bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of 2 open-sourced 3-dimensional modeling techniques for orthopaedic application
Authors: Chai Yuan , Simic Robert , Smith Paul N. , Valter Krisztina , Limaye Ajay , Li Rachel W.
Published: September 2022

Objectives: Although 3-dimensional (3D) printing is becoming more widely adopted for clinical applications, it is yet to be accepted as part of standard practice. One of the key applications of this technology is orthopaedic surgical planning for urgent trauma cases. Anatomically accurate replicas of patients' fracture models can be produced to guide intervention. These high-quality models facilitate the design and printing of patient-specific implants and surgical devices. Therefore, a fast and accurate workflow will help orthopaedic surgeons to generate high-quality 3D printable models of complex fractures. Currently, there is a lack of access to an uncomplicated and inexpensive workflow.

Methods: Using patient DICOM data sets (n = 13), we devised a novel, simple, open-source, and rapid modeling process using Drishti software and compared its efficacy and data storage with the 3D Slicer image computing platform. We imported the computed tomography image directory acquired from patients into the software to isolate the model of bone surface from surrounding soft tissue using the minimum functions. One pelvic fracture case was further integrated into the customized implant design practice to demonstrate the compatibility of the 3D models generated from Drishti.

Results: The data sizes of the generated 3D models and the processing files that represent the original DICOM of Drishti are on average 27% and 12% smaller than that of 3D Slicer, respectively (both P < 0.05). The time frame needed to reach the stage of viewing the 3D bone model and the exporting of the data of Drishti is 39% and 38% faster than that of 3D Slicer, respectively (both P < 0.05). We also constructed a virtual model using third-party software to trial the implant design.

Conclusions: Drishti is more suitable for urgent trauma cases that require fast and efficient 3D bone reconstruction with less hardware requirement. 3D Slicer performs better at quantitative preoperative planning and multilayer segmentation. Both software platforms are compatible with third-party programs used to produce customized implants that could be useful for surgical training.

Level of Evidence: Level V.
Male partner age, viral load, and HIV infection in adolescent girls and young women: evidence from eight sub-Saharan African countries
Authors: Ayton Sarah , Schwitters Amee , Mantell Joanne E. , Nuwagaba-Biribonwoha Harriet , Hakim Avi , Hoffman Susie , Biraro Sam , Philip Neena , Wiesner Lubbe , Gummerson Elizabeth , Brown Kristin , Nyogea Daniel , Barradas Danielle , Nzima Masauso , Fischer-Walker Christa , Payne Danielle , Mulenga Lloyd , Mgomella George , Kirungi Wilford L. , Maile Limpho , Aibo Dorothy , Musuka Godfrey , Mugurungi Owen , Low Andrea
Published: September 2022

Objective:

We aimed to elucidate the role of partnerships with older men in the HIV epidemic among adolescent girls and young women (AGYW) aged 15–24 years in sub-Saharan Africa.

Design:

Analysis of Population-based HIV Impact Assessments in Eswatini, Lesotho, Malawi, Namibia, Tanzania, Uganda, Zambia, and Zimbabwe.

Methods:

We examined associations between reported partner age and recent HIV infection among AGYW, incorporating male population-level HIV characteristics by age-band. Recent HIV infection was defined using the LAg avidity assay algorithm. Viremia was defined as a viral load of more than 1000 copies/ml, regardless of serostatus. Logistic regression compared recent infection in AGYW with older male partners to those reporting younger partners. Dyadic analysis examined cohabitating male partner age, HIV status, and viremia to assess associations with AGYW infection.

Results:

Among 17 813 AGYW, increasing partner age was associated with higher odds of recent infection, peaking for partners aged 35–44 (adjusted odds ratio = 8.94, 95% confidence interval: 2.63–30.37) compared with partners aged 15–24. Population-level viremia was highest in this male age-band. Dyadic analyses of 5432 partnerships confirmed the association between partner age-band and prevalent HIV infection (male spousal age 35–44-adjusted odds ratio = 3.82, 95% confidence interval: 2.17–6.75). Most new infections were in AGYW with partners aged 25–34, as most AGYW had partners in this age-band.

Conclusion:

These results provide evidence that men aged 25–34 drive most AGYW infections, but partners over 9 years older than AGYW in the 35–44 age-band confer greater risk. Population-level infectiousness and male age group should be incorporated into identifying high-risk typologies in AGYW.
False-Positive for Pulmonary Emboli on Ventilation/Perfusion Scan Due to Improper Patient Positioning During Tracer Administration
Authors: Ulaner Gary A. , Grigore Catalan
Published: September 2022

A 67-year-old woman presented with shortness of breath and a ventilation/perfusion scan was performed. Initial images demonstrated mismatched bilateral apical defects that would be classified as high probability for pulmonary emboli. However, it was unusual that the defects were only in the bilateral apices. Investigation discovered that 99mTc-MAA was administered while the patient was in a seated position. Repeat scan the following day with the patient in the correct, supine, position during 99mTc-MAA administration demonstrated no defects. In this case, incorrect patient positioning could have resulted in an incorrect diagnosis of pulmonary emboli and inappropriate treatment of the patient.
DIAGNOSTIC ACCURACY AND ADDED VALUE OF INFECTION BIOMARKERS IN PATIENTS WITH POSSIBLE SEPSIS IN THE EMERGENCY DEPARTMENT
Authors: Christensen Erik E. , Binde Christina , Leegaard Marianne , Tonby Kristian , Dyrhol-Riise Anne-Ma , Kvale Dag , Amundsen Erik K. , Holten Aleksander R.
Published: September 2022

Background: Biomarkers for early recognition of infection are warranted. The hypothesis of this study was that calprotectin, C-reactive protein (CRP), IL-6 and procalcitonin (PCT), alone or in combination, provide clinically useful information to the clinicians for early identification of infection in patients with possible sepsis in the emergency department (ED). Biomarker dynamics in the first week of hospitalization were explored. Methods: Adult patients in rapid response teams in the ED were included in a prospective observational study (n = 391). Patients who received antibiotics after biomarker availability were excluded. The ED clinician (EDC) decision whether to start antibiotics was registered. Calprotectin, CRP, IL-6, and PCT were analyzed in blood samples drawn within 15 min after ED arrival and in a subgroup for 1 week. Infection likelihood was evaluated post hoc. Results: In identifying patients with infection, CRP (area under the receiver operating characteristic curve [AUC], 0.913) and IL-6 (AUC, 0.895) were superior to calprotectin (AUC, 0.777) and PCT (AUC, 0.838). The best regression model predicting infections included EDC, CRP, and IL-6. Using optimal cutoff values, CRP and IL-6 in combination reached 95% positive and 90% negative predictive values for infection. The EDC undertreated or overtreated 65 of 391 patients (17%), and CRP and IL-6 optimal cutoff values could correct this in 32 of 65 patients (49%). Longitudinal samples revealed that IL-6 peaked in the ED, whereas CRP and PCT peaked later. Conclusion: C-reactive protein and IL-6 were superior to calprotectin and PCT for recognizing infection in patients with possible sepsis in the ED. Combining these two biomarkers with different dynamics improved recognition of infection and could aid clinical management in rapid response teams in the ED.
Water uptake by gecko β-keratin and the influence of relative humidity on its mechanical and volumetric properties
Authors: Khani Marzieh , Materzok Tobias , Eslami Hossein , Gorb Stanislav , Müller-Plathe Florian
Published: September 2022

Grand canonical ensemble molecular dynamics simulations are done to calculate the water content of gecko β-keratin as a function of relative humidity (RH). For comparison, we experimentally measured the water uptake of scales of the skin of cobraNaja nigricollis. The calculated sigmoidal sorption isotherm is in good agreement with experiment. To examine the softening effect of water on gecko keratin, we have calculated the mechanical properties of dry and wet keratin samples, and we have established relations between the mechanical properties and the RH. We found that a higher RH causes a decrease in the Young's modulus, the yield stress, the yield strain, the stress at failure and an increase in the strain at failure of the gecko keratin. At low RHs (less than 80%), the change in the mechanical properties is small, with most of the changes occurring at higher RHs. The changes in the macroscopic properties of the keratin are explained by the action of sorbed water on the molecular scale. It causes keratin to swell, thereby increasing the distances between amino acids. This has a weakening effect on amino acid interactions and softens the keratin material. The effect is more pronounced at higher RHs.
Variability in repeated economic games: comparing trust game decisions to other social trust measures
Authors: Safra L. , Lettinga N. , Jacquet P. O. , Chevallier C.
Published: September 2022

Economic games are well-established tools that offer a convenient approach to study social behaviour. Although widely used, recent evidence suggests that decisions made in the context of standard economic games are less predictive of real-world behaviour than previously assumed. A possible explanation for this discrepancy is that economic games decisions in the laboratory are more likely to be influenced by the current situation, while questionnaires are specifically designed to measure people's average behaviour across a long period of time. To test this hypothesis, we performed a longitudinal study where 275 respondents played 16 Trust games every two days within a three-week period, and filled out a questionnaire that measures social trust. This study confirmed the instability of our measure of trust behaviour over time and the substantial stability of questionnaire responses. However, we found a significant association between self-reported social trust and participants' average behaviour in the trust game measured across sessions, but also with participants' behaviour measured only in Session 1. Nevertheless, analysis of behavioural changes in the Trust games over time revealed different behavioural profiles, highlighting how economic games and questionnaires can complement each other in the study of social trust.
Pulsed supplies of small fish facilitate time-limited intraguild predation in salmon-stocked streams
Authors: Hasegawa Koh , Fukui Sho
Published: September 2022

Pulsed supplies of prey generally increase predator food intake. However, it is unclear whether this holds true when predators and pulsed prey are in the same guild (i.e. intraguild (IG) predators and prey). IG prey may increase IG-predator food intake through predation, but they may decrease food intake through competition. To test these hypotheses, we compared the food intake of white-spotted charr (
Salvelinus leucomaenis
) (IG predator) in streams that were stocked or unstocked with masu salmon (
Oncorhynchus masou
) fry (IG prey) in streams in Hokkaido, Japan. One day after stocking, mean stomach content weight of charr was six times higher than in unstocked streams due to fry consumption. In particular, large charr showed intense piscivory. However, predation on fry was rare after about three weeks. Some factors that could explain this time-limited IG predation include the growth and decreasing abundance of fry over time and the acquisition of predator-avoidance behaviour. In days other than the first-day post-stocking, food intake by charr did not differ between stocked and unstocked streams. No effects of interspecific competition on charr food intake were observed.
Acorn worm ossicle ultrastructure and composition and the origin of the echinoderm skeleton
Authors: Larouche-Bilodeau Charles , Cameron Christopher B.
Published: September 2022

Here, we describe the shape and mineral composition of ossicles from eight acorn worm species, bringing the total known biomineralizing enteropneusts to 10 and confirming that ossicles are widespread in Enteropneusta. Three general forms were identified including a globular form that occurs in all three major enteropneust families. The biomineral compositions included all three polymorphs of calcium carbonate; calcite, aragonite and vaterite, and low to high magnesium concentrations. Calcite was the most common and characteristic of echinoderm ossicles. Based on these findings we hypothesize that an enteropneust-like ancestor to the Ambulacraria had ectodermal ossicles, formed in an extracellular occluded space bordered by a sheath of sclerocyte cells. The ossicles were microscopic, monotypic globular shaped, calcite ossicles with low to high Mg content and MSP130 proteins. The ossicles lacked intercalation with other ossicles. The function of acorn worm ossicles is unknown, but the position of ossicles in the trunk epithelia and near to the surface suggests predator deterrence, to provide grip on the walls of a burrow or tube, as storage of metabolic waste, or to regulate blood pH, rather than as an endoskeleton function seen in fossil and crown group Echinodermata.
Building blocks that govern spontaneous and programmed pattern formation in pre-compressed bilayers
Authors: Shen Jiajia , Pirrera Alberto , Groh Rainer M. J.
Published: September 2022

Surface wrinkling in stiff-film/soft-substrate bilayers is a common phenomenon in biological systems and is increasingly being exploited in thin-film technology. While the onset of surface wrinkling in end-compressed bilayers is well understood, questions remain with regards to the evolution of the wrinkling pattern in the intermediate and deep post-wrinkling regimes, especially when the substrate is strongly pre-compressed. Here, we explore the bifurcation landscape of end-compressed bilayers with strongly pre-compressed substrates, using hyperelastic, plane strain finite-elements and generalized path-following algorithms. After bifurcating from a flat into a sinusoidally wrinkled state, bilayers undergo further
n
-tupling bifurcations into stable wrinkling patterns of longer wavelength whose periodicity

n
=
{
4
,
…
,
8
}

is a function of overall bilayer length. These five
n
-tupling wrinkling patterns are shown to be independent localizations of the deformation mode and are accordingly identified as stable ‘building blocks’ that govern the intermediate post-wrinkling regime. Additional end-shortening into the deep post-wrinkling regime then leads to further period doubling and coalescence of the building blocks. Beyond a certain length threshold, a bilayer can form a combinatorial side-by-side arrangement of the five building blocks. In the limit of an infinitely long bilayer, this leads to the phenomenon known as spatial chaos with the emergence of an infinite set of possible wrinkling patterns. In reality, though, the precise side-by-side arrangement of the building blocks is governed by the initial conditions. We show that the morphological evolution of the wrinkling pattern can be programmed by a judicial placement of manufactured dents in the thin film, creating new manufacturing capabilities for textured bilayers.
The histone code of the fungal genus Aspergillus uncovered by evolutionary and proteomic analyses
Authors: Zhang Xin , Noberini Roberta , Bonaldi Tiziana , Collemare Jerome , Seidl Michael F.
Published: September 2022

Chemical modifications of DNA and histone proteins impact the organization of chromatin within the nucleus. Changes in these modifications, catalysed by different chromatin-modifying enzymes, influence chromatin organization, which in turn is thought to impact the spatial and temporal regulation of gene expression. While combinations of different histone modifications, the histone code, have been studied in several model species, we know very little about histone modifications in the fungal genus Aspergillus, whose members are generally well studied due to their importance as models in cell and molecular biology as well as their medical and biotechnological relevance. Here, we used phylogenetic analyses in 94 Aspergilli as well as other fungi to uncover the occurrence and evolutionary trajectories of enzymes and protein complexes with roles in chromatin modifications or regulation. We found that these enzymes and complexes are highly conserved in Aspergilli, pointing towards a complex repertoire of chromatin modifications. Nevertheless, we also observed few recent gene duplications or losses, highlighting Aspergillus species to further study the roles of specific chromatin modifications. SET7 (KMT6) and other components of PRC2 (Polycomb Repressive Complex 2), which is responsible for methylation on histone H3 at lysine 27 in many eukaryotes including fungi, are absent in Aspergilli as well as in closely related Penicillium species, suggesting that these lost the capacity for this histone modification. We corroborated our computational predictions by performing untargeted MS analysis of histone post-translational modifications in Aspergillus nidulans. This systematic analysis will pave the way for future research into the complexity of the histone code and its functional implications on genome architecture and gene regulation in fungi.
Adeno-associated virus type 2 in children from the United States with acute severe hepatitis
Authors: Servellita Venice , Gonzalez Alicia Sotomayor , Lamson Daryl M. , Foresythe Abiodun , Huh Hee Jae , Bazinet Adam L. , Bergman Nicholas H. , Bull Robert L. , Garcia Karla Y. , Goodrich Jennifer S. , Lovett Sean P. , Parker Kisha , Radune Diana , Hatada April , Pan Chao-Yang , Rizzo Kyle , Bertumen J Bradford , Morales Christina , Oluniyi Paul E. , Nguyen Jenny , Tan Jessica , Stryke Doug , Jaber Rayah , Leslie Matthew T. , Lyons Zin , Hedman Hayden , Parashar Umesh , Sullivan Maureen , Wroblewski Kelly , Oberste M. Steven , Tate Jacqueline E. , Baker Julia M. , Sugerman David , Potts Caelin , Lu Xiaoyan , Chhabra Preeti ,   CDC Pediatric Hepatitis of Unknown Etiology Working Group, Ingram L. Amanda , Shiau Henry , Britt William , Gutierrez Sanchez Luz Helena , Ciric Caroline , Rostad Christina A. , Vinjé Jan , Kirking Hannah L. , Wadford Debra A. , Raborn R. Taylor , George Kirsten St. , Chiu Charles Y.
Published: September 2022

As of August 2022, cases of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze 27 samples, including nasopharyngeal swab, stool, plasma, and/or whole blood, from 16 such cases from 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) presenting from October 1, 2021 to May 22, 2022, in parallel with whole blood samples from 45 controls. Among the 13 cases for whom whole blood was available, adeno-associated virus 2 (AAV2) sequences were detected in 92% (12 of 13) (p<0.001), while adenovirus sequences were detected in 100%, of which 11 (84.6%) were genotyped as human adenovirus type 41 (HAdV-41), one as HAdV-40, and one as HAdV-2. Co-infections of herpesviruses, Epstein-Barr virus (EBV) or human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in all 13 cases. In contrast, AAV2 and HAdV-41 were not detected in any control, and EBV, HHV-6, or EV-A71 were each only detected in one or two of 45 controls (p<0.001). Analysis of assembled AAV2 viral genome sequences identified 35 coding mutations relative to the AAV2 reference genome, predominantly located in the VP1 capsid and assembly-activating protein (AAP) proteins, and AAV2 genomes from cases clustered together by phylogenetic analysis. Our findings of a distinct AAV2 strain in nearly all cases of acute severe hepatitis of unknown etiology in conjunction with one or more infecting helper viruses suggest that disease pathogenesis and/or severity may be related to co-infection with AAV2.
Disentangling rural-urban modern contraceptive utilization disparity among sexually active women of reproductive age in Sierra Leone: a Blinder-Oaxaca decomposition analysis
Authors: Luwedde Mary , Katantazi Nehemiah , Sserwanja Quraish , Mukunya David , Kamara Kassim
Published: September 2022

Background

Sierra Leone has one of the world’s highest rates of maternal mortality. Preventing unintended pregnancies reduces the burden of maternal morbidity and mortality. Unfortunately, 25% of reproductive-age women do not have access to modern contraceptive services, and the proportion of demand met for modern contraception remains low at 46% in Sierra Leone. Rural Sierra Leonean women use modern contraception less frequently than urban women. This study aimed to quantify the rural-urban disparity in modern contraceptive use among Sierra Leonean women of reproductive age and to identify factors that explain it.

Method

Data from 2019 Sierra Leone demographic health survey was used. Participants were sexually active women aged 15 to 49 (n=13,975). Modern contraceptive use was the outcome variable. Explanatory variables were grouped into materialistic, behavioral/cultural, and psychosocial theoretical perspectives. Descriptive statistics, intermediary analysis, and blinder Oaxaca decomposition analysis were used to summarize and identify the factors that explain inequalities in modern contraceptive use between rural and urban women. Data were analyzed using Stata version 14.0.

Results

There was a rural-urban disparity in modern contraceptive use of 18 percentage points favoring urban women. The exposure variables explained 68% of this disparity. Education (76%), marital status (39%), hearing about family planning on the radio (16%), age of respondent (13%), problems with distance to a healthcare facility (12%), and problems getting permission to seek treatment (9%) made a significant contribution to the explanation of the modern contraceptive use disparity between urban and rural women.

Conclusions

There was a large rural-urban disparity in modern contraceptive use in Sierra Leone that favoured urban women. Material, behavior/cultural, psychosocial, and demographic explanatory factors jointly explained 68% of the disparity in modern contraceptive utilization between rural and urban women. To close the rural-urban disparity in modern contraceptive use, policy makers must address inequities in education, mass media (radio), and healthcare access. Rural women should be empowered to have the autonomy to access healthcare. Educating men about modern contraceptives and involving them in contraceptive programs can increase rural women’s ability to get permission to seek care hence increasing modern contraceptive utilization and consequently bridging the rural-urban gap.
Closed-loop spinal cord stimulation is superior in restoring locomotion in rodent models of Parkinson’s Disease
Authors: Rees Benjamin , Borda Eleonora , Nicolelis Miguel A. L. , Yadav Amol P.
Published: September 2022

Dorsal column stimulation (DCS) of the spinal cord is emerging as a promising new technology to treat Parkinson’s disease (PD). However, optimal stimulation settings that maximize its therapeutic effect on PD symptoms are yet to be determined. Here we demonstrate a closed-loop DCS (CLDCS) paradigm – a substantial advancement from previously tested continuous high-frequency DCS – in a bilateral intrastriatal 6-hydroxydopamine (6-OHDA) rodent model of PD. Firstly, CLDCS, triggered by corticostriatal beta frequency oscillations facilitated a pro-locomotion brain state that restored locomotion and reduced akinesia. Secondly, CLDCS was better at disrupting ongoing beta oscillations and achieved it with lesser overall charge delivery than continuous open-loop stimulation. These results indicate that CLDCS is markedly better than traditional spinal cord stimulation methods and can potentially be highly effective in treating PD symptoms. We envision that the CLDCS approach can be beneficial in the treatment of other neurological disorders which showcase similar pathological neuronal oscillations.
DEED: A Dataset for Dream-related Emotion Research
Authors: Liu Wanqiu , Zhang Yupeng , Ma Pengcheng , Zheng Lei , Zhou Di , Chen Zhengbo , Shen Mingming , Cai Yongchun , Lu Zhengyi , Liu Qiao , Luo Junwen , Wang Xiaoan
Published: September 2022

Emotion is closely related to human cognition and behaviour. In recent years, scholars have conducted extensive research on emotion in waking state based on electroencephalography (EEG) and achieved certain results. However, Emotional activity continues after sleep, with a concentrated response of sleep emotions in dreams. Sleep emotions are concentrated in dreams, which can better reflect a series of real physical and psychological states of the human body. Currently, there is no publicly available dataset for the assessment of dream mood. Therefore, we present a physiological dataset Dream Emotion Evaluation Dataset (DEED) for the assessment of dream mood, which recorded EEG signals from 38 participants over 89 whole sleep nights and 533 dream segments(after exclusion of unqualified nights, those dream segments are extracted from 82 whole sleep nights). We studied the correlations between the subjective ratings and the EEG signals and brain network patterns for dream emotions. In addition, the relationship between the asymmetry of left and right brain bands and positive and negative dream emotions was studied. The machine learning algorithm was also used to classify different emotional EEG, which confirmed the validity of the dataset. In the meantime, we encourage other researchers to explore the underlying neural mechanisms involved in sleep.
Extraordinary selection on the human X chromosome associated with archaic admixture
Authors: Skov L. , Coll Macià M. , Lucotte E. , Cavassim M.I.A. , Castellano D. , Schierup M.H. , Munch K.
Published: September 2022

The X chromosome in non-African human populations shows less diversity and less Neanderthal introgression than expected under the standard neutral model. We analyzed 162 X chromosomes from human males worldwide and discovered 14 chromosomal regions where haplotypes of several hundred kilobases rapidly rose to high frequencies in non-Africans. These observations cannot be explained by neutral genetic drift in realistic demographic scenarios and are only consistent with partial selective sweeps produced by strong selection. Using an approach for inferring individual Neanderthal-derived haplotypes, which do not rely on an archaic reference genome, we further discover that the swept haplotypes are devoid of the archaic ancestry otherwise typical of the affected chromosomal regions. The ancient Ust’-Ishim male carries its expected proportion of these haplotypes, implying that the sweeps must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selection in great ape evolution. We propose that this puzzling combination of observations points to a general mechanism of positive selection unique to the X chromosome.
Synaptic scale dopamine disruption in Huntington’s Disease model mice imaged with near infrared catecholamine nanosensors
Authors: Yang Sarah J. , del Bonis O’Donnell Jackson Travis , Giordani Francesca , Wang Jeffery , Lui Alison , Piekarski David , Irrinki Ashvin , Schaffer David V. , Landry Markita P.
Published: September 2022

Dopamine neuromodulation is a critical process that facilitates learning, motivation, and motor control. Disruption of these processes has been implicated in several neurological and psychiatric disorders including Huntington’s Disease (HD). While several treatments for physical and psychiatric HD symptoms target dopaminergic neuromodulation, the mechanism by which dopaminergic dysfunction occurs during HD is unknown. This is partly due to limited capability to visualize dopamine dynamics at the spatiotemporal resolution of both neuromodulator release (ms) and dopaminergic boutons (µm). Here we employ near-infrared fluorescent catecholamine nanosensors (nIRCats) to image dopamine release within the brain striatum of R6/2 Huntington’s Disease Model (R6/2) mice. We find that stimulated dorsal striatal dopamine release decreases with progressive motor degeneration and that these decreases are primarily driven by a decrease in the number of dopamine hotspots combined with decreased release intensity and decreased release fidelity. Using nIRCat’s high spatial resolution, we show that dopamine hotspots in late HD show increased ability to add new dopamine hotspots at high extracellular calcium concentrations and track individual dopamine hotspots over repeated stimulations and pharmacological wash to measure dopamine hotspots release fidelity. Compellingly, we demonstrate that antagonism of D2-autoreceptors using Sulpiride and direct blocking of Kv1.2 channels using 4-Aminopyradine (4-AP) increases the fidelity of dopamine hotspot activity in WT striatum but not in late HD striatum, indicating that D2-autoreceptor regulation of dopamine release through Kv1.2 channels is compromised in late HD. These findings, enabled by nIRCats, provide a more detailed look into how dopamine release is disrupted and dysregulated during Huntington’s Disease to alter the coverage of dopamine modulation across the dorsal striatum.

SIGNIFICANCE STATEMENT

Huntington’s Disease (HD) is a neurodegenerative disorder with no cure. Dysfunction of dopamine signaling is known to deteriorate in HD but has not been studied at the spatial level of individual release sites. Here, we image dopamine release from individual hotspots in brain slices from R6/2 HD mice at early and late disease timepoints with dopamine nanosensors. We track single dopamine hotspots and find that dopamine hotspot number, release intensity, and release fidelity decrease in HD, and demonstrate that changes in D2-autoreceptor regulation manifest through changes in hotspot release fidelity thus compromising dopamine coverage across the dorsal lateral striatum. These findings highlight dopaminergic neurons in cortico-striatal signaling during HD as a promising new therapeutic target for HD treatment.
Safety, Immunogenicity and Efficacy of NVX-CoV2373 in Adolescents in PREVENT-19: A Randomized, Phase 3 Trial
Authors: Áñez Germán , Dunkle Lisa M. , Gay Cynthia L. , Kotloff Karen L. , Adelglass Jeffrey M. , Essink Brandon , Campbell James D. , Cloney-Clark Shane , Zhu Mingzhu , Plested Joyce S. , Roychoudhury Pavitra , Greninger Alexander L. , Patel Nita , McGarry Alice , Woo Wayne , Cho Iksung , Glenn Gregory M. , Dubovsky Filip ,   the 2019nCoV-301 – Pediatric Expansion Study Group
Published: September 2022

BACKGROUND

Over 20% of cases and 0.4% of deaths from Covid-19 occur in children. Following demonstration of safety and efficacy of the adjuvanted, recombinant spike protein vaccine NVX-CoV2373 in adults, the PREVENT-19 trial enrolled adolescents.

METHODS

Safety, immunogenicity, and efficacy of NVX-CoV2373 were evaluated in adolescents aged 12 to <18 years in an expansion of PREVENT-19, a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States. Participants were randomized 2:1 to two doses of NVX-CoV2373 or placebo 21 days apart, and followed for a median of 2 months after second vaccination. Primary end points were serologic non-inferiority of neutralizing antibody (NA) responses compared with young adults (18 to <26 years) in PREVENT-19, protective efficacy against laboratory-confirmed Covid-19, and assessment of reactogenicity/safety.

RESULTS

Among 2,247 participants randomized between April–June 2021, 1,491 were allocated to NVX-CoV2373 and 756 to placebo. Post-vaccination, the ratio of NA geometric mean titers in adolescents compared to young adults was 1.5 (95% confidence interval [CI] 1.3 to 1.7). Twenty Covid-19 cases (all mild) occurred: 6 among NVX-CoV2373 and 14 among placebo recipients (vaccine efficacy [VE]: 79.5%, 95% CI, 46.8 to 92.1). All sequenced viral genomes (11/20) were identified as Delta variant (Delta variant VE: 82.0% [95% CI: 32.4 to 95.2]). Reactogenicity was largely mild-to-moderate, transient, and more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments.

CONCLUSIONS

NVX-CoV2373 was safe, immunogenic, and efficacious in the prevention of Covid-19 and those cases caused by the Delta variant in adolescents.

(Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802).
Gabapentin for Postoperative Pain Management in Lumbar Fusion Surgery
Authors: Perez Eli A , Ray Emanuel , Park Brian J , Gold Colin J , Carnahan Ryan M , Banks Matthew , Sanders Robert D. , Olinger Catherine R , Mueller Rashmi N , Woodroffe Royce W
Published: September 2022

Study Design

Retrospective cohort study

Objectives

To investigate the effect of perioperative gabapentin administration on postoperative pain and opioid use in elderly patients after elective posterior lumbar fusion.

Methods

This was a single-center study of patients over the age of 65 who underwent elective posterior lumbar fusion. The cohort was stratified into two groups based on perioperative gabapentin administration defined as use both in the immediate preoperative period and postoperatively during hospitalization. Mean daily visual analogue scale (VAS) pain scores and mean daily morphine equivalent dosage (MED) during the postoperative hospital stay were compared between these groups using traditional regression and inverse probability weighting.

Results

There were 350 patients who received gabapentin perioperatively and 78 patients who did not receive gabapentin. Multivariate regression did not demonstrate a difference in daily MED (ß=-6.6 mg, p=0.816) or daily pain scores (ß=0.04, p=0.257) averaged over the first seven postoperative days. Sub-analysis stratifying by each individual postoperative day also did not demonstrate a difference in MED or pain scores.

Conclusion

This study did not find perioperative gabapentin administration to be beneficial in reducing postoperative VAS pain scores or opioid use in the acute postoperative period for elderly patients undergoing posterior lumbar fusion. These findings are consistent with recent literature suggesting gabapentin is of minimal benefit in postoperative multimodal analgesia regimens.

Level of Evidence

3
Automated Classification of Fat-infiltrated Axillary Lymph Nodes on Screening Mammograms
Authors: Song Qingyuan , diFlorio-Alexander Roberta M. , Sieberg Ryan T. , Dwan Dennis , Boyce William , Stumetz Kyle , Patel Sohum D. , Karagas Margaret R. , Mackenzie Todd A. , Hassanpour Saeed
Published: September 2022

Objectives

Fat-infiltrated axillary lymph nodes (LNs) are unique sites for ectopic fat deposition. Early studies showed a strong correlation between fatty LNs and obesity-related diseases. Large-scale studies are needed to confirm these preliminary results but this is hampered by the scarcity of labeled data. With the long-term goal of developing a rapid and generalizable tool to aid data labeling, we developed an automated deep learning (DL)-based pipeline to classify the status of fatty LNs on screening mammograms.

Methods

Our internal dataset included 886 mammograms from a tertiary academic medical institution, with a binary status of the fat-infiltrated LNs based on the size and morphology of the largest visible axillary LN. A two-stage DL model training and fine-tuning pipeline was developed to classify the fat-infiltrated LN status using the internal training and development dataset. The model was evaluated on a held-out internal test set and a subset of the Digital Database for Screening Mammography.

Results

Our model achieved an accuracy of 0.97 (95% CI: 0.94-0.99) on 264 internal testing mammograms and an accuracy of 0.82 (95% CI: 0.77-0.86) on 70 external testing mammograms. The model successfully extracted meaningful LN-related features from the mammograms.

Conclusion

This study confirmed the feasibility of using a DL model for fat-infiltrated LN classification. The model provides a practical tool to identify fatty LNs on mammograms and to allow for future large-scale studies to evaluate the role of fatty LNs as an imaging biomarker of obesity-associated pathologies.

Advances in knowledge

Our study is the first to classify fatty LNs using an automated DL approach.
Prevalence of SARS-CoV-2 Antibodies after the Omicron Surge, Kingston, Jamaica, 2022
Authors: Anzinger Joshua J. , Cameron-McDermott Suzette M. , Phillips Yakima Z.R. , Mendoza Leshawn , Anderson Mark , Cloherty Gavin , Strachan-Johnson Susan , Lindo John F. , Figueroa J. Peter
Published: September 2022

A cross-sectional SARS-CoV-2 serosurvey was conducted after the Omicron surge in Jamaica using 1,540 samples collected during March – May 2022 from persons attending antenatal, STI and non-communicable diseases clinics in Kingston, Jamaica. SARS-CoV-2 spike receptor binding domain (RBD) and/or nucleocapsid IgG antibodies were detected for 88.4% of the study population, with 77.0% showing evidence of previous SARS-CoV-2 infection. Of persons previously infected with SARS-CoV-2 and/or with COVID-19 vaccination, 9.6% were negative for spike RBD IgG, most of which were unvaccinated previously infected persons. Amongst unvaccinated previously infected people, age was associated with testing spike RBD IgG negative. When considering all samples, median spike RBD IgG levels were 131.6 BAU/mL for unvaccinated persons with serological evidence of past infection, 90.3 BAU/mL for vaccinated persons without serological evidence of past infection, and 896.1 BAU/mL for vaccinated persons with serological evidence of past infection. Our study of the first reported SARS-CoV-2 serosurvey in Jamaica shows extensive SARS-CoV-2 population immunity, identifies a substantial portion of the population lacking spike RBD IgG, and provides additional evidence for increasing COVID-19 vaccine coverage in Jamaica.
From toxic waste to beneficial nutrient: acetate boostsE. coligrowth at low glycolytic flux
Authors: Millard Pierre , Gosselin-Monplaisir Thomas , Uttenweiler-Joseph Sandrine , Enjalbert Brice
Published: September 2022

Acetate, a major by-product of glycolytic metabolism inEscherichia coliand many other microorganisms, has long been considered a toxic waste compound that inhibits microbial growth. This counterproductive auto-inhibition represents a major problem in biotechnology and has puzzled the scientific community for decades. Recent studies have revealed that acetate is also a co-substrate of glycolytic nutrients and a global regulator ofE. colimetabolism and physiology. Here, we used a systems biology strategy to investigate the mutual regulation of glycolytic and acetate metabolism. Computational and experimental results demonstrate that reducing the glycolytic flux enhances co-utilization of acetate with glucose. Acetate metabolism thus compensates for the reduction in glycolytic flux and eventually buffers carbon uptake so that acetate, far from being toxic, actually enhancesE. coligrowth under these conditions. We validated this mechanism using three orthogonal strategies: chemical inhibition of glucose uptake, glycolytic mutant strains, and alternative substrates with a natively low glycolytic flux. Acetate makesE. colimore robust to glycolytic perturbations and is a valuable nutrient, with a beneficial effect on microbial growth.
Regulation of cellular LDL uptake by PROX1 and CHD7
Authors: Serrano-Zayas Candilianne , Holding Matthew L. , Khan Taslima G. , Tang Vi T. , Skidmore Jennifer M , Martin Donna M , Ginsburg David , Emmer Brian T.
Published: September 2022

An elevated level of low-density lipoprotein (LDL) in the bloodstream is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). The low-density lipoprotein receptor (LDLR) is a critical regulator of circulating LDL, and increasing LDLR activity is an effective therapeutic approach to reduce circulating LDL cholesterol levels. In this study, we characterize PROX1 and CHD7, two genes we previously identified in a genome-scale CRISPR screen as positive regulators of LDL uptake in HuH7 cells. We found that although disruption of either PROX1 or CHD7 significantly reduced LDL uptake, only PROX1 disruption significantly reduced the cellular levels of LDLR mRNA and surface-displayed LDLR protein. Consistent with a direct role for PROX1 in LDLR gene regulation, we also observed in publicly available data sets the presence of two liver-specific PROX1 binding sites near the LDLR locus, one of which colocalized with biochemical hallmarks of enhancer activity in hepatic tissue. Both PROX1 LDLR binding sites contained predicted PROX1 transcription factor binding motifs and colocalized with binding sites for HNF4α, a known interactor for PROX1 and regulator of hepatic lipid metabolism and LDL uptake. In contrast to PROX1, no CHD7 binding sites were detected near the LDLR locus. Together, our results support a model in which both PROX1 and CHD7 promote cellular LDL uptake through distinct mechanisms, with PROX1 directly promoting LDLR gene expression and CHD7 functioning through an LDLR-independent pathway.
The effect of metal remediation on the virulence and antimicrobial resistance of the opportunistic pathogenPseudomonas aeruginosa
Authors: Lear Luke , Hesse Elze , Newsome Laura , Gaze William , Buckling Angus , Vos Michiel
Published: September 2022

Metal contamination poses both a direct threat to human health as well as an indirect threat through its potential to affect bacterial pathogens. Metals can not only co-select for antibiotic resistance, but also might affect pathogen virulence via increased siderophore production. Siderophores are extracellular compounds released to increase ferric iron uptake — a common limiting factor for pathogen growth within hosts – making them an important virulence factor. However, siderophores can also be positively selected for to detoxify non-ferrous metals, and consequently metal stress can potentially increase bacterial virulence. Anthropogenic methods to remediate environmental metal contamination commonly involve amendment with lime-containing materials, but whether this reducesin situco-selection for antibiotic resistance and virulence remains unknown. Here, using microcosms containing metal-contaminated river water and sediment, we experimentally test whether metal remediation by liming reduces co-selection for these traits in the opportunistic pathogenPseudomonas aeruginosaembedded within a natural microbial community. To test for the effects of environmental structure, which can impact siderophore production, microcosms were incubated under either static or shaking conditions. EvolvedP. aeruginosapopulations had greater fitness in the presence of toxic concentrations of copper than the ancestral strain, but this effect was reduced in the limed treatments. EvolvedP. aeruginosapopulations showed increased resistance to the clinically-relevant antibiotics apramycin, cefotaxime, and trimethoprim, regardless of lime addition or environmental structure. Although we found virulence to be significantly associated with siderophore production, neither virulence nor siderophore production significantly differed between the four treatments. We therefore demonstrate that although remediation via liming reduced the strength of selection for metal resistance mechanisms, it did not mitigate metal-imposed selection for antibiotic resistance or virulence inP. aeruginosa. Consequently, metal-contaminated environments may select for antibiotic resistance and virulence traits even when treated with lime.

Graphical abstract
Zika virus spreads through infection of lymph node-resident macrophages
Authors: Reynoso Glennys V. , Gordon David N. , Kalia Anurag , Aguilar Cynthia C. , Malo Courtney S. , Aleshnick Maya , Dowd Kimberly A. , Cherry Christian R. , Shannon John P. , Vrba Sophia M. , Maciejewski Sonia , Asano Kenichi , Pierson Theodore C. , Hickman Heather D.
Published: September 2022

Zika virus (ZIKV) is an arthopod-vectored flavivirus that disseminates from the infection site into peripheral tissues, where it can elicit virus-induced pathology. To move through the body, ZIKV is thought to exploit the mobility of myeloid cells, in particular monocytes and dendritic cells. However, multiple distinct steps during viral spread culminate in peripheral tissue infection, and the timing and mechanisms underlying mobile immune cell shuttling of virus remain unclear. To understand the very early steps in ZIKV dissemination from the skin, we kinetically and spatially mapped ZIKV-infected lymph nodes (LNs), an intermediary stop en route to the blood. Contrary to dogma, migratory immune cells were not required for large quantities of virus to reach the LN or blood. Instead, ZIKV rapidly infected a subset of immobile macrophages in the LN, which shed virus through the lymphatic pathway into the blood. Importantly, infection of LN macrophages alone was sufficient to initiate viremia. Together, our studies indicate that sessile macrophages that live and die in the LN contribute to initial ZIKV spread to the blood. These data build a more complete picture of ZIKV movement through the body and identify an alternate anatomical site for potential antiviral intervention.

Highlights

ZIKV infects and replicates in distinct LN macrophage populations

LN macrophage infection results in infectious virus in the blood

Virus reaches the blood in the absence of DC migration or monocyte infection

Nodal macrophage infection does not sustain viremia or induce morbidity

Graphical abstract

Caption:

ZIKV infects lymph node macrophages, which shed infectious virus into the lymph and then blood.