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Abstract The exceptional Drinfel’d algebra (EDA) is a Leibniz algebra introduced to provide an algebraic underpinning with which to explore generalised notions of U-duality in M-theory. In essence, it provides an M-theoretic analogue of the way a Drinfel’d double encodes generalised T-dualities of strings. In this note we detail the construction of the EDA in the case where the regular U-duality group is E 6(6). We show how the EDA can be realised geometrically as a generalised Leibniz parallelisation of the exceptional generalised tangent bundle for a six-dimensional group manifold G, endowed with a Nambu-Lie structure. When the EDA is of coboundary type, we show how a natural generalisation of the classical Yang-Baxter equation arises. The construction is illustrated with a selection of examples including some which embed Drinfel’d doubles and others that are not of this type.

Background/Aims Aspiration therapy (AT) involves endoscopic placement of a gastrostomy tube with an external device that allows patients to drain 30% of ingested calories after meals. Its efficacy for inducing weight loss has been shown. This study aimed to assess the effect of AT on obesity-related comorbidities. Methods A meta-analysis of studies that assessed AT outcomes was conducted through December 2018. Primary outcomes were changes in comorbidities at 1 year following AT. Secondary outcomes were the amount of weight loss at up to 4 years and pooled serious adverse events (SAEs). Results Five studies with 590 patients were included. At 1 year, there were improvements in metabolic conditions: mean difference (MD) in systolic blood pressure: -7.8 (-10.7 – -4.9) mm Hg; MD in diastolic blood pressure: -5.1 (-7.0 – 3.2) mm Hg; MD in triglycerides: -15.8 (-24.0 – -7.6) mg/dL; MD in high-density lipoprotein: 3.6 (0.7–6.6) mg/dL; MD in hemoglobin A1c (HbA1c): -1.3 (-1.8 – -0.8) %; MD in aspartate transaminase: -2.7 (-4.1 – -1.3) U/L; MD in alanine transaminase: -7.5 (-9.8 – -5.2) U/L. At 1 (n=218), 2 (n=125), 3 (n=46), and 4 (n=27) years, the patients experienced 17.8%, 18.3%, 19.1%, and 18.6% total weight loss (TWL), corresponding to 46.3%, 46.2%, 48.0%, and 48.7% excess weight loss (EWL) (p

Abstract We build on the results of [1] for generalised frame fields on generalised quotient spaces and study integrable deformations for ℂP n . In particular we show how, when the target space of the Principal Chiral Model is a complex projective space, a two-parameter deformation can be introduced in principle. The second parameter can however be removed via a diffeomorphism, which we construct explicitly, in accordance with the results stemming from a thorough integrability analysis we carry out. We also elucidate how the deformed target space can be seen as an instance of generalised Kähler, or equivalently bi-Hermitian, geometry. In this respect, we find the generic form of the pure spinors for ℂP n and the explicit expression for the generalised Kähler potential for n = 1, 2.

Kemp eliminases are artificial enzymes that catalyze the concerted deprotonation and ring-opening of benzisoxazoles. Here, the authors use room-temperature X-ray crystallography to investigate changes to the conformational ensemble of the Kemp eliminase HG3 along a directed evolutionary trajectory, and develop an experimentally guided, ensemble-based computational enzyme design procedure.

Abstract Recent work has shown that two-dimensional non-linear σ-models on group manifolds with Poisson-Lie symmetry can be understood within generalised geometry as exemplars of generalised parallelisable spaces. Here we extend this idea to target spaces constructed as double cosets M = G ˜ $$ \tilde{G} $$ \𝔻/H. Mirroring conventional coset geometries, we show that on M one can construct a generalised frame field and a H -valued generalised spin connection that together furnish an algebra under the generalised Lie derivative. This results naturally in a generalised covariant derivative with a (covariantly) constant generalised intrinsic torsion, lending itself to the construction of consistent truncations of 10-dimensional supergravity compactified on M . An important feature is that M can admit distinguished points, around which the generalised tangent bundle should be augmented by localised vector multiplets. We illustrate these ideas with explicit examples of two-dimensional parafermionic theories and NS5-branes on a circle.

Abstract We explore geometries that give rise to a novel algebraic structure, the Exceptional Drinfeld Algebra, which has recently been proposed as an approach to study generalised U-dualities, similar to the non-Abelian and Poisson-Lie generalisations of T-duality. This algebra is generically not a Lie algebra but a Leibniz algebra, and can be realised in exceptional generalised geometry or exceptional field theory through a set of frame fields giving a generalised parallelisation. We provide examples including “three-algebra geometries”, which encode the structure constants for three-algebras and in some cases give novel uplifts for CSO(p, q, r) gaugings of seven-dimensional maximal supergravity. We also discuss the M-theoretic embedding of both non-Abelian and Poisson-Lie T-duality.

Background/Aims Endoscopic ultrasound fine-needle aspiration (EUS-FNA) is preferred for sampling of lymph nodes (LNs) adjacent to the gastrointestinal wall; however, fine-needle biopsy (FNB) may provide improved diagnostic outcomes. This study aimed to evaluate the comparative efficacy and safety of FNA versus FNB for LN sampling. Methods This was a multicenter retrospective study of prospectively collected data to evaluate outcomes of EUS-FNA and EUS-FNB for LN sampling. Characteristics analyzed included sensitivity, specificity, accuracy, the number of needle passes, diagnostic adequacy of rapid on-site evaluation (ROSE), cell-block analysis, and adverse events. Results A total of 209 patients underwent EUS-guided LN sampling. The mean lesion size was 16.22±8.03 mm, with similar sensitivity and accuracy between FNA and FNB ([67.21% vs. 75.00%, respectively, p=0.216] and [78.80% vs. 83.17%, respectively, p=0.423]). The specificity of FNB was better than that of FNA (100.00% vs. 93.62%, p=0.01). The number of passes required for diagnosis was not different. Abdominal and peri-hepatic LN location demonstrated FNB to have a higher sensitivity (81.08% vs. 64.71%, p=0.031 and 80.95% vs. 58.33%, p=0.023) and accuracy (88.14% vs. 75.29%, p=0.053 and 88.89% vs. 70.49%, p=0.038), respectively. ROSE was a significant predictor for accuracy (odds ratio, 5.16; 95% confidence interval, 1.15–23.08; p=0.032). No adverse events were reported in either cohort. Conclusions Both EUS-FNA and EUS-FNB are safe for the diagnosis of LNs. EUS-FNB is preferred for abdominal LN sampling. EUS-FNA+ ROSE was similar to EUS-FNB alone, showing better diagnosis for EUS-FNB than traditional FNA. While ROSE remained a significant predictor for accuracy, due to its poor availability in most centers, its use may be limited to cases with previous inconclusive diagnoses.

The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors.

This case report describes a complex trauma patient who developed hyperkalemia secondary to heparin. Heparin is a commonly used drug in trauma patients. Physicians need to be aware of this potentially harmful adverse reaction in these high-risk patients.

Background/Aims: Peroral endoscopic myotomy (POEM) has recently come to the forefront in the management of achalasia. We aimed to analyze the efficacy and safety of the use of electrocautery enhanced scissors (EES) for POEM. Methods: This retrospective cohort study prospectively collected the data of all adult patients (aged ≥18 years) with normal foregut anatomy who underwent POEM using EES. The patients’ baseline characteristics and procedure details (time, tunnel length, myotomy length, depth, and location) were recorded. The primary outcome was clinical success (3-month post-procedure Eckardt score of ≤3). The secondary outcomes were technical success and adverse events. A paired Student’s t-test was performed. Results: Fifteen patients were included in this study. The technical success rate of myotomy using EES was 100%. Fellows participated in the myotomy in all cases. The clinical success rate was 93.3% (14/15). The mean pre-Eckardt score was 5.4±2.5, while the mean post-Eckardt score was 1.3±1.3, which indicated a significant improvement (p≤0.0001). The most common treatment-related adverse events were post-procedure pain (4, 26.7%) and symptomatic reflux disease (4, 26.7%). Conclusions: In the largest series to date on the use of EES in POEM, we demonstrated that this technique has both technical and clinical efficacy as well as an excellent safety profile.

Background/Aims: The diagnosis of biliary strictures can be challenging. There are no systematic reviews studying same-session endoscopic retrograde cholangiopancreatography (ERCP)-based tissue sampling and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for the diagnosis of biliary strictures. Methods: A systematic review was conducted on studies analyzing same-session EUS and ERCP for tissue diagnosis of suspected malignant biliary strictures. The primary outcome was the accuracy of each method individually compared to the two methods combined. The secondary outcome was the accuracy of each method in pancreatic and biliary etiologies. In the meta-analysis, we used Forest plots, summary receiver operating characteristic curves, and estimates of the area under the curve for intention-to-treat analysis. Results: Of the 12,132 articles identified, six were included, resulting in a total of 497 patients analyzed. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and accuracy of the association between the two methods were: 86%, 98%, 12.50, 0.17, and 96.5%, respectively. For the individual analysis, the sensitivity, specificity and accuracy of EUS-FNA were 76%, 100%, and 94.5%, respectively; for ERCP-based tissue sampling, the sensitivity, specificity, and accuracy were 58%, 98%, and 78.1%, respectively. For pancreatic lesions, EUS-FNA was superior to ERCP-based tissue sampling. However, for biliary lesions, both methods had similar sensitivities. Conclusions: Same-session EUS-FNA and ERCP-based tissue sampling is superior to either method alone in the diagnosis of suspected malignant biliary strictures. Considering these results, combination sampling should be performed when possible.

Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an “inappropriately normal” FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere—even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics. Keywords: TIO, Paraneoplastic syndrome, Tumor-induced osteomalacia, Fibroblast growth factor 23, 68Ga-DOTATATE, MRI, DXA, Burosumab

Abstract The recent coronavirus disease (COVID-19), caused by SARS-CoV-2, is inarguably the most challenging coronavirus outbreak relative to the previous outbreaks involving SARS-CoV and MERS-CoV. With the number of COVID-19 cases now exceeding 2 million worldwide, it is apparent that (i) transmission of SARS-CoV-2 is very high and (ii) there are large variations in disease severity, one component of which may be genetic variability in the response to the virus. Controlling current rates of infection and combating future waves require a better understanding of the routes of exposure to SARS-CoV-2 and the underlying genomic susceptibility to this disease. In this mini-review, we highlight possible genetic determinants of COVID-19 and the contribution of aerosol exposure as a potentially important transmission route of SARS-CoV-2.

Abstract Poisson-Lie duality provides an algebraic extension of conventional Abelian and non-Abelian target space dualities of string theory and has seen recent applications in constructing quantum group deformations of holography. Here we demonstrate a natural upgrading of Poisson-Lie to the context of M-theory using the tools of exceptional field theory. In particular, we propose how the underlying idea of a Drinfeld double can be generalised to an algebra we call an exceptional Drinfeld algebra. These admit a notion of “maximally isotropic subalgebras” and we show how to define a generalised Scherk-Schwarz truncation on the associated group manifold to such a subalgebra. This allows us to define a notion of Poisson-Lie U-duality. Moreover, the closure conditions of the exceptional Drinfeld algebra define natural analogues of the cocycle and co-Jacobi conditions arising in Drinfeld double. We show that upon making a further coboundary restriction to the cocycle that an M-theoretic extension of Yang-Baxter deformations arise. We remark on the application of this construction as a solution-generating technique within supergravity.

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme.

Purpose: The purpose of this study was to investigate how learning in two graduate health science courses at a comprehensive state university was structured and provided opportunities for clinical reasoning. Method: This study adopted a grounded theory approach. Participants included two graduate instructors, one in Occupational Therapy (OT) and one Communication Disorders (CD), and their students (n = 62). Three data sources included transcripts from 36 h of instructor–student discourse within graduate health science classrooms over the course of a full semester, detailed field notes about the environment and instructor–student interactions, and transcripts from in-depth, open-ended interviews with each instructor focusing on their intended participation frameworks and scaffolding strategies. Results: The findings indicate that students' demonstration of clinical reasoning skills in the classroom were impacted by the participation frameworks instructors adopted and that instructor perceptions did not always match recorded interactions. Discussion: The pedagogies instructors use, the social dynamics in the classroom, class structure and format, and instructor expectations are highly influential on the high-level problem solving required in clinical reasoning that graduate health science students need to demonstrate. Conclusion: Results of this study highlight how instructional practices can inadvertently undermine the clinical reasoning skills students demonstrate in the classroom environment and are representative of a common struggle in education.

Abstract Background Bacteriophages encode genes that modify bacterial functions during infection. The acquisition of phage-encoded virulence genes is a major mechanism for the rise of bacterial pathogens. In coral reefs, high bacterial density and lysogeny has been proposed to exacerbate reef decline through the transfer of phage-encoded virulence genes. However, the functions and distribution of these genes in phage virions on the reef remain unknown. Results Here, over 28,000 assembled viral genomes from the free viral community in Atlantic and Pacific Ocean coral reefs were queried against a curated database of virulence genes. The diversity of virulence genes encoded in the viral genomes was tested for relationships with host taxonomy and bacterial density in the environment. These analyses showed that bacterial density predicted the profile of virulence genes encoded by phages. The Shannon diversity of virulence-encoding phages was negatively related with bacterial density, leading to dominance of fewer genes at high bacterial abundances. A statistical learning analysis showed that reefs with high microbial density were enriched in viruses encoding genes enabling bacterial recognition and invasion of metazoan epithelium. Over 60% of phages could not have their hosts identified due to limitations of host prediction tools; for those which hosts were identified, host taxonomy was not an indicator of the presence of virulence genes. Conclusions This study described bacterial virulence factors encoded in the genomes of bacteriophages at the community level. The results showed that the increase in microbial densities that occurs during coral reef degradation is associated with a change in the genomic repertoire of bacteriophages, specifically in the diversity and distribution of bacterial virulence genes. This suggests that phages are implicated in the rise of pathogens in disturbed marine ecosystems.

Physicochemical tests represent important tools for the analytical control strategy of biotherapeutics. For adenoviral modalities, anion-exchange high performance liquid chromatography (AEX-HPLC) represents an important methodology, as it is able to simultaneously provide information on viral particle concentration, product purity and surface charge in a high-throughput manner. During product development of an adenoviral-based therapeutic, an accelerated stability study was performed and showed changes in each of the AEX-HPLC reportable attributes. These changes also correlated with a decrease in product infectivity prompting a detailed characterization of the impurity and mechanism of the surface charge change. Characterization experiments identified the impurity to be free hexon trimer, suggesting that capsid degradation could be contributing to both the impurity and reduced particle concentration. Additional mass spectrometry characterization identified deamidation of specific hexon residues to be associated with the external surface charge modification observed upon thermal stress conditions. To demonstrate a causal relationship between deamidation and surface charge changes observed by AEX-HPLC, site-directed mutagenesis experiments were performed. Through this effort, it was concluded that deamidation of asparagine 414 was responsible for the surface charge alteration observed in the AEX-HPLC profile but was not associated with the reduction in infectivity. Overall, this manuscript details critical characterization efforts conducted to enable understanding of a pivotal physicochemical test for adenoviral based therapeutics.

Introduction: The availability of targeted therapies has transformed the management of advanced NSCLC; however, most patients do not undergo guideline-recommended tumor genotyping. The impact of plasma-based next-generation sequencing (NGS) performed simultaneously with diagnostic biopsy in suspected advanced NSCLC has largely been unexplored. Methods: We performed a prospective cohort study of patients with suspected advanced lung cancer on the basis of cross-sectional imaging results. Blood from the time of biopsy was sequenced using a commercially available 74-gene panel. The primary outcome measure was time to first-line systemic treatment compared with a retrospective cohort of consecutive patients with advanced NSCLC with reflex tissue NGS. Results: We analyzed the NGS results from 110 patients with newly diagnosed advanced NSCLC: cohorts 1 and 2 included 55 patients each and were well balanced regarding baseline demographics. In cohort 1, plasma NGS identified therapeutically informative driver mutations in 32 patients (58%) (13 KRAS [five KRAS G12C], 13 EGFR, two ERRB2, two MET, one BRAF, one RET). The NGS results were available before the first oncology visit in 85% of cohort 1 versus 9% in cohort 2 (p < 0.0001), with more cohort 1 patients receiving a guideline-concordant treatment recommendation at this visit (74% versus 46%, p = 0.005). Time-to-treatment was significantly shorter in cohort 1 compared with cohort 2 (12 versus 20 d, p = 0.003), with a shorter time-to-treatment in patients with specific driver mutations (10 versus 19 d, p = 0.001). Conclusions: Plasma-based NGS performed at the time of diagnostic biopsy in patients with suspected advanced NSCLC is associated with decreased time-to-treatment compared with usual care.

Quasi-elastic neutron scattering (QENS) and small angle neutron scattering (SANS), in combination with isotopic contrast variation, have been used to determine the structure and dynamics of three-component lipid membranes, in the form of vesicles, comprising an unsaturated [palmitoyl-oleoyl-phosphatidylcholine (POPC) or dioleoyl-phosphatidylcholine (DOPC)], a saturated phospholipid (dipalmitoyl-phosphatidylcholine (DPPC)), and cholesterol, as a function temperature and composition. SANS studies showed vesicle membranes composed of a 1:1:1 molar ratio of DPPC:DOPC:cholesterol and a 2:2:1 molar ratio of DPPC:POPC:cholesterol phase separated, forming lipid rafts of ∼18 and ∼7 nm diameter respectively, when decreasing temperature from 308 to 297 K. Phase separation was reversible upon increasing temperature. The larger rafts observed in systems containing DOPC are attributed to the greater mis-match in lipid alkyl chains between DOPC and DPPC, than for POPC and DPPC. QENS studies, over the temperature range 283–323K, showed that the resulting data were best modelled by two Lorentzian functions: a narrow component, describing the “in-plane” lipid diffusion, and a broader component, describing the lipid alkyl chain segmental relaxation. The overall “in-plane” diffusion was found to show a significant reduction upon increasing temperature due to the vesicle membranes transitioning from one containing rafts to one where the component lipids are homogeneously mixed. The use of different isotopic combinations allowed the measured overall reduction of in-plane diffusion to be understood in terms of an increase in diffusion of the saturated DPPC lipid and a corresponding decrease in diffusion of the unsaturated DOPC/POPC lipid. As the rafts are considered to be composed principally of saturated lipid and cholesterol, the breakdown of rafts decreases the exposure of the DPPC to cholesterol whilst increasing the exposure of cholesterol to unsaturated lipid. These results show the sensitivity of lipid diffusion to local cholesterol concentration, and the importance of considering the local, rather that the global composition of a membrane when understanding the diffusion processes of lipids within the membrane. The novel combination of SANS and QENS allows a non-intrusive approach to characterize the structure and dynamics occurring in phase-separated model membranes which are designed to mimic the lateral heterogeneity of lipids seen in cellular membranes–a heterogeneity that can have pathological consequences.

Purpose: To evaluate differences in the retinal microvasculature and structure and choroidal structure among men and women with Alzheimer’s disease (AD) compared with age-matched cognitively normal male and female controls. Design: Case-control study of participants ≥ 50 years of age. Participants: A total of 202 eyes of 139 subjects (101 cases and 101 controls). Methods: All participants and controls underwent OCT and OCT angiography (OCTA), and parameters of subjects with AD were compared with those of cognitively normal controls. Main Outcome Measures: The foveal avascular zone (FAZ) area, vessel density (VD), and perfusion density (PD) in the superficial capillary plexus within the 3- and 6-mm circle and ring using Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay on OCTA; central subfield thickness (CST), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT. Results: No significant sex differences in VD or PD were found in the AD or control cohorts; however, there were greater differences in VD and PD among AD female participants than AD male participants compared with their respective controls. The CST and FAZ area were not different between male and female AD participants. Among controls, men had a thicker CST (P < 0.001) and smaller FAZ area (P = 0.003) compared with women. The RNFL thickness, GCIPL thickness, and CVI were similar among male and female AD participants and controls. Conclusions: There may be a loss of the physiologic sex-related differences in retinal structure and microvasculature in those with AD compared with controls. Further studies are needed to elucidate the pathophysiological basis for these findings.

BackgroundAntiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study.MethodsAALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13–21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13–23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen.FindingsOne hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model.InterpretationBy late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide.

Fish are widely reported to ingest microplastics with low levels accumulating in the tissues, but owing to analytical constraints, much less is known about the potential accumulation of nanoplastics via the gut. Recently, the labelling of plastics with inorganic metals (e.g., palladium) has allowed measurements of nanoplastic uptake. The aim of the current study was to quantitatively assess the uptake of nanoplastics by the fish gut using palladium-doped nanoplastics (with a mean hydrodynamic radius of 202 ± 7 nm). By using an ex vivo gut sac exposure system, we show that in 4 h between 200 and 700 million nanoplastics (representing 2.5–9.4% of the administered nanoplastics dose) can enter the mucosa and muscularis layers of the intestine of salmon. Of the particles taken up, up to 700,000 (representing 0.6% of that taken into the tissue) of the nanoplastics passed across the gut epithelium of the anterior intestine and exit into the serosal saline. These data, generated in highly controlled conditions provide a proof-of-concept study, suggesting the potential for nanoplastics to distribute throughout the body, indicating the potential for systemic exposure in fish.

Learning and memory are important for successful education and career progression. We assess these functions in young people (YP) with perinatal HIV (PHIV) (with or without a previous AIDS-defining illness) and a comparable group of HIV-negative YP. 234 PHIV and 68 HIV-negative YP completed 9 tests; 5 National Institutes of Health (NIH) Toolbox tests (2 executive function, 1 speed of information processing, 2 memory); 2 Hopkins Verbal Learning Test Revised (HVLT-R) (learning (L), delayed recall (R)), and 2 verbal application measures. Z-scores for each test were calculated using normative data and averaged by domain where appropriate. The effect of predictors on test scores in the three domains with the lowest z-scores were analysed using linear regression. 139(59%) and 48(71%) PHIV and HIV-negative YP were female, 202(86%) and 52(76%) Black, and median age was 19 [17, 21] and 18 [16, 21] years respectively. 55(24%) PHIV had a previous Center for Disease Control and Prevention (CDC) class C AIDS-defining diagnosis (PHIV/C). For HVLT-R, there was a trend towards PHIV/C YP having the lowest mean z-scores (L -1.5 (95% CI -1.8,-1.2), R -1.7 (-2.0,-1.4)) followed by PHIV without a CDC C diagnosis (L -1.3 (-1.4,-1.1), R -1.4 (-1.5,-1.2)) and then the HIV-negative group (L -1.0 (-1.3,-0.7), R -1.1 (-1.3,-0.8)); all were greater than 1 SD below the reference mean. The same trend was seen for verbal application measures; however, z-scores were within 1 SD below the reference mean. NIH Toolbox tests were similar for all groups. In multivariable analyses PHIV/C and Black ethnicity predicted lower HVLT-R scores. Black ethnicity also predicted lower executive function scores, however each year increase in age predicted higher scores. In conclusion, cognitive performance in verbal learning and recall fell below population normative scores, and was more pronounced in PHIV/C, supporting wider findings that earlier antiretroviral therapy initiation, before the occurrence of AIDS-defining conditions, may protect aspects of cognitive development.

IntroductionIn order to study the role of the microbiome in hematopoietic stem cell transplantation (HCT), researchers collect stool samples from patients at various time points throughout HCT. However, stool collection requires active subject participation and may be limited by patient reluctance to handling stool.MethodsWe performed a prospective study on the impact of financial incentives on stool collection rates. The intervention group consisted of allogeneic HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group of allogeneic HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for possible changes in collections over time, we also compared a contemporaneous control group of autologous HCT patients from 05/2017-05/2018 with a historical control group of autologous HCT patients from 11/2016-05/2017; neither autologous HCT group was compensated. The collection rate was defined as the number of samples provided divided by the number of time points we attempted to obtain stool.ResultsThere were 35 allogeneic HCT patients in the intervention group, 19 allogeneic HCT patients in the historical control group, 142 autologous HCT patients in the contemporaneous control group (that did not receive a financial incentive), and 75 autologous HCT patients in the historical control group. Allogeneic HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allogeneic HCT patients (80% vs 37%, pConclusionOur results demonstrate that a modest incentive can significantly increase collection rates. These results may help to inform the design of future studies involving stool collection.

An 85-year-old male presented to the podiatry clinic following a 1st to 5th left toe amputation as a complication of severe peripheral arterial disease and nonhealing wound despite endovascular intervention with an angiogram. At the visit, cellulitis with gangrene of the surgical site was noted. The patient was admitted to the brick and mortar (BAM) hospital and taken to surgery for a transmetatarsal amputation of the left limb. In the immediate postoperative period, the incisional margins appeared dusky creating concern for flap viability. The medical team recommended a vascular bypass versus a below-knee amputation. However, given the age, comorbidities, and nutritional status, the family refused further surgical intervention. As such, Mayo Clinic’s home hospital program, Advanced Care at Home (ACH), was consulted for continued nonsurgical acute management at home. The patient was transferred to ACH and transported home three days after BAM admission to continue IV antibiotic therapy and wound care. Discharge from ACH occurred 11 days after admission to the BAM hospital. This case highlights the importance of developing health care alternatives to traditional hospitalization and demonstrates that ACH can manage highly complex, elder postoperative patients from the comfort of their homes.

Editor-in-Chief's Note: The Texas Water Journal accepted a request by authors, Justin C. Thompson, Charles W. Kreitler, and Michael H. Young, to reply to the commentary by Robert E. Mace on their article published in the Texas Water Journal (2021) 12(1):202-205, regarding “Exploring Groundwater Recoverability in Texas: Maximum Economically Recoverable Storage,” published in the Texas Water Journal (2020) 11(1):152-171, by Justin C. Thompson, Charles W. Kreitler, and Michael H. Young. The opinions expressed in this commentary are the opinions of the individual authors and not the opinion of the Texas Water Journal or the Texas Water Resources Institute.

Deep Brain Stimulation (DBS) is an important tool in the treatment of pharmacologically resistant neurological movement disorders such as essential tremor (ET) and Parkinson's disease (PD). However, the open-loop design of current systems may be holding back the true potential of invasive neuromodulation. In the last decade we have seen an explosion of activity in the use of feedback to “close the loop” on neuromodulation in the form of adaptive DBS (aDBS) systems that can respond to the patient's therapeutic needs. In this paper we summarize the accomplishments of a 5-year study at the University of Washington in the use of neural feedback from an electrocorticography strip placed over the sensorimotor cortex. We document our progress from an initial proof of hardware all the way to a fully implanted adaptive stimulation system that leverages machine-learning approaches to simplify the programming process. In certain cases, our systems out-performed current open-loop approaches in both power consumption and symptom suppression. Throughout this effort, we collaborated with neuroethicists to capture patient experiences and take them into account whilst developing ethical aDBS approaches. Based on our results we identify several key areas for future work. “Graded” aDBS will allow the system to smoothly tune the stimulation level to symptom severity, and frequent automatic calibration of the algorithm will allow aDBS to adapt to the time-varying dynamics of the disease without additional input from a clinician. Additionally, robust computational models of the pathophysiology of ET will allow stimulation to be optimized to the nuances of an individual patient's symptoms. We also outline the unique advantages of using cortical electrodes for control and the remaining hardware limitations that need to be overcome to facilitate further development in this field. Over the course of this study we have verified the potential of fully-implanted, cortically driven aDBS as a feasibly translatable treatment for pharmacologically resistant ET.

The exposome overhauls conventional environmental health impact research paradigms and provides a novel methodological framework that comprehensively addresses the complex, highly dynamic interplays of exogenous exposures, endogenous exposures, and modifiable factors in humans. Holistic assessments of the adverse health effects and systematic elucidation of the mechanisms underlying environmental exposures are major scientific challenges with widespread societal implications. However, to date, few studies have comprehensively and simultaneously measured airborne pollutant exposures and explored the associated biomarkers in susceptible healthy elderly subjects, potentially resulting in the suboptimal assessment and management of health risks. To demonstrate the exposome paradigm, we describe the rationale and design of a comprehensive biomarker and biomonitoring panel study to systematically explore the association between individual airborne exposure and adverse health outcomes. We used a combination of personal monitoring for airborne pollutants, extensive human biomonitoring, advanced omics analysis, confounding information, and statistical methods. We established an exploratory panel study of Biomarkers of Air Pollutant Exposure in Chinese people aged 60–69 years (China BAPE), which included 76 healthy residents from a representative community in Jinan City, Shandong Province. During the period between September 2018 and January 2019, we conducted prospective longitudinal monitoring with a 3-day assessment every month. This project: (1) leveraged advanced tools for personal airborne exposure monitoring (external exposures); (2) comprehensively characterized biological samples for exogenous and endogenous compounds (e.g., targeted and untargeted monitoring) and multi-omics scale measurements to explore potential biomarkers and putative toxicity pathways; and (3) systematically evaluated the relationships between personal exposure to air pollutants, and novel biomarkers of exposures and effects using exposome-wide association study approaches. These findings will contribute to our understanding of the mechanisms underlying the adverse health impacts of air pollution exposures and identify potential adverse clinical outcomes that can facilitate the development of effective prevention and targeted intervention techniques.

BackgroundScreening mammography is recommended for the early detection of breast cancer. The processes for ordering screening mammography often rely on a health care provider order and a scheduler to arrange the time and location of breast imaging. Self-scheduling after automated ordering of screening mammograms may offer a more efficient and convenient way to schedule screening mammograms. ObjectiveThe aim of this study was to determine the use, outcomes, and efficiency of an automated mammogram ordering and invitation process paired with self-scheduling. MethodsWe examined appointment data from 12 months of scheduled mammogram appointments, starting in September 2019 when a web and mobile app self-scheduling process for screening mammograms was made available for the Mayo Clinic primary care practice. Patients registered to the Mayo Clinic Patient Online Services could view the schedules and book their mammogram appointment via the web or a mobile app. Self-scheduling required no telephone calls or staff appointment schedulers. We examined uptake (count and percentage of patients utilizing self-scheduling), number of appointment actions taken by self-schedulers and by those using staff schedulers, no-show outcomes, scheduling efficiency, and weekend and after-hours use of self-scheduling. ResultsFor patients who were registered to patient online services and had screening mammogram appointment activity, 15.3% (14,387/93,901) used the web or mobile app to do either some mammogram self-scheduling or self-cancelling appointment actions. Approximately 24.4% (3285/13,454) of self-scheduling occurred after normal business hours/on weekends. Approximately 9.3% (8736/93,901) of the patients used self-scheduling/cancelling exclusively. For self-scheduled mammograms, there were 5.7% (536/9433) no-shows compared to 4.6% (3590/77,531) no-shows in staff-scheduled mammograms (unadjusted odds ratio 1.24, 95% CI 1.13-1.36; P

Objective The study evaluates the relationship of coronary stenosis, atherosclerotic plaque characteristics (APCs) and age using artificial intelligence enabled quantitative coronary computed tomographic angiography (AI-QCT).Methods This is a post-hoc analysis of data from 303 subjects enrolled in the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial who were referred for invasive coronary angiography and subsequently underwent coronary computed tomographic angiography (CCTA). In this study, a blinded core laboratory analysing quantitative coronary angiography images classified lesions as obstructive (≥50%) or non-obstructive (65 had more PV and CP than patients 65 had more CP than younger patients in both obstructive (29.2 mm3 vs 48.2 mm3; p

We observed differential infectivity and product yield between two recombinant chimpanzee adenovirus C68 constructs whose primary difference was genome length. To determine a possible reason for this outcome, we characterized the proportion and composition of the empty and packaged capsids. Both analytical ultracentrifugation (AUC) and differential centrifugation sedimentation (DCS, a rapid and quantitative method for measuring adenoviral packaging variants) were employed for an initial assessment of genome packaging and showed multiple species whose abundance deviated between the virus builds but not manufacturing campaigns. Identity of the packaging variants was confirmed by charge detection mass spectrometry (CDMS), the first known application of this technique to analyze adenovirus. The empty and packaged capsid populations were separated via preparative ultracentrifugation and then combined into a series of mixtures. These mixtures showed the oft-utilized denaturing A260 adenoviral particle titer method will underestimate the actual particle titer by as much as three-fold depending on the empty/full ratio. In contrast, liquid chromatography with fluorescence detection proves to be a superior viral particle titer methodology.

We investigated racial disparities in a 30-day composite outcome of readmission and death among patients admitted across a 5-hospital health system following an index COVID-19 admission. A dataset of 1,174 patients admitted between March 1, 2020 and August 21, 2020 for COVID-19 was retrospectively analyzed for odds of readmission among Black patients compared to all other patients, with sequential adjustment for demographics, index admission characteristics, type of post-acute care, and comorbidities. Tabulated results demonstrated a significantly greater odds of 30-day readmission or death among Black patients (18.0% of Black patients vs. 11.3% of all other patients; Univariate Odds Ratio: 1.71, p = 0.002). Sequential adjustment via logistic regression revealed that the odds of 30-day readmission or death were significantly greater among Black patients after adjustment for demographics, index admission characteristics, and type of post-acute care, but not comorbidities. Stratification by type of post-acute care received on discharge revealed that the same disparity in odds of 30-day readmission or death existed among patients discharged home without home services, but not those discharged to home with home services or to a skilled nursing facility or acute rehab facility. Collectively, the findings suggest that weighing comorbidity burdens in post-acute care decisions may be relevant in addressing racial disparities in 30-day outcomes following discharge from an index COVID-19 admission.

We have successfully designed a uranyl ion (U(VI)-specific peptide and used it in the fabrication of an electrochemical sensor. The 12-amino acid peptide sequence, (n) DKDGDGYIpTAAE (c), originates from calmodulin, a Ca(II)-binding protein, and contains a phosphothreonine that enhances the sequence’s affinity for U(VI) over Ca(II). The sensing mechanism of this U(VI) sensor is similar to other electrochemical peptide-based sensors, which relies on the change in the flexibility of the peptide probe upon interacting with the target. The sensor was systematically characterized using alternating current voltammetry (ACV) and cyclic voltammetry. Its limit of detection was 50 nM, which is lower than the United States Environmental Protection Agency maximum contaminant level for uranium. The signal saturation time was ~40 min. In addition, it showed minimal cross-reactivity when tested against nine different metal ions, including Ca(II), Mg(II), Pb(II), Hg(II), Cu(II), Fe(II), Zn(II), Cd(II), and Cr(VI). Its reusability and ability to function in diluted aquifer and drinking water samples were further confirmed and validated. The response of the sensor fabricated with the same peptide sequence but with a nonphosphorylated threonine was also analyzed, substantiating the positive effects of threonine phosphorylation on U(VI) binding. This study places emphasis on strategic utilization of non-standard amino acids in the design of metal ion-chelating peptides, which will further diversify the types of peptide recognition elements available for metal ion sensing applications.

The ubiquitous access and exponential growth of information available on social media networks have facilitated the spread of fake news, complicating the task of distinguishing between this and real news. Fake news is a significant social barrier that has a profoundly negative impact on society. Despite the large number of studies on fake news detection, they have not yet been combined to offer coherent insight on trends and advancements in this domain. Hence, the primary objective of this study was to fill this knowledge gap. The method for selecting the pertinent articles for extraction was created using the preferred reporting items for systematic reviews and meta-analyses (PRISMA). This study reviewed deep learning, machine learning, and ensemble-based fake news detection methods by a meta-analysis of 125 studies to aggregate their results quantitatively. The meta-analysis primarily focused on statistics and the quantitative analysis of data from numerous separate primary investigations to identify overall trends. The results of the meta-analysis were reported by the spatial distribution, the approaches adopted, the sample size, and the performance of methods in terms of accuracy. According to the statistics of between-study variance high heterogeneity was found with τ2 = 3.441; the ratio of true heterogeneity to total observed variation was I2 = 75.27% with the heterogeneity chi-square (Q) = 501.34, the degree of freedom = 124, and p ≤ 0.001. A p-value of 0.912 from the Egger statistical test confirmed the absence of a publication bias. The findings of the meta-analysis demonstrated satisfaction with the effectiveness of the recommended approaches from the primary studies on fake news detection that were included. Furthermore, the findings can inform researchers about various approaches they can use to detect online fake news.

There is a paucity of radiologic literature regarding age-related cataract, and little is known about any differences in the imaging appearance of the natural crystalline lens on computed tomography (CT) exams among different demographic groups. In this retrospective review of 198 eyes in 103 adults who underwent dual-energy computed tomography (DECT) exams of the head, regions of interest spanning 3–5 mm were placed over the center of the lens, and the x-ray attenuation of each lens was recorded in Hounsfield Units (HU) at 3 energy levels: 40 keV, 70 keV, and 190 keV. Generalized estimating equations (GEEs) were used to assess the association of clinical or demographic data with lens attenuation. The mean HU values were significantly lower for the older vs. younger group at 40 keV (GEE p-value = 0.022), but there was no significant difference at higher energy levels (p > 0.05). Mean HU values were significantly higher for females vs. males and non-whites vs. non-Hispanic whites at all 3 energy levels in bivariate and multivariable analyses (all p-value < 0.05). There was no significant association between lens attenuation and either diabetes or smoking status. The crystalline lens of females and non-whites had higher attenuation on DECT which may suggest higher density or increased concentration of materials like calcium and increased potential for cataract formation. Given the large scope of cataracts as a cause of visual impairment and the racial disparities that exist in its detection and treatment, further investigation into the role of opportunistic imaging to detect cataract formation is warranted.

Western North American sagebrush shrublands and steppe face accelerating risks from fire-driven feedback loops that transition these ecosystems into self-reinforcing states dominated by invasive annual grasses. In response, sagebrush conservation decision-making is increasingly done through the lens of resilience to fire and annual grass invasion resistance. Operationalizing resilience and resistance concepts requires place-based understanding of resilience and resistance variation among landscapes over time. Place-based insights allow for landscape prioritization in targeted areas of significance such as protected-area sagebrush ecosystems that exhibit inherently low resilience and are therefore at high risk of loss. We used a multi-scale approach to evaluate sagebrush resiliency and strategic planning across 1) the US National Park system, 2) a regional suite of five parks, and 3) for two specific park case studies. First, we summarized broad patterns of relative resilience to fire and resistance to annual grass invasion across all parks with sagebrush ecosystems. We found that national parks represented ~11% of US protected-area sagebrush ecosystems and reflected a similar low-resilience bias that occurs across the biome, broadly. Climate change is likely to shift both low- and high-resilience park sagebrush ecosystems towards moderate resiliency, creating new opportunities and constraints for park conservation. Approximately seventy park units include at least some sagebrush shrublands or steppe, but we identified 40 parks with substantial amounts (>20% of park area) that can be included in an agency-wide conservation strategy. Second, we examined detailed patterns of resilience and resistance, fire history and fire risk, cheatgrass (Bromus tectorum) invasion, and sagebrush shrub (Artemisia spp.) persistence in five national park units in Columbia Basin and Snake River Plain sagebrush steppe, contextualized by the broader summary. In these five parks, fire frequency and size increased in recent decades. Cheatgrass invasion and sagebrush persistence correlated strongly with resilience, burn frequency (0–3 fires since ~1940), and burn probability, but with important variation, in part mediated by local-scale topography. Third, we used these insights to assemble strategic sagebrush ecosystem fire protection mapping scenarios in two additional parks – Lava Beds National Monument and Great Basin National Park. Readily available and periodically updated geospatial data including soil surveys, fire histories, vegetation inventories, and long-term monitoring support resiliency-based adaptive management through tactical planning of pre-fire protection, post-fire restoration, and triage. Our assessment establishes the precarious importance of the US national park system to sagebrush ecosystem conservation and an operational strategy for place-based and science-supported conservation.

Adolescent alcohol use is associated with adverse psychosocial outcomes, including an increased risk of alcohol use disorder in adulthood. It is therefore important to identify risk factors of alcohol initiation in adolescence. Research to date has shown that altered neural activation to reward is associated with alcohol use in adolescence; however, few studies have focused on neural activation to loss and alcohol use. The current study examined neural activation to loss and reward among 64 alcohol naive 12−14 year olds that did (n = 20) and did not initiate alcohol use by a three year follow-up period. Results showed that compared to adolescents that did not initiate alcohol use, adolescents that did initiate alcohol use by the three year follow-up period had increased activation to loss in the left striatum (i.e., putamen), right precuneus, and the brainstem/pons when they were alcohol naive at baseline. By contrast, alcohol initiation was not associated with neural activation to winning a reward. These results suggest that increased activation in brain regions implicated in salience, error detection/self-referential processing, and sensorimotor function, especially to negative outcomes, may represent an initial vulnerability factor for alcohol use in adolescence.

In response to the environmental damage caused by urbanization, Nature-based Solutions (NbS) are being implemented to enhance biodiversity and ecosystem processes with mutual benefits for society and nature. Although the field of NbS is flourishing, experiments in different geographic locations and environmental contexts have produced variable results, with knowledge particularly lacking for the subtidal zone. This study tested the effects of physical complexity on colonizing communities in subtidal habitats in two urban locations: (1) Plymouth, United Kingdom (northeast Atlantic) and (2) Tel Aviv, Israel (eastern Mediterranean) for 15- and 12-months, respectively. At each location, physical complexity was manipulated using experimental tiles that were either flat or had 2.5 or 5.0 cm ridges. In Plymouth, biological complexity was also manipulated through seeding tiles with habitat-forming mussels. The effects of the manipulations on taxon and functional richness, and community composition were assessed at both locations, and in Plymouth the survival and size of seeded mussels and abundance and size of recruited mussels were also assessed. Effects of physical complexity differed between locations. Physical complexity did not influence richness or community composition in Plymouth, while in Tel Aviv, there were effects of complexity on community composition. In Plymouth, effects of biological complexity were found with mussel seeding reducing taxon richness, supporting larger recruited mussels, and influencing community composition. Our results suggest that outcomes of NbS experiments are context-dependent and highlight the risk of extrapolating the findings outside of the context in which they were tested.

Introduction: Prosthetic joint infection (PJI) due to Streptococcus bovis group (SBG), specifically S. bovis biotype I (S. gallolyticus), is rare and associated with colorectal carcinoma. Little has been published regarding SBG PJI. We analyzed nine cases of SBG PJI at our institution, the largest series to date.Methods: The medical records of patients diagnosed with SBG PJI between 2000-2017 were reviewed. Patients were followed until death, failure, or loss to follow-up. Mean follow-up was 37 months (range 0.5-74 months).Results: Nine PJI in 8 patients with mean prosthesis age at diagnosis of 8 years (range 4 weeks-17 years) were identified. The median duration between symptom onset and treatment was 38 weeks (range 0.3 weeks-175 weeks). 8/9 had their PJI eradicated with treatment based on acuity of symptoms. Acute PJI (2) was treated with DAIR, and chronic PJI (7) was treated with 2-stage revision arthroplasty. 1 PJI with chronic PJI developed recurrent infection after initial treatment. All patients received post-operative IV antibiotics. 7/8 patients received Ceftriaxone. Three patients received lifelong oral antibiotics. 7/8 patients underwent colonoscopy. 5/7 patients were found to have polyps following PJI diagnosis with one carcinoma and two dysplastic polyps. The two patients without polyps had identifiable gastrointestinal (GI) mucosal abnormality: tooth extraction prior to symptom onset and diverticulosis on chronic anticoagulation.Conclusion: SBG PJI is typically due to hematologic seeding. Colonoscopy should be pursued for patients with SBG PJI. Surgical treatment dictated by infection acuity and 6-week course of Ceftriaxone seems sufficient to control infection.

Physicians have a lot to consider when they place a patient on the ventilator. This article reviews the literature and provides the physician with a clear guide to managing the ventilator in the ICU. This manuscript is meant to be a practical guide to managing the ventilator at the patient's bedside.