoperative stay was 11 days (range 6-35 days). Only one postoperative complication Clavien-Dindo ³3 occurred (8,3%). SF36 HRQol questionnaire revealed excellent postoperative quality of life after LN.Conclusion: Laparoscopic nephrectomy in ADPKD patients is a safe and effective operative procedure independent of kidney size with excellent postoperative outcomes and benefits of minimally invasive surgery.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (

BackgroundUnderstanding movement patterns of anadromous fishes is critical to conservation management of declining wild populations and preservation of habitats. Yet, infrequent observations of individual animals fundamentally constrain accurate descriptions of movement dynamics.MethodsIn this study, we synthesized over a decade (2006–2018) of acoustic telemetry tracking observations of green sturgeon (Acipenser medirostris) in the Sacramento River system to describe major anadromous movement patterns.ResultsWe observed that green sturgeon exhibited a unimodal in-migration during the spring months but had a bimodal distribution of out-migration timing, split between an ‘early’ out-migration (32%) group during May - June, or alternatively, holding in the river until a ‘late’ out-migration (68%), November - January. Focusing on these out-migration groups, we found that river discharge, but not water temperature, may cue the timing of migration, and that fish showed a tendency to maintain out-migration timing between subsequent spawning migration events.ConclusionsWe recommend that life history descriptions of green sturgeon in this region reflect the distinct out-migration periods described here. Furthermore, we encourage the continued use of biotelemetry to describe migration timing and life history variation, not only this population but other green sturgeon populations and other species.

Obesity is a universal epidemic and underlies comorbidities including type 2 diabetes and cardiovascular disease. Adipocytes store dietary metabolites within lipid droplets to avoid lipotoxicity and to provide energy to the body through metabolic processes such as lipid and glucose metabolism. Collaborative studies demonstrated that the extracellular matrix protein procollagen C-endopeptidase enhancer 2 (PCPE2) mediates the ability of scavenger receptor BI (SR-BI) to transport cholesterol into hepatocytes and adipocytes.It remains unknown if SR-BI and PCPE2 also play roles in other adipocyte metabolic processes and if their cooperative partnership is conserved. This knowledge gap prompted us to test the hypothesis that PCPE2 facilitates SR-BI’s ability to regulate metabolic processes in adipocytes. We validated a differentiated adipocyte model system using mesenchymal stem cells isolated from ears of wild-type (WT), SR-BI -/- , and PCPE2 - /- mice by demonstrating increased lipid droplet formation, mRNA expression of adipogenesis markers, and secretion of adiponectin over a 9-day post-differentiation period across genotypes. We used this model system to test the roles SR-BI and PCPE2in glucose and lipid metabolism. Compared to WT adipocytes, glucose uptake in SR-BI -/- and PCPE2 -/- adipocytes was decreased by 5.4% and 12.6%, respectively, despite increases in surface GLUT4 levels. We also observed that adipocytes lacking PCPE2 had an increased response to insulin through AKT signaling, which may be responsible for the increased surface expression of GLUT4. Loss of SR-BI or PCPE2 in adipocytes did not affect palmitic acid uptake, despite elevated mRNA expression of fatty acid transporters ( Cd36, Fabp4 ) compared to WT adipocytes. SR-BI -/- and PCPE2 -/- adipocytes showed an inverse response to insulin when measuring phosphorylation of fatty acid regulatory proteins (AMPK, ACC) compared to WT adipocytes, suggesting altered lipid metabolism in adipocytes lacking SR-BI or PCPE2. Together, our data suggest that, individually, SR-BI or PCPE2 is important for glucose uptake and fatty acid regulation, but not fatty acid uptake. Further investigations will determine whether a partnership is required for optimal metabolic function in adipocytes.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

Iodide‐mediated surface etching can tailor the surface plasmon resonance of gold nanostars through etching of the high‐energy facets of the nanoparticle protrusions in a rapid and sensitive way. By exploring the underlying mechanisms of this etching and the key parameters influencing it (such as iodide, oxygen, pH, and temperature), we show its potential in a sensitive biosensing system. Horseradish peroxidase‐catalyzed oxidation of iodide enables control of the etching of gold nanostars to spherical gold nanoparticles, where the resulting spectral shift in the surface plasmon resonance yields a distinct color change of the solution. We further develop this enzyme‐modulated surface etching of gold nanostars into a versatile platform for plasmonic immunoassays, where a high sensitivity is possible by signal amplification via magnetic beads and click chemistry., We outline a rapid and sensitive nanoparticle etching‐based strategy for biosensing. Iodide modulates the plasmonic features of gold nanostars by etching them into spherical nanoparticles, being a versatile biosensing platform for enzyme detection and plasmonic immunoassays.

Objective Evaluate reproductive function in nulligravid and gravid women after levonorgestrel 52 mg intrauterine system (IUS) discontinuation based on time to pregnancy. Study design We evaluated women participating in the ACCESS IUS multicenter, Phase 3, open-label clinical trial of the Liletta(®) levonorgestrel 52 mg IUS who discontinued the IUS within 60 months of use and desired pregnancy. Study staff contacted participants every three months after IUS discontinuation for up to 12 months to determine whether pregnancy occurred. We excluded women who opted to stop attempting to conceive before 12 months. We evaluated 12-month conception rates in participants 16–35 years at IUS placement, comparing dichotomous outcomes using Fisher’s exact test. We performed a multivariable analysis to assess the association of baseline characteristics, age at discontinuation, duration of IUS use, and positive sexually transmitted infection testing during IUS use with conception. Results Among 165 women who attempted to conceive, 142 (86.1%) did so within 12 months with a median time to conception of 92 days. The 12-month conception rates did not differ between nulligravid (66/76 [86.8%]) and gravid (76/89 [85.4%]) women (p = 0.83) and nulliparous (78/90 [86.7%]) and parous (64/75 [85.3%]) women (p = 0.83). In multivariable analysis, only obesity (aOR 0.3 [95% CI 0.1–0.8]) was associated with ability to conceive. Conclusions After levonorgestrel 52 mg IUS discontinuation, women have rapid return of fertility in the year post-removal. Fertility rates after IUS removal do not vary based on gravidity, parity, age at discontinuation, or duration of IUS use. Implications This contemporary IUS study included a large population of nulligravid and nulliparous women. IUS use over many years does not effect spontaneous fertility after IUS discontinuation, regardless of gravidity or parity. Providers and patients should have no concern about the impact of IUS use on future fertility.

BACKGROUND: Fractional myocardial blood volume (fMBV) estimated using ferumoxytol-enhanced MRI (FE-MRI) has the potential to capture a hemodynamic response to myocardial hypoperfusion during contrast steady state without reliance on gadolinium chelates. Ferumoxytol has a long intravascular half-life and its use for steady-state MRI is off-label. PURPOSE: To optimize and evaluate a two-compartment model for estimation of fMBV based on FE-MRI. STUDY TYPE: Prospective ANIMAL MODEL: Nine healthy swine; one swine with artificially-induced single-vessel coronary stenosis. FIELD STRENGTH/SEQUENCE: 3.0T clinical magnet using the 5(3)3(3)3 Modified Look-Locker Inversion Recovery (MOLLI) sequence. ASSESSMENT: Myocardial longitudinal spin-lattice relaxation rate (R1) was measured using the MOLLI sequence before and at contrast steady state following seven ferumoxytol infusions (0.125 – 4.0 mg/kg). fMBV and water exchange were estimated using a two-compartment model. Model-fitted fMBV was compared to simple fast-exchange fMBV approximation and percent change in pre and post-ferumoxytol R1. Dose under-sampling schemes were investigated to reduce acquisition duration. STATISTICAL TESTS: Variation in fMBV was assessed with a one-way analysis of variance (ANOVA). Fast-exchange fMBV and ferumoxytol dose under-sampling were evaluated using Bland-Altman analysis. RESULTS: Healthy normal swine showed a mean mid-ventricular fMBV of 7.2 ± 1.4% and water exchange rate of 11.3 ± 5.1 s(−1). There was inter-subject variation in fMBV (p

Siderophores are iron-chelating molecules produced by microorganisms and plants to acquire exogenous iron. Siderophore biosynthetic enzymology often produces elaborate and unique molecular through unusual reactions to enable specific recognition by the producing organisms. Herein, we report the structure of two siderophore analogs from Agrobacterium fabrum strain C58, which we named fabrubactin (FBN) A and FBN B. Additionally, we characterized the substrate specificities of the NRPS and PKS components. The structures suggest unique Favorskii-like rearrangements of the molecular backbone that we propose are catalyzed by the flavin-dependent monooxygenase, FbnE. FBN A and B contain a 1,1-dimethyl-3-amino-1,2,3,4-tetrahydro-7,8-dihydroxy-quinolin (Dmaq) moiety previously seen only in the anachelin cyanobacterial siderophores. We provide evidence that Dmaq is derived from L-DOPA and propose a mechanism for the formation of the mature Dmaq moiety. Our bioinformatic analyses suggest that FBN A and B and the anachelins belong to a large and diverse siderophore family widespread throughout the Rhizobium/Agrobacterium group, α-proteobacteria, and cyanobacteria.

Chemical investigation of a marine sponge-associated Bacillus sp. led to the discovery of bacillibactins E and F (1 and 2). Despite containing the well-established cyclic triester core of iron-binding natural products such as enterobactin, bacillibactins E and F (1 and 2) are the first bacterial siderophores that contain nicotinic and benzoic acid moieties. The structures of the new compounds, including their absolute configurations, were determined by extensive spectroscopic analyses and Marfey's method. A plausible biosynthetic pathway to 1 and 2 is proposed; this route bears great similarity to other previously established bacillibactin-like pathways but appears to differentiate itself by a promiscuous DhbE, which likely installs the nicotinic moiety of 1 and the benzoic acid group of 2.

Previous research has shown that cognitive development is sensitive to socio-economic status (SES) and multilinguistic experiences. However, these effects are difficult to disentangle and SES may modulate the effects of multilingualism. The present study used data from a large cohort of pupils who took part in the Study of Cognition, Adolescents and Mobile Phones (SCAMP) at ages 11-12 (T1) and 13-15 years old (T2). Cognitive measures were derived from tasks of cognitive flexibility, verbal, spatial and visuo-spatial working memory, speech processing and non-verbal reasoning. Using SES information collected through questionnaires (school type, level of deprivation, parental education and occupation), the sample was clustered into high/medium/low SES groups. Comparisons focused on 517 monolingual and 329 multilingual pupils in the high/low SES groups. Having controlled for multiple comparisons, the results indicated a significant beneficial effect of bilingualism in measures of working memory, visuo-spatial processing and non-verbal reasoning. These effects were present in both high and low SES individuals and sustained at both times of development, with a particularly significant improvement of working memory abilities in low SES bilinguals at T2 as compared to monolingual peers. Theoretical and practical implications of these findings are considered and guidance for educators is discussed.

Background In patients receiving mechanical ventilation, spontaneous awakening trials reduce morbidity and mortality when paired with spontaneous breathing trials. However, spontaneous awakening trials are not performed every day they are indicated and little is known about spontaneous awakening trial protocol use in cardiac intensive care units. Local Problem Spontaneous awakening trial completion rate at the study institution was low and no trial protocol was regularly used. Methods A preintervention-postintervention retrospective cohort study was performed in adult patients with at least 24 hours of invasive mechanical ventilation in Michigan Medicine’s cardiac intensive care unit. Patients with SARS-CoV-2 infection were excluded. Data included demographics, sedation, mechanical ventilation duration, and in-hospital mortality. A nurse-driven spontaneous awakening trial protocol modified for the cardiac intensive care unit was implemented in October 2020. Results Compared with the preintervention cohort (n = 29, May through July 2020), the postintervention cohort (n = 27, October 2020 through February 2021) had a higher ratio of number of trials performed to number of days eligible for trial (0.91 vs 0.52; P < .01). Median continuous sedative infusion duration was shorter after intervention (2.3 vs 3.6 days; P = .02). Median mechanical ventilation duration (3.8 vs 4.7 days; P = .18) and mortality (41% vs 41%; P = .95) were similar between groups. Conclusions Spontaneous awakening trial protocol implementation led to a higher trial completion rate and a shorter duration of continuous sedative infusion. Larger studies are needed to assess the impact of protocolized spontaneous awakening trials on cardiac intensive care unit patient outcomes.

Aims Recent data suggest that the incidence of malignant appendiceal tumours is increasing. This study aimed to determine temporal trends in the incidence of malignant appendiceal tumours within England and a possible influence by demographic factors. Methods All incident cases of appendiceal tumours in patients aged 20 years and above were identified from the National Cancer Registration and Analysis Service database between 1995 and 2016 using ICD-9/10 codes. Cancers were categorized according to histology. Joinpoint regression analysis was used to investigate changes in age-standardized incidence rates by age, sex, histological subtype and index of multiple deprivation quintiles, based on socioeconomic domains (income, employment, education, health, crime, barriers to housing and services and living environment). Average annual per cent changes (AAPCs) were estimated by performing Monte-Carlo permutation analysis. Results A total of 7333 tumours were diagnosed and 7056 patients were analysed, comprising 3850 (54.6 per cent) neuroendocrine tumours (NETs), 1892 (26.8 per cent) mucinous adenocarcinomas and 1314 (18.6 per cent) adenocarcinoma (not otherwise specified). The overall incidence of appendiceal tumours increased from 0.3 per 100 000 to 1.6 per 100 000 over the study interval. Incidence rate increases of comparable magnitude were observed across all age groups, but the AAPC was highest among patients aged 20–29 years (15.6 per cent, 95 per cent c.i 12.7–18.6 per cent) and 30–39 years (14.2 per cent, 12.2–16.2 per cent) and lowest among those aged 70–79 years (6.8 per cent, 5.7–8.0 per cent). Similar incidence rate increases were reported across all socioeconomic deprivation quintiles and in both sexes. Analysis by grade of NET showed that grade 1 tumours accounted for 63 per cent between 2010 and 2013, compared with 2 per cent between 2000 and 2003. Conclusions The incidence rate of malignant appendiceal tumours has increased significantly since 1995 and is mainly attributed to an increase in NETs. The increased diagnosis of low-grade NETs may in part be due to changes in pathological classification systems.

Lipid nanoparticles (LNPs) are versatile structures with tunable physicochemical properties that are ideally suited as a platform for vaccine delivery and RNA therapeutics. A key barrier to LNP rational design is the inability to relate composition and structure to intracellular processing and function. Here Single Particle Automated Raman Trapping Analysis (SPARTA) is combined with small-angle X-ray and neutron scattering (SAXS/SANS) techniques to link LNP composition with internal structure and morphology and to monitor dynamic LNP-phospholipase D (PLD) interactions. This analysis demonstrates that PLD, a key intracellular trafficking mediator, can access the entire LNP lipid membrane to generate stable, anionic LNPs. PLD activity on vesicles with matched amounts of enzyme substrate is an order of magnitude lower, indicating that the LNP lipid membrane structure can be used to control enzyme interactions. This represents an opportunity to design enzyme-responsive LNP solutions for stimuli-responsive delivery and diseases where PLD is dysregulated.

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites

Lateral flow tests, commonly based on metal plasmonic nanoparticles, are rapid, robust, and low-cost. However, improvements in analytical sensitivity are required to allow detection of low-abundance biomarkers, for example detection of low antigen concentrations for earlier or asymptomatic diagnosis of infectious diseases. Efforts to improve sensitivity often require changes to the assay. Here, we developed optical methods to improve the sensitivity of absorption-based lateral flow tests, requiring no assay modifications to existing tests. We experimentally compared five different lock-in and subtraction-based methods, exploiting the narrow plasmonic peak of gold nanoparticles for background removal by imaging at different light wavelengths. A statistical framework and three fitting models were used to compare limits of detection, giving a 2.0-5.4-fold improvement. We then demonstrated the broad applicability of the method to an ultrasensitive assay, designing 530 nm composite nanoparticles to increase the particle volume, and therefore light absorption per particle, whilst retaining the plasmonic peak to allow background removal and without adding any assay steps. This multifaceted, modular approach gave a combined 58-fold improvement in the fundamental limit of detection using a biotin-avidin model over 50 nm gold nanoparticles with single-wavelength imaging. Applying to a sandwich assay for the detection of HIV capsid protein gave a limit of detection of 170 fM. Additionally, we developed an open-source software tool for performing the detection limit analysis used in this work.

Perceived younger age is associated with positive health outcomes in existing literature. Few studies have examined these associations using a wide range of variables in large sample of adults of all ages. The objective of present study was to characterize the discrepancy between chronological age (CA) and subjective age (SA) in a large sample of community-dwelling adults across the lifespan, investigate associations with mental, physical, and cognitive health, and examine how it is related to a broad array of psychosocial variables relevant to well-being. Cross-sectional data from 1,004 individuals aged 21-100+ years from the Successful AGing Evaluation (SAGE) study were used for this analysis. Data included self-report measures of physical health (SF-36 - Physical Component), mental health composite score (created using CES-D Happiness scale, Satisfaction with Life Scale, SF-36 Mental Component, Brief Symptom Inventory Anxiety Scale, Patient Health Questionnaire-9, and Perceived Stress Scale), Telephone Interview for Cognitive Status - modified (TICS-m), and validated measures of various positive psychological variables such as meaning in life and optimism. On average, SA was 11.5 years younger than CA (SD 11.3). The discrepancy increased with CA. A younger SA compared to CA was associated with better mental and physical health in all age groups and was positively associated with measures of presence of meaning in life, successful aging, optimism, personal mastery, resilience, curiosity, hope, and social support. The association between age discrepancy and cognitive functioning was not statistically significant. These findings indicate that SA is potentially valuable for the purposes of clinical assessment and intervention, and this possibility should be investigated in future research.

Wisdom is a multi-component trait that is important for mental health and well-being. In this study, we sought to understand gender differences in relative strengths in wisdom. A total of 659 individuals aged 27–103 years completed surveys including the 3-Dimensional Wisdom Scale (3D-WS) and the San Diego Wisdom Scale (SD-WISE). Analyses assessed gender differences in wisdom and gender’s moderating effect on the relationship between wisdom and associated constructs including depression, loneliness, well-being, optimism, and resilience. Women scored higher on average on the 3D-WS but not on the SD-WISE. Women scored higher on compassion-related domains and on SD-WISE Self-Reflection. Men scored higher on cognitive-related domains and on SD-WISE Emotion Regulation. There was no impact of gender on the relationships between wisdom and associated constructs. Women and men have different relative strengths in wisdom, likely driven by sociocultural and biological factors. Tailoring wisdom interventions to individuals based on their profiles is an important next step.