bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors
Authors: Davis Jessie R. , Wang Xiao , Witte Isaac P. , Huang Tony P. , Levy Jonathan M. , Raguram Aditya , Banskota Samagya , Seidah Nabil G. , Musunuru Kiran , Liu David R.
Published: July 2022

The viral delivery of base editors has been complicated by their size and by the limited packaging capacity of adeno-associated viruses (AAVs). Typically, dual-AAV approaches based on trans-splicing inteins have been used. Here we show that, compared with dual-AAV systems, AAVs with size-optimized genomes incorporating compact adenine base editors (ABEs) enable efficient editing in mice at similar or lower doses. Single-AAV-encoded ABEs retro-orbitally injected in mice led to editing efficiencies in liver (66%), heart (33%) and muscle (22%) tissues that were up to 2.5-fold those of dual-AAV ABE8e, and to a 93% knockdown (on average) of human PCSK9 and of mouse Pcsk9 and Angptl3 in circulation, concomitant with substantial reductions of plasma cholesterol and triglycerides. Moreover, three size-minimized ABE8e variants, each compatible with single-AAV delivery, collectively offer compatibility with protospacer-adjacent motifs for editing approximately 82% of the adenines in the human genome. ABEs encoded within single AAVs will facilitate research and therapeutic applications of base editing by simplifying AAV production and characterization, and by reducing the dose required for the desired level of editing.
Development and initial validation of a dog quality of life instrument
Authors: Schmutz Amandine , Spofford Nathaniel , Burghardt Walter , De Meyer Geert
Published: July 2022

The increasing attention for the dog-owner relationship combined with advances in nutrition and veterinary care have made wellbeing a focal point for dog owners, veterinarians, and dog product and service providers. While canine wellbeing can be quantified by survey-based quality of life instruments like those used in human healthcare, there are currently few instruments available that can do this reliably and at scale. Here we report the development and initial validation of a canine quality of life instrument specifically designed to quantify wellbeing in the general dog population. The instrument is based on a simple 32-question survey and includes 5 daytime domains (energetic, mobile, relaxed, happy, sociable) and 3 mealtime domains (relaxed, interested and satisfied). It captures specific health-related aspects as well as more general wellbeing aspects and, in an initial sample of 2813 dogs, already provides useful insights on canine wellbeing. We believe that data collection at scale with this instrument will help bring optimal wellbeing to the dogs we care for.
Association between changes in working status and hand-grip strength among Korean middle-aged and older adults: a longitudinal panel study
Authors: Yun Il , Park Yu Shin , Park Eun-Cheol , Jang Sung-In
Published: July 2022

We investigated the association between working status changes and hand-grip strength (HGS) among middle-aged and older Korean adults using data from the 2006–2018 Korean Longitudinal Study of Aging. After excluding those with less than normal HGS in the baseline year, newly added panels, and missing values, 3843 participants (2106 men; 1737 women) were finally included. After adjusting for potential confounders, we used a 2-year lagged multivariable generalized estimating equation model to examine this association longitudinally. Men who quit working or who continued to be non-working were more likely to have lower HGS than those who continued to work (working → non-working, adjusted odds ratio [OR]: 1.47, 95% confidence interval [CI] 1.26–1.70; non-working → non-working, adjusted OR: 1.52, 95% CI 1.34–1.72). Compared to women who continued to work, the other three groups showed high ORs with low HGS (working → non-working, adjusted OR: 1.19, 95% CI 1.01–1.40; non-working → working, adjusted OR: 1.18, 95% CI 0.98–1.42; non-working → non-working, adjusted OR: 1.38, 95% CI 1.22–1.56). Middle-aged and older adults whose working status changed to non-working were at higher risk of reduced HGS than others and required muscular strength training interventions to improve HGS and prevent sarcopenia.
Using a two-sample mendelian randomization analysis to explore the relationship between physical activity and Alzheimer’s disease
Authors: Zhang Bowen , Huang Xiaowen , Wang Xiliang , Chen Xiaorui , Zheng Caifang , Shao Weihao , Wang Gaili , Zhang Weidong
Published: July 2022

Evidence from previous epidemiological studies on the effect of physical activity on the risk of Alzheimer’s disease (AD) is conflicting. We performed a two-sample Mendelian randomization analysis to verify whether physical activity is causally associated with AD. This study used two-sample Mendelian randomization (MR) analysis to estimate the association between physical activity (including overall activity, sedentary behavior, walking, and moderate-intensity activity) and AD. Genetic instruments for physical activity were obtained from published genome-wide association studies (GWAS) including 91,105 individuals from UK Biobank. Summary-level GWAS data were extracted from the International Genomics of Alzheimer’s Project IGAP (21,982 patients with AD and 41,944 controls). Inverse Variance Weighted (IVW) was used to estimate the effect of physical activity on AD. Sensitivity analyses including weighted median, MR-Egger, MR-PRESSO, and leave-one-out analysis were used to estimate pleiotropy and heterogeneity. Mendelian randomization evidences suggested a protective relationship between walking and AD (odds ratio (OR) = 0.30, 95% confidence interval (CI), 0.13–0.68, P = 0.0039). Genetically predicted overall activity, sedentary behavior, and moderate-intensity activity were not associated with AD. In summary, this study provided evidence that genetically predicted walking might associate with a reduced risk of AD. Further research into the causal association between physical activity and AD could help to explore the real relationship and provide more measures to reduce AD risk.
Impact of active surveillance for prostate cancer on the risk of depression and anxiety
Authors: Sypre Davidson , Pignot Géraldine , Touzani Rajae , Marino Patricia , Walz Jochen , Rybikowski Stanislas , Maubon Thomas , Branger Nicolas , Salem Naji , Mancini Julien , Gravis Gwenaelle , Bendiane Marc-Karim , Bouhnik Anne-Deborah
Published: July 2022

Active surveillance (AS) is a standard treatment option for low risk localized prostate cancer. However, the risk of anxiety and depression compared to other curative strategies, namely radical prostatectomy (RP) and radiotherapy (RT), is controversial. This study consisted in a French representative sample of 4174 5-years cancer survivors. Self-reported data, including quality-of-life assessment, were prospectively collected through telephone interviews. Among the 447 survivors with PC, we selected 292 patients with localized prostate cancer, T1–T2 stage, Gleason score ≤ 7 and we compared anxiety and depressive symptoms according to treatment strategy. Among patients on AS, 14.9% received curative treatment during the 5 years of follow-up. Anxiety was reported in 34.3% of cases in the AS group versus 28.6% in the RP group and 31.6% in the RT group (p = 0.400), while depressive symptoms were reported in 14.9% of cases in the AS group versus 10.7% in the RP group and 22.8% in the RT group (p = 0.770). Consumption of anxiolytics reported did not vary significantly between the 3 groups (p = 0.330). In conclusion, patients managed with AS for localized prostate cancer do not report more anxiety or depressive symptoms than patients managed with curative treatment, encouraging the extended use of active surveillance.
Convergence of virulence and antimicrobial resistance in increasingly prevalent Escherichia coli ST131 papGII+ sublineages
Authors: Biggel Michael , Moons Pieter , Nguyen Minh Ngoc , Goossens Herman , Van Puyvelde Sandra
Published: July 2022

Escherichia coli lineage ST131 is an important cause of urinary tract and bloodstream infections worldwide and is highly resistant to antimicrobials. Specific ST131 lineages carrying invasiveness-associated papGII pathogenicity islands (PAIs) were previously described, but it is unknown how invasiveness relates to the acquisition of antimicrobial resistance (AMR). In this study, we analysed 1638 ST131 genomes and found that papGII+ isolates carry significantly more AMR genes than papGII-negative isolates, suggesting a convergence of virulence and AMR. The prevalence of papGII+ isolates among human clinical ST131 isolates increased dramatically since 2005, accounting for half of the recent E. coli bloodstream isolates. Emerging papGII+ lineages within clade C2 were characterized by a chromosomally integrated blaCTX-M-15 and the loss and replacement of F2:A1:B- plasmids. Convergence of virulence and AMR is worrying, and further dissemination of papGII+ ST131 lineages may lead to a rise in severe and difficult-to-treat extraintestinal infections.
The 1, 2-ethylenediamine SQ109 protects against tuberculosis by promoting M1 macrophage polarization through the p38 MAPK pathway
Authors: Singh Mona , Kumar Santosh , Singh Baldeep , Jain Preeti , Kumari Anjna , Pahuja Isha , Chaturvedi Shivam , Prasad Durbaka Vijay Raghava , Dwivedi Ved Prakash , Das Gobardhan
Published: July 2022

Directly Observed Treatment Short-course (DOTs), is an effective and widely recommended treatment for tuberculosis (TB). The antibiotics used in DOTs, are immunotoxic and impair effector T cells, increasing the risk of re-infections and reactivation. Multiple reports suggest that addition of immune-modulators along with antibiotics improves the effectiveness of TB treatment. Therefore, drugs with both antimicrobial and immunomodulatory properties are desirable. N1-(Adamantan-2-yl)-N2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]ethane-1,2-diamine (SQ109) is an asymmetric diamine derivative of adamantane, that targets Mycobacterial membrane protein Large 3 (MmpL3). SQ109 dissipates the transmembrane electrochemical proton-gradient necessary for cell-wall biosynthesis and bacterial activity. Here, we examined the effects of SQ109 on host-immune responses using a murine TB model. Our results suggest the pro-inflammatory nature of SQ109, which instigates M1-macrophage polarization and induces protective pro-inflammatory cytokines through the p38-MAPK pathway. SQ109 also promotes Th1 and Th17-immune responses that inhibit the bacillary burden in a murine model of TB. These findings put forth SQ109 as a potential-adjunct to TB antibiotic therapy.
Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program
Authors: DiCorpo Daniel , Gaynor Sheila M. , Russell Emily M. , Westerman Kenneth E. , Raffield Laura M. , Majarian Timothy D. , Wu Peitao , Sarnowski Chloé , Highland Heather M. , Jackson Anne , Hasbani Natalie R. , de Vries Paul S. , Brody Jennifer A. , Hidalgo Bertha , Guo Xiuqing , Perry James A. , O’Connell Jeffrey R. , Lent Samantha , Montasser May E. , Cade Brian E. , Jain Deepti , Wang Heming , D’Oliveira Albanus Ricardo , Varshney Arushi , Yanek Lisa R. , Lange Leslie , Palmer Nicholette D. , Almeida Marcio , Peralta Juan M. , Aslibekyan Stella , Baldridge Abigail S. , Bertoni Alain G. , Bielak Lawrence F. , Chen Chung-Shiuan , Chen Yii-Der Ida , Choi Won Jung , Goodarzi Mark O. , Floyd James S. , Irvin Marguerite R. , Kalyani Rita R. , Kelly Tanika N. , Lee Seonwook , Liu Ching-Ti , Loesch Douglas , Manson JoAnn E. , Minster Ryan L. , Naseri Take , Pankow James S. , Rasmussen-Torvik Laura J. , Reiner Alexander P. , Reupena Muagututi’a Sefuiva , Selvin Elizabeth , Smith Jennifer A. , Weeks Daniel E. , Xu Huichun , Yao Jie , Zhao Wei , Parker Stephen , Alonso Alvaro , Arnett Donna K. , Blangero John , Boerwinkle Eric , Correa Adolfo , Cupples L. Adrienne , Curran Joanne E. , Duggirala Ravindranath , He Jiang , Heckbert Susan R. , Kardia Sharon L. R. , Kim Ryan W. , Kooperberg Charles , Liu Simin , Mathias Rasika A. , McGarvey Stephen T. , Mitchell Braxton D. , Morrison Alanna C. , Peyser Patricia A. , Psaty Bruce M. , Redline Susan , Shuldiner Alan R. , Taylor Kent D. , Vasan Ramachandran S. , Viaud-Martinez Karine A. , Florez Jose C. , Wilson James G. , Sladek Robert , Rich Stephen S. , Rotter Jerome I. , Lin Xihong , Dupuis Josée , Meigs James B. , Wessel Jennifer , Manning Alisa K.
Published: July 2022

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
A native IgE in complex with profilin provides insights into allergen recognition and cross-reactivity
Authors: García-Ramírez Benjamín , Mares-Mejía Israel , Rodríguez-Hernández Annia , Cano-Sánchez Patricia , Torres-Larios Alfredo , Ortega Enrique , Rodríguez-Romero Adela
Published: July 2022

Allergies have become a rising health problem, where plentiful substances can trigger IgE-mediated allergies in humans. While profilins are considered minor allergens, these ubiquitous proteins are primary molecules involved in cross-reactivity and pollen-food allergy syndrome. Here we report the first crystal structures of murine Fab/IgE, with its chains naturally paired, in complex with the allergen profilin fromHevea brasiliensis(Hev b 8). The crystallographic models revealed that the IgE’s six complementarity-determining regions (CDRs) interact with the allergen, comprising a rigid paratope-epitope surface of 926 Å2, which includes an extensive network of interactions. Interestingly, we also observed previously unreported flexibility at Fab/IgE’s elbow angle, which did not influence the shape of the paratope. The Fab/IgE exhibits a high affinity for Hev b 8, even when using 1 M NaCl in BLI experiments. Finally, based on the encouraging cross-reactivity assays using two mutants of the maize profilin (Zea m 12), this antibody could be a promising tool in IgE engineering for diagnosis and research applications.
ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude
Authors: Li Huilin , Ou Jiali , Li Yaqun , Xu Niannian , Li Qing , Wu Ping , Peng Chao , Tang Yun-Chi , Chang Hung-Chun
Published: July 2022

Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKIIδ expression and increases BMAL1 activity via eliciting CaMKIIδ-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKIIδ-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders.
Anaerobic oxidation has a minor effect on mitigating seafloor methane emissions from gas hydrate dissociation
Authors: Stranne Christian , O’Regan Matt , Hong Wei-Li , Brüchert Volker , Ketzer Marcelo , Thornton Brett F. , Jakobsson Martin
Published: July 2022

Continental margin sediments contain large reservoirs of methane stored as gas hydrate. Ocean warming will partly destabilize these reservoirs which may lead to the release of substantial, yet unconstrained, amounts of methane. Anaerobic oxidation of methane is the dominant biogeochemical process to reduce methane flux, estimated to consume 90% of the methane produced in marine sediments today. This process is however neglected in the current projections of seafloor methane release from gas hydrate dissociation. Here, we introduce a fully coupled oxidation module to a hydraulic-thermodynamic-geomechanical hydrate model. Our results show that for seafloor warming rates > 1 °C century−1, the efficiency of anaerobic oxidation of methane in low permeability sediments is poor, reducing the seafloor methane emissions by <5%. The results imply an extremely low mitigating effect of anaerobic oxidation of methane on climate warming-induced seafloor methane emissions.
Photosynthetic microorganisms effectively contribute to bryophyte CO2 fixation in boreal and tropical regions
Authors: Jassey Vincent E J , Hamard Samuel , Lepère Cécile , Céréghino Régis , Corbara Bruno , Küttim Martin , Leflaive Joséphine , Leroy Céline , Carrias Jean-François
Published: July 2022

Photosynthetic microbes are omnipresent in land and water. While they critically influence primary productivity in aquatic systems, their importance in terrestrial ecosystems remains largely overlooked. In terrestrial systems, photoautotrophs occur in a variety of habitats, such as sub-surface soils, exposed rocks, and bryophytes. Here, we study photosynthetic microbial communities associated with bryophytes from a boreal peatland and a tropical rainforest. We interrogate their contribution to bryophyte C uptake and identify the main drivers of that contribution. We found that photosynthetic microbes take up twice more C in the boreal peatland (~4.4 mg CO2.h−1.m−2) than in the tropical rainforest (~2.4 mg CO2.h−1.m−2), which corresponded to an average contribution of 4% and 2% of the bryophyte C uptake, respectively. Our findings revealed that such patterns were driven by the proportion of photosynthetic protists in the moss microbiomes. Low moss water content and light conditions were not favourable to the development of photosynthetic protists in the tropical rainforest, which indirectly reduced the overall photosynthetic microbial C uptake. Our investigations clearly show that photosynthetic microbes associated with bryophyte effectively contribute to moss C uptake despite species turnover. Terrestrial photosynthetic microbes clearly have the capacity to take up atmospheric C in bryophytes living under various environmental conditions, and therefore potentially support rates of ecosystem-level net C exchanges with the atmosphere.
Asymmetric [3+2] spiroannulation of pyrazolone-derived Morita–Baylis–Hillman carbonates with alkynyl ketones: facile access to spiro[cyclopentadiene-pyrazolone] scaffolds
Authors: Wei Xingfu , Huang Yue , Wang Wenyao , Wei Shiqiang , Qu Jingping , Wang Baomin
Published: July 2022

An organocatalyzed asymmetric [3+2] spiroannulation reaction of pyrazolone-derived MBH carbonates with alkynyl ketones was described, affording chiral spiro[cyclopentadiene-pyrazolone] scaffolds in good yields with high degrees of enantiocontrol.
Visible-light-driven site-selective alkylation of the benzo core of coumarins
Authors: Tripathi Krishna N. , Singh Shashank , Akhtar Naved , Manna Kuntal , Singh Ravi P.
Published: July 2022

An unprecedented, straightforward photochemical platform for efficient site-selective C–H alkylation of the C-7 position of coumarins has been reported.
A VSi2P4/FeCl2 van der Waals heterostructure: a two-dimensional reconfigurable magnetic diode
Authors: Han Jiangchao , Feng Yulin , Gao Guoying
Published: July 2022

The spin-dependent transmission path in the VSi2P4/FeCl2 heterostructure.
Cyrene: a bio-based novel and sustainable solvent for organic synthesis
Authors: Stini Naya A. , Gkizis Petros L. , Kokotos Christoforos G.
Published: July 2022

This review highlights the use of Cyrene as an alternative green solvent in organic synthesis.
BaTb0.3Fe0.7O3−δ: a new proton-conductor-derived cathode for proton-conducting solid oxide fuel cells
Authors: Zhang Liling , Dai Gui , Yu Shoufu , Ma Chengjian , Dai Hailu , Bi Lei
Published: July 2022

BaTb0.3Fe0.7O3−δ, a new proton-conductor-derived cathode, has been proposed as a cathode for proton-conducting solid oxide fuel cells with high performance.
Kalman and Cauchy clustering for anomaly detection based authentication of IoMTs using extreme learning machine
Authors: Mohamed Tamara Saad , Aydin Sezgin , Alkhayyat Ahmed , Malik Rami Q.
Published: July 2022

The vulnerabilities of the Internet of Things (IoTs) in general and the Internet of Mobile Things (IoMTs) in particular motivate researchers to equip them with security systems against intruders and attacks. The integration of anomaly detection with intrusion detection for IoMTs has not been addressed adequately. This paper tackles this issue through building a Kalman filter and Cauchy clustering algorithm for anomaly detection and using them for authentication nodes within IoMTs using the Extreme Learning Machine classifier. The algorithm of this proposed work is composed of various components; first, the Kalman filter‐based model for estimating the trajectory of pedestrians within an indoor environment based on fusing WiFi with IMU data. Second, trustworthiness assessment for detecting anomaly behaviour in IoMT based on the estimated trajectory using the Kalman filter. Third, the trust IDS model for IoMT systems by integrating anomaly detection with online learning for attacks identification using an online sequential extreme learning machine. The algorithm has been implemented and evaluated using TamperU dataset for WiFi fingerprinting and KDD99 for intrusion detection. Furthermore, a comparison with benchmarks (the algorithms which used in other studies) for intrusion and anomaly detection proves the superiority of this proposed approach in terms of all the considered classification metrics.
Star formation and AGN feedback in the local Universe: Combining LOFAR and MaNGA
Authors: Mulcahey C. R. , Leslie S. K. , Jackson T. M. , Young J. E. , Prandoni I. , Hardcastle M. J. , Roy N. , Małek K. , Magliocchetti M. , Bonato M. , Röttgering H. J. A. , Drabent A.
Published: July 2022

The effect of active galactic nuclei (AGN) on their host galaxies – in particular their levels of star formation – remains one of the key outstanding questions of galaxy evolution. Successful cosmological models of galaxy evolution require a fraction of energy released by an AGN to be redistributed into the interstellar medium to reproduce the observed stellar mass and luminosity function and to prevent the formation of over-massive galaxies. Observations have confirmed that the radio-AGN population is energetically capable of heating and redistributing gas at all phases, however, direct evidence of AGN enhancing or quenching star formation remains rare. With modern, deep radio surveys and large integral field spectroscopy (IFS) surveys, we can detect fainter synchrotron emission from AGN jets and accurately probe the star-forming properties of galaxies, respectively. In this paper, we combine data from the LOw Frequency ARray Two-meter Sky Survey (LoTSS) with data from one of the largest optical IFS surveys, Mapping Nearby Galaxies at Apache Point Observatory (MaNGA), to probe the star-forming properties of 307 local (z < 0.15) galaxies that host radio-detected AGN (RDAGN). We compare our results to a robust control sample of non-active galaxies that each match the stellar mass, redshift, visual morphology, and inclination of a RDAGN host. We find that RDAGN and control galaxies have broad star-formation rate (SFR) distributions, typically lie below the SFMS, and have negative stellar light-weighted age gradients. These results indicate that AGN selected based on their current activity are not responsible for suppressing their host galaxies’ star formation. Rather, our results support the maintenance mode role that radio AGN are expected to have in the local Universe.
Kinematics and mass distributions for non-spherical deprojected Sérsic density profiles and applications to multi-component galactic systems
Authors: Price S. H. , Übler H. , Förster Schreiber N. M. , de Zeeuw P. T. , Burkert A. , Genzel R. , Tacconi L. J. , Davies R. I. , Price C. P.
Published: July 2022

Using kinematics to decompose the mass profiles of galaxies, including the dark matter contribution, often requires parameterization of the baryonic mass distribution based on ancillary information. One such model choice is a deprojected Sérsic profile with an assumed intrinsic geometry. The case of flattened, deprojected Sérsic models has previously been applied to flattened bulges in local star-forming galaxies (SFGs), but can also be used to describe the thick, turbulent disks in distant SFGs. Here, we extend this previous work that derived density (ρ) and circular velocity (vcirc) curves by additionally calculating the spherically-enclosed 3D mass profiles (Msph). Using these profiles, we compared the projected and 3D mass distributions, quantified the differences between the projected and 3D half-mass radii (Re; r1/2, mass, 3D), and compiled virial coefficients relating vcirc(R) and Msph(< r = R) or Mtot. We quantified the differences between mass fraction estimators for multi-component systems, particularly for dark matter fractions (ratio of squared circular velocities versus ratio of spherically enclosed masses), and we considered the compound effects of measuring dark matter fractions at the projected versus 3D half-mass radii. While the fraction estimators produce only minor differences, using different aperture radius definitions can strongly impact the inferred dark matter fraction. As pressure support is important in analyses of gas kinematics (particularly, at high redshifts), we also calculated the self-consistent pressure support correction profiles, which generally predict less pressure support than for the self-gravitating disk case. These results have implications for comparisons between simulation and observational measurements, as well as for the interpretation of SFG kinematics at high redshifts. We have made a set of precomputed tables and the code to calculate the profiles publicly available.
Interactive spatial speech recognition maps based on simulated speech recognition experiments
Authors: Schädler Marc René
Published: July 2022

In their everyday life, the speech recognition performance of human listeners is influenced by diverse factors, such as the acoustic environment, the talker and listener positions, possibly impaired hearing, and optional hearing devices. Prediction models come closer to considering all required factors simultaneously to predict the individual speech recognition performance in complex, that is, e.g. multi-source dynamic, acoustic environments. While such predictions may still not be sufficiently accurate for serious applications, such as, e.g. individual hearing aid fitting, they can already be performed. This raises an interesting question:What could we do if we had a perfect speech intelligibility model?In a first step, means to explore and interpret the predicted outcomes of large numbers of speech recognition experiments would be helpful, and large amounts of data demand an accessible, that is, easily comprehensible, representation. In this contribution, an interactive, that is, user manipulable, representation of speech recognition performance is proposed and investigated by means of a concrete example, which focuses on the listener’s head orientation and the spatial dimensions – in particular width and depth – of an acoustic scene. An exemplary modeling toolchain, that is, a combination of an acoustic model, a hearing device model, and a listener model, was used to generate a data set for demonstration purposes. Using the spatial speech recognition maps to explore this data set demonstrated the suitability of the approach to observe possibly relevant listener behavior. The proposed representation was found to be a suitable target to compare and validate modeling approaches in ecologically relevant contexts, and should help to explore possible applications of future speech recognition models. Ultimately, it may serve as a tool to use validated prediction models in the design of spaces and devices which take speech communication into account.
Die Zusatzweiterbildung Klinische Akut- und Notfallmedizin
Authors: Schunk Domagoj , Malsy Manuela , Zimmermann Markus
Published: July 2022

German emergency departments have experienced significant development in recent years due to changes in health care policy as well as continued professionalism in emergency department
medical care. The German Medical Association has taken this development into account and included an additional post residency fellowship training program in emergency medicine into their
2018 model training regulation guidelines. The specialized training in emergency medicine covers the initial diagnosis and treatment of patients in the emergency department as well as
medical decision making and coordination of further specialist medical care in interdisciplinary cooperation. The following article provides information about requirements, content, and
duration of the fellowship training program in emergency medicine, which has now been introduced in emergency departments throughout Germany.
Leitliniengerechte Synkopenabklärung
Authors: Diehl Rolf R.
Published: July 2022

Synkopen bilden bei älteren Menschen häufige Sturzursachen. Die beste Sturzprophylaxe besteht in der ätiologischen Abklärung und Behandlung des Synkopenleidens. Die aktuellen Synkopenleitlinien der Deutschen Gesellschaft für Neurologie empfehlen bei Synkopenverdacht zunächst eine hypothesenorientierte Basisdiagnostik, in deren Zentrum die Anamnese mit einer sorgfältigen Exploration der verschiedenen Phasen des Ablaufes einer vorübergehenden Bewusstlosigkeit steht. Zur Basisdiagnostik gehören ferner ein 12-Kanal-EKG und Blutdruckmessungen im Liegen und im Stehen (aktiver Stehtest). Vasovagale Synkopen können bereits nach Anamnese und ohne weitere Zusatzdiagnostik diagnostiziert werden, wenn die Ohnmachten in typischen Situationen (z. B. Verletzungskontext) auftreten und ihnen Prodromi wie Wärmegefühl oder Schwitzen vorausgehen. Bei älteren Patienten bilden orthostatische Blutdruckabfälle durch eine zentrale oder periphere Schädigung des autonomen Nervensystems einen häufigen Synkopenmechanismus, weshalb der aktive Stehtest besonders beim älteren Menschen oft weitere Zusatzdiagnostik überflüssig macht.
Evaluation der langfristigen klinischen und ökonomischen Auswirkungen einer Behandlung mit Ofatumumab gegenüber Dimethylfumarat und Glatirameracetat bei Patienten mit schubförmiger Multipler Sklerose aus gesellschaftlicher Sicht in Deutschland
Authors: Koeditz Dominik , Frensch Jürgen , Bierbaum Martin , Ness Nils-Henning , Ettle Benjamin , Ziemssen Tjalf
Published: July 2022

Hintergrund Es gibt Hinweise darauf, dass bei schubförmiger Multipler Sklerose (Relapsing Multiple Sclerosis; RMS) ein früher Beginn einer hochwirksamen Therapie einer Eskalationsstrategie überlegen sein könnte.

Ziel Mit Hilfe einer Kosten-Folgen-Analyse sollen die klinischen und gesundheitsökonomischen Auswirkungen verschiedener Behandlungsszenarien mit Ofatumumab (OMB), Dimethylfumarat (DMF) bzw. Glatirameracetat (GA) simuliert werden: ein sofortiger Behandlungsbeginn mit OMB als Ersttherapie, ein früher Wechsel auf OMB nach einem Jahr unter Behandlung mit DMF oder GA, ein später Wechsel nach 5 Jahren bzw. kein Wechsel.

Methodik Der Simulation wurde ein EDSS-basiertes Markov-Modell mit einem Zeithorizont von 10 Jahren zugrunde gelegt. Bei jedem Zyklusübergang waren eine Progression, eine Verbesserung bzw. eine Stabilisierung des EDSS, ein Behandlungsabbruch, Schub oder Tod möglich. Inputdaten für das Modell stammten aus OMB-Studien, einer Netzwerk-Metaanalyse, aus Fachveröffentlichungen und öffentlich verfügbaren Quellen.

Ergebnisse Ein später Wechsel auf OMB resultierte im Vergleich mit der sofortigen OMB-Behandlung in einem geringeren Anteil an Patienten mit einem EDSS von 0 bis 3 nach 10 Jahren (∆ –7,5 % DMF; ∆ –10,3 % GA), in mehr Schüben (∆ + 0,72 DMF; ∆ + 1,23 GA) und in geringeren Beschäftigungsquoten (∆ –4,0 % DMF; ∆ –5,6 % GA). Dies gilt ebenso für den Vergleich eines späten mit einem frühen Wechsel. Das Szenario ohne Therapieumstellung führte zu schlechteren Ergebnissen. Die Arzneimittelkosten waren bei sofortiger bzw. früher OMB-Behandlung höher, wurden aber nahezu ausgeglichen durch niedrigere Kosten für die Patientenversorgung (u. a. stationäre bzw. informelle Pflege, gemeinschaftliche und soziale Dienstleistungen) und geringere Produktivitätsverluste.

Schlussfolgerung Eine sofortige Behandlung mit OMB bzw. ein früher Wechsel auf OMB führen zu besseren Ergebnissen hinsichtlich Klinik und Produktivität im Vergleich zu spätem oder keinem Wechsel auf OMB. Dabei bleiben die sofortige bzw. frühe OMB-Behandlung nahezu kostenneutral.
Choroidal Manifestation of Smoldering Myeloma: Case Report
Authors: Sokolenko Ekaterina , Johansson Patricia , Ting Saskia , Bechrakis Nikolaos E. , Fiorentzis Miltiadis
Published: July 2022

This case illustrates clinical, histopathological, immunohistochemical, and molecular pathological diagnostic testing of smoldering myeloma with atypical ophthalmic manifestations. In our
case, the choroidal lesion presented as a solitary manifestation of a systemic disease. Choroidal lesions of monoclonal plasma cells are extremely rare and should be included in the
differential diagnosis of amelanotic choroidal lesions, even if the histopathological examination of the primary lesion is not informative. Clinical course, immunohistochemistry, and
molecular pathology are essential components of the diagnostic pathway.
Oft übersehen – Ohnmacht und Kreislaufstörungen im Alter
Authors: Haubrich Christina
Published: July 2022

Bei älteren Patienten ist davon auszugehen, dass etwa die Hälfte aller Stürze unklarer Ursache auf Synkopen zurückzuführen ist. Gründe hierfür sind unter anderem die fehlende Erinnerung an Beschwerden wie Schwindel oder Benommenheit im Vorfeld des Sturzes und die oft atypischen Beschwerden. Dies trifft insbesondere auf ältere Patienten mit neurologischen bzw. neurodegenerativen Erkrankungen zu. Begünstigend hierfür sind zentrale und periphere neurovegetative Störungen, aber auch Vorerkrankungen des Herzens, Polypharmazie und Veränderungen des Salz-Wasserhaushaltes. In der Behandlung von Stürzen unklarer Ursache sollten Synkopen deshalb besonders berücksichtigt werden. Das beinhaltet die Anamnese neurologischer und kardiologisch-internistischer Risikofaktoren, die orientierende Untersuchung der Kreislaufregulation mittels verkürztem Schellong-Test sowie ggf. die Diagnostik neurovegetativer Kreislaufregulation bzw. autonome Funktionsdiagnostik. Der Behandlungserfolg hängt davon ab, ob medikamentöse und nicht medikamentöse Behandlungsempfehlungen interdisziplinär abgestimmt sind. Um erfolgreich vorbeugen zu können, sollten Patienten und Angehörige über das Risiko von Stürzen und Synkopen aufgeklärt werden.
Natural Dibenzo[b,f]oxepines, Pacharin and Bauhiniastatin-1, Isolated from Bauhinia acuruana Induce Apoptosis on Breast Cancer Cells via MCL-1 Protein
Reduction
Authors: Souza Silvia de Maria , Souza Luciano Santos de , Silva Valdenizia Rodrigues , Soares Milena Botelho Pereira , Bezerra Daniel Pereira , Gois Roberto Wagner da Silva , Silva Horlando Carlota da , Santiago Gilvandete Maria Pinheiro , Militao Gardenia Carmen Gadelha
Published: July 2022

Herein, we describe the antiproliferative effects of two natural dibenzo [b,f]oxepines, pacharin and bauhiniastatin-1, isolated from Bauhinia acuruana on a breast cancer cell
line and the mode of action underlying the cytotoxicity. Both compounds were cytotoxic in a panel of six tumor lines analyzed by the MTT assay, and IC50 values ranged from 7.8 to
45.1 µM, including human breast adenocarcinoma (MCF-7) cells. In contrast, none of the compounds were cytotoxic on normal human peripheral blood mononuclear cells (IC50
> 100 µM). Human breast adenocarcinoma (MCF-7) cells treated with pacharin or bauhiniastatin-1 20 µM for 24 h presented a reduction in cell volume and intensification of chromatin
condensation, DNA fragmentation, and apoptotic cells. These findings became more evident after 48 h of exposure. Antiapoptotic B-cell lymphoma-2 family members, such as myeloid cell
leukemia-1 and B-cell lymphoma-extra large, are important targets in cancer cells since their overexpression confers resistance to cancer treatments. A significant reduction of the myeloid
cell leukemia-1 protein levels in human breast adenocarcinoma (MCF-7) cells after 24 h of treatment with pacharin or bauhiniastatin-1 at 20 µM was observed, while the B-cell lymphoma-extra
large protein content was reduced in bauhiniastatin-1-treated cells at 40 µM only. The cytotoxic effects of pacharin and bauhiniastatin-1 are likely linked to myeloid cell leukemia-1
inhibition, which leads to the apoptosis of breast adenocarcinoma cells.
Osteogenesis Imperfecta: Multidisciplinary and Goal-Centered Care
Authors: Chang Bryston , Keating Sarah , Mikhael Michel , Lim Jina
Published: July 2022

We describe a case of osteogenesis imperfecta (OI) in a late preterm female of 35-week gestation. The mother did have a history of substance abuse, poor prenatal care, and hypertension. On the day of delivery, an ultrasound revealed skeletal dysplasia and breech with nonreassuring fetal tracing, leading to an emergency cesarean. The clinical exam was concerning for OI, and postnatal care was focused on optimizing respiratory status and minimizing pain and discomfort during routine care. Genetics, endocrine, orthopaedics, and palliative care were all involved to diagnose and educate the family. Support and education were needed for bedside staff to minimize angst at performing routine care, given the high risk of fractures. While initially stable on minimal oxygen, once the diagnosis of type III OI was made, a progressively deforming condition with respiratory status decompensation, the family wished to minimize suffering, limited aggressive medical care, and focused on comfort. The infant eventually died from respiratory failure in the neonatal intensive care unit. We present this case to demonstrate the need for an interdisciplinary team approach to support both family and staff in cases of OI.
A Facile and Efficient One-Pot Procedure for the Synthesis of Novel 2-Substituted 3-Thioxoisoindolin-1-one Derivatives
Authors: Adib Mehdi , Mahdavi Mohammad , Gholami Fatemeh , Moazzam Ali , Bahadorikhalili Saeed , Hosseini Samanesadat , Larijani Bagher
Published: July 2022

In this paper, a novel and efficient method is reported for the synthesis of novel 2-substituted 3-thioxoisoindolin-1-one derivatives. The method is based on the solvent-free reaction of 2-carboxybenzaldehyde with aliphatic amines and sulfur at 100 °C. This reaction is intensely significant, especially in pharmacy applications, due to the facile synthesis of asymmetric thioxoisoindolin-1-one derivatives with phthalimide backbones.
Monitoring Lung Injury Severity and Ventilation Intensity during Mechanical Ventilation
Authors: Rezoagli Emanuele , Laffey John G. , Bellani Giacomo
Published: July 2022

Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure burden by high hospital mortality. No specific pharmacologic treatment is currently available and its ventilatory management is a key strategy to allow reparative and regenerative lung tissue processes. Unfortunately, a poor management of mechanical ventilation can induce ventilation induced lung injury (VILI) caused by physical and biological forces which are at play. Different parameters have been described over the years to assess lung injury severity and facilitate optimization of mechanical ventilation. Indices of lung injury severity include variables related to gas exchange abnormalities, ventilatory setting and respiratory mechanics, ventilation intensity, and the presence of lung hyperinflation versus derecruitment. Recently, specific indexes have been proposed to quantify the stress and the strain released over time using more comprehensive algorithms of calculation such as the mechanical power, and the interaction between driving pressure (DP) and respiratory rate (RR) in the novel DP multiplied by four plus RR [(4 × DP) + RR] index. These new parameters introduce the concept of ventilation intensity as contributing factor of VILI. Ventilation intensity should be taken into account to optimize protective mechanical ventilation strategies, with the aim to reduce intensity to the lowest level required to maintain gas exchange to reduce the potential for VILI. This is further gaining relevance in the current era of phenotyping and enrichment strategies in ARDS.
Endoscopic Approaches to the Management of Biliary Tract Pathology: The Use of Therapeutic Endoscopic Ultrasound
Authors: Hosmer Amy E.
Published: July 2022

Endoscopic ultrasound–guided biliary drainage (EUS-BD) procedures aid in the treatment of biliary diseases and can be considered in the setting of failed conventional endoscopic retrograde cholangiopancreatography, surgically altered gastrointestinal or biliary anatomy with an inaccessible major papilla, malignant obstruction precluding biliary access, or a contraindication to percutaneous biliary access. Although device innovations and technical improvements continue to advance the field of therapeutic EUS, further investigations are required. The purpose of this review is to highlight recent literature on the indications, techniques, capabilities, and outcomes of EUS-BD. Recent literature has demonstrated that EUS-BD is a safe and effective treatment option in the management of biliary diseases. Current studies have assessed the various EUS-BD techniques and have attempted to clarify the optimal treatment algorithm for those with complex biliary pathologies.
Predictive Factors of Research Productivity among Ophthalmology Residents: A Benchmark Analysis
Authors: Hang Abraham , Pradeep Tejus , Jessani Hassan , Kalra Gagan , Waxman Evan L. , Zhang Matthew , Fu Roxana
Published: July 2022

Introduction Positive and negative associations between prior publications and future research productivity is described in other fields, but no such analysis exists for ophthalmology. We conducted a study to determine characteristics of residents exhibiting research productivity during residency.

Methods Using San Francisco Match and Program Web sites, a roster of ophthalmology residents in 2019 to 2020 was compiled, and publication data was collected via PubMed and Google Scholar on a random sample of 100 third-year residents.

Results The median number of publications generated by ophthalmology residents before residency is 2 (range 0–13). Thirty-seven, 23, and 40 residents had zero, one, and two or more papers published during residency, respectively, with a median of 1 (range 0–14). On univariate analysis, compared with residents who published zero or one paper, those who published ≥ 2 were more likely to have more preresidency publications (odds ratio [OR] 1.30; p = 0.005), attend a top-25 ranked residency program by multiple metrics including Doximity reputation (OR 4.92; p < 0.001), and have attended a top-25 ranked medical school program by U.S. News and World Report (OR 3.24; p = 0.03). However, on adjusted analyses, the only factor that remained significant for predicting publications in residency was whether the residency program attended was top 25 ranked (OR 3.54; p = 0.009).

Discussion/Conclusion With the advent of the United States Medical Licensing Examination Step 1 pass/fail system, greater emphasis will be placed on other metrics, including research. This is the first benchmark analysis examining factors predictive of publication productivity in ophthalmology residents. Our study suggests that the residency program attended, not the medical school attended or prior publication history, plays an influential role in the number of publications produced during residency, highlighting the importance of factors to support research on the institutional level, such as mentorship and funding, rather than historical factors in research productivity by the resident.
Playing to Pretend or “Pretending” to Play: Play in Children with Autism Spectrum Disorder
Authors: Westby Carol
Published: July 2022

Children diagnosed with autism spectrum disorder (ASD) exhibit early delays and deficits in play. In infancy, they engage in unusual exploratory behaviors with toys. As toddlers, they are slow to develop functional play, and in preschool some children with ASD fail to develop symbolic play despite having the necessary cognitive and language skills. Furthermore, when children with ASD are engaged in play, they demonstrate less playfulness. This article reviews the literature on the characteristics of exploratory, functional, and symbolic/pretend play in children with ASD and possible reasons for their unusual patterns of play development. Increased quantity and quality of play are frequent therapeutic goals for children with ASD. If play interventions are to be successful, it is critical that speech-language pathologists have an adequate assessment of children's play skills. Several frameworks and tools appropriate for assessing play in typical children and children with ASD are described.
A Review of the Nature and Development of Lying and Deception and Considerations for Teaching Prosocial Lying to Autistic Persons
Authors: Hutchins Tiffany L.
Published: July 2022

Compared with their neurotypical (NT) counterparts, persons with autism appear to be less inclined to tell lies and less skilled in delivering sophisticated forms of deception. At the same time, some forms of deception like white lies and prosocial lies are frequent in human interaction because they are important for social success. This article challenges the reader to evaluate the therapeutic potential for prosocial deception and teaching white-lie telling to autistic persons. The nature and development of antisocial and prosocial lying in NT development and autism are reviewed. Considerations for when to (and when not to) teach the skill of empathic lying are discussed and recommendations for how to teach the comprehension and production of prosocial lies are offered.