bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical classification of patients with COVID-19 pneumonia was predicted by Radiomics using chest CT
Authors: Xiong Fei , Wang Ye , You Tao , Li Han han , Fu Ting ting , Tan Huibin , Huang Weicai , Jiang Yuanliang
Published: March 2021

In 2020, the new type of coronal pneumonitis became a pandemic in the world, and has firstly been reported in Wuhan, China. Chest CT is a vital component in the diagnostic algorithm for patients with suspected or confirmed COVID-19 infection. Therefore, it is necessary to conduct automatic and accurate detection of COVID-19 by chest CT.

The clinical classification of patients with COVID-19 pneumonia was predicted by Radiomics using chest CT.

From the COVID-19 cases in our institution, 136 moderate patients and 83 severe patients were screened, and their clinical and laboratory data on admission were collected for statistical analysis. Initial CT Radiomics were modeled by automatic machine learning, and diagnostic performance was evaluated according to AUC, TPR, TNR, PPV and NPV of the subjects. At the same time, the initial CT main features of the two groups were analyzed semi-quantitatively, and the results were statistically analyzed.

There was a statistical difference in age between the moderate group and the severe group. The model cohort showed TPR 96.9%, TNR 99.1%, PPV98.4%, NPV98.2%, and AUC 0.98. The test cohort showed TPR 94.4%, TNR100%, PPV100%, NPV96.2%, and AUC 0.97. There was statistical difference between the two groups with grade 1 score (P = .001), the AUC of grade 1 score, grade 2 score, grade 3 score and CT score were 0.619, 0.519, 0.478 and 0.548, respectively.

Radiomics’ Auto ML model was built by CT image of initial COVID -19 pneumonia, and it proved to be effectively used to predict the clinical classification of COVID-19 pneumonia. CT features have limited ability to predict the clinical typing of Covid-19 pneumonia.
High expression of MMP28 indicates unfavorable prognosis in pancreatic cancer
Authors: Chen Zhitao , Huang Jiacheng , Li Mengxia , Zhang Lele , Wan Dalong , Lin Shengzhang
Published: March 2021

To investigate the expression pattern and diagnostic performance of matrix metalloproteinase 28 (MMP28) in pancreatic cancer (PC).

The RNA-seq data of PC and normal pancreas tissue were acquired from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression. Clinical information of PC that included prognostic data was obtained from TCGA. Later, Fisher exact test was applied for comparison of different clinicopathological features between high and low expression of MMP28 in PC. Afterwards, Kaplan-Meier survival analysis and Cox analysis (univariate and multivariate analysis) were used to explore the prognostic performance of MMP28 in PC cohort. Finally, gene set enrichment analysis (GSEA) revealed the potential signaling pathways related to high expression of MMP28 in PC.

Upregulation of MMP28 was identified in PC tissue compared to normal pancreas tissue (P < .001). Overexpression of MMP28 was related to histological grade (P < .001), M classification (P = .014), and survival status (P = .028). Kaplan-Meier survival analysis revealed that high level of MMP28 implied unfavorable prognosis in PC (P = .002). Multivariate analysis confirmed that MMP28 was an independent risk factor in PC (hazard rate = 1.308, P = .018). Our GSEA analysis found that signaling pathways including glycolysis, p53 pathway, notch signaling, estrogen response late, cholesterol homeostasis, estrogen response early, mitotic spindle, and transforming growth factor beta signaling were enriched in the group with higher MMP28 expression.

High expression of MMP28 could be identified in PC, which also served as an independent risk element for PC.
Ghrelin, Obestatin and Their Receptors As Well As Metabotropic Glutamate Receptor Assessment in Chronic Functional Constipation in Children
Authors: Czkwianianc Elzbieta , Kolejwa Michal , Bossowski Artur , Wawrusiewicz‐Kurylonek Natalia , Glowacka Ewa , Makosiej Aleksandra , Goscik Joanna , Socha‐Banasiak Anna , Makosiej Ryszard
Published: March 2021

Objectives:

The aim of this study was to examine the role of ghrelin, obestatin, and glutamate and their receptors in the pathogenesis of children functional constipation.

Methods:

Children ages 4–17 were the subject of the study: 121 children with constipation (55 boys and 66 girls), 36 patients of the same age (26 boys and 10 girls) were the controls. Expression of ghrelin, obestatin, and glutamate receptors on gastric and colon specimens taken by endoscopy were assessed. The concentration of the above agents was estimated in serum by the enzyme‐linked immunosorbent assay test.

Results:

The lower median serum concentrations of ghrelin, in the constipated children than in controls were confirmed (1.9 ng/mL vs 2.6 ng/mL, P < 0.05). The expression of the metabotropic receptor 7 for glutamate (mGlu7) RNA was higher in the stomach (32.49 vs 31.47, P < 0.05), and was lower in the rectum in constipated patients compared to the control group (31.76 vs 32.62, P < 0.05). A negative correlation between the concentration of ghrelin in serum and colonic transient time (P = 0.01, rho = −0.23) was shown in the study group.

Higher median expression of obestatin receptor G protein‐coupled receptor39 in rectal mucosae was found in a constipated group than in the controls (29.9 vs 26.9, P < 0.05).

Conclusion:

Ghrelin, and receptors for ghrelin, obestatin, and glutamate in gastrointestinal mucosa play a role in the pathogenesis of functional constipation in children.
A Personalized Shared Decision-Making Tool for Osteoarthritis Management of the Knee
Authors: Johnson Charla B.
Published: March 2021

Shared decision making (SDM) is a key component of patient-centered care where clinical evidence and the patient's preference and values are considered. Physical activity and weight loss are often recommendations in the treatment plan, especially in mild to moderate stage of osteoarthritis (OA). Movement is Life™ created an innovative SDM tool providing a framework for patient-centered discussions. The tool leverages an underlying Markov Model and represents the likely pain, activity levels, and lost productivity at three future time points. Comparing the patient's likely progression depending on treatment choices to doing nothing, the patient has an illustration of their future state. The tool provides a consistent communication pathway and may reduce disparities by addressing unconscious bias. Orthopaedic nurses can be a catalyst for change in the clinic setting by providing education, counseling, and health coaching to promote physical activity and weight management as a recommended treatment option for early OA symptom management.
A Swallowing Screening Test Enhances a Better Recognition of Patients with a Hip Fracture at Risk for Oropharyngeal Dysphagia
Authors: Wijnen Hugo , Schmitz Peter P. , Jansen Martine , Hendrix Linda , van Susante Job L. C. , Willems Hanna
Published: March 2021

Oropharyngeal dysphagia (OD) is commonly encountered in elderly patients with hip fracture. It is easily overlooked and predisposes patients to life-threatening postoperative pneumonia. The aim of this study was to evaluate whether OD screening by nurses results in a better recognition of patients at risk for OD. After the introduction of the Standardized Swallowing Assessment by nurses, the incidence of increased risk for OD and the prevention of OD complications were monitored (intervention group; N = 92) and compared with a historical control group (N = 81). The risk for OD was diagnosed in 27 patients (29%) in the intervention group in comparison with 12 patients (15%) in the control group (p < .05). The number of diet modifications increased from 12 (15%) in the control group to 25 (27%) in the intervention group (p < .05). A simple screening test results in better recognition of increased OD risk and, in turn, the early initiation of measures to avoid aspiration.
Global estimates for the lifetime cost of managing HIV
Authors: Tran Huynh , Saleem Kanwal , Lim Megumi , Chow Eric P.F. , Fairley Christopher K. , Terris-Prestholt Fern , Ong Jason J.
Published: March 2021

Objective:

There are an estimated 38 million people with HIV (PWH), with significant economic consequences. We aimed to collate global lifetime costs for managing HIV.

Design:

We conducted a systematic review (PROSPERO: CRD42020184490) using five databases from 1999 to 2019.

Methods:

Studies were included if they reported primary data on lifetime costs for PWH. Two reviewers independently assessed the titles and abstracts, and data were extracted from full texts: lifetime cost, year of currency, country of currency, discount rate, time horizon, perspective, method used to estimate cost and cost items included. Descriptive statistics were used to summarize the discounted lifetime costs [2019 United States dollars (USD)].

Results:

Of the 505 studies found, 260 full texts were examined and 75 included. Fifty (67%) studies were from high-income, 22 (29%) from middle-income and three (4%) from low-income countries. Of the 65 studies, which reported study perspective, 45 (69%) were healthcare provider and the remainder were societal. The median lifetime costs for managing HIV differed according to: country income level: $5221 [interquartile range (IQR)]: 2978–11 177) for low-income to $377 820 (IQR: 260 176–541 430) for high-income; study perspective: $189 230 (IQR: 14 794–424 069) for healthcare provider, to $508 804 (IQR: 174 781–812 418) for societal; and decision model: $190 255 (IQR: 13 588–429 772) for Markov cohort, to $283 905 (IQR: 10 558–453 779) for microsimulation models.

Conclusion:

Estimating the lifetime costs of managing HIV is useful for budgetary planning and to ensure HIV management is affordable for all. Furthermore, HIV prevention strategies need to be strengthened to avert these high costs of managing HIV.
Assessment of retinal microvascular health by optical coherence tomography angiography among persons with HIV
Authors: Collins Lauren F. , Shantha Jessica G. , Nesper Peter L. , Sheth Anandi N. , Fawzi Amani A. , Yeh Steven , Ofotokun Ighovwhera
Published: March 2021

Microvasculopathy may link HIV-related chronic inflammation and premature multimorbidity. In this proof-of-concept study, we used optical coherence tomography angiography (OCTA) to evaluate the retina as a convenient assessment of microvascular health among persons with HIV (PWH) undergoing surveillance ophthalmic care at Emory from 2018 to 2021. Among patients with longstanding HIV, OCTA identified microvascular abnormalities even among eyes without clinical retinal disease. Retinovascular evaluation by OCTA is a feasible, noninvasive technique for assessing microvasculopathy among PWH.
Tesamorelin improves fat quality independent of changes in fat quantity
Authors: Lake Jordan E. , La Kristen , Erlandson Kristine M. , Adrian Stefan , Yenokyan Gayane , Scherzinger Ann , Dubé Michael P. , Stanley Takara , Grinspoon Steven , Falutz Julian , Mamputu Jean-Claude , Marsolais Christian , McComsey Grace A. , Brown Todd T.
Published: March 2021

Objectives:

Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density.

Design:

Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated.

Methods:

CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader.

Results:

Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (−91 HU both arms, P = 0.80) and SAT density (−94 HU tesamorelin, −95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P < 0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P < 0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5–7.3), P = 0.001) or SAT (+3.5 HU, 95% confidence interval (2.3–4.7), P < 0.001] area change.

Conclusion:

In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.
Broadly neutralizing HIV-1 antibody reactivity in HIV tests: implications for diagnostics
Authors: Smith Tara , Masciotra Silvina , Luo Wei , Sullivan Vickie , Switzer William M. , Johnson Jeffrey A. , Heneine Walid
Published: March 2021

Objective:

Passive immunization with broadly neutralizing antibodies (bNAbs) is under evaluation for HIV prevention. BNAbs target gp120 or gp41, two HIV envelope antigens commonly present in diagnostic tests. Depending on bNAb type and dose administered to humans, serum levels can reach nearly 1 mg/ml and wane over several weeks to months. We investigated the reactivity of bNAbs in HIV serological tests to inform diagnostic testing practices for persons treated with these products.

Design and methods:

The antigp120 bNAbs VRCO1, PGT121, PGT145, 3BNC117, 10–1074 and N6 and antigp41 bNAbs 10E8 and 10E8v4 were tested with the laboratory-based Bio-Rad Ag/Ab Combo assay, the point-of-care single-use Determine Combo, OraQuick, Reveal G4, SureCheck, Uni-Gold, INSTI and DPP HIV-1/2 assays, and the supplemental Geenius and HIV-1 Western Blot assays.

Results:

At 1 mg/ml, all bNAbs were nonreactive in four screening tests. OraQuick, SureCheck, Reveal G4 and INSTI detected at least two bNAbs each; SureCheck exhibited reactivity to six bNAbs. Geenius was HIV-1 indeterminate (gp160+) with all bNAbs except PGT121, which was HIV antibody-negative. HIV-1 Western Blot was indeterminate (gp41+/gp160+) with 10E8 and 10E8v4 and negative with the remaining bNAbs. There was no correlation between the test antigen construct(s) and bNAb reactivity.

Conclusion:

We identified a laboratory-based Ag/Ab EIA and three single-use rapid HIV tests that are nonreactive against a panel of bNAbs supporting some diagnostic tests can distinguish HIV-1 infection events among persons receiving bNAb immunoprophylaxis. Evaluation of HIV diagnostic tests prior to clinical use may identify suitable serologic assays for persons administered bNAbs.
Modulation of the Permeability-Inducing Factor Angiopoietin-2 Through Bifonazole in Systemic Inflammation
Authors: Pape Thorben , Idowu Temitayo Opemipo , Etzrodt Valerie Maritta , Stahl Klaus , Seeliger Benjamin , Haller Hermann , David Sascha
Published: March 2021

Background:

Vascular barrier breakdown in sepsis represents a key component of the maladaptive host response to infection and the release of endothelial Angiopoietin-2 (Angpt-2) is a mechanistic driver of endothelial hyperpermeability. Angpt-2 is associated with morbidity and mortality but a targeted therapeutic approach is not available. We screened for U.S. Food and Drug Administration (FDA) approved drugs that might have off-target effects decreasing Angpt-2 and therefore, ameliorating capillary leakage.

Methods:

Endothelial cells were isolated from human umbilical veins (HUVECs) and used for in vitro studies at baseline and after stimulation (FDA-library screening, RT-PCR, ELISA, immunocytochemistry, MTT assay). On the functional level, we assessed real-time transendothelial electrical resistance (TER) using an electric cell-substrate impedance sensing device.

Results:

We found that the anti-fungal Bifonazole (BIFO) reduces spontaneous Angpt-2 release in a time- and dose-dependent manner after 8, 12, and 24 h (24 h: veh: 15.6 ± 0.7 vs. BIFO: 8.6 ± 0.8 ng/mL, P < 0.0001). Furthermore, we observed a reduction in its intra-cellular content by 33% (P < 0.001). Stimulation with tumor necrosis factor α induced a strong release of Angpt-2 that could analogously be blocked by additional treatment with BIFO (veh: 1.58 ± 0.2 vs. BIFO: 1.02 ± 0.1, P < 0.0001). Quantification of endothelial permeability by TER revealed that BIFO was sufficient to reduce Thrombin-induced barrier breakdown (veh: 0.82 ± 0.1 vs. BIFO: 1.01 ± 0.02, P < 0.05).

Conclusion:

The antifungal BIFO reduces both release and biosynthesis of the endothelial-destabilizing factor Angpt-2 in vitro thereby improving vascular barrier function. Additional studies are needed to further investigate the underlying mechanism and to translate these findings to in vivo models.
Evaluation of Evidence, Pharmacology, and Interplay of Fluid Resuscitation and Vasoactive Therapy in Sepsis and Septic Shock
Authors: Barlow Brooke , Bissell Brittany D.
Published: March 2021

We sought to review the pharmacology of vasoactive therapy and fluid administration in sepsis and septic shock, with specific insight into the physiologic interplay of these agents. A PubMed/MEDLINE search was conducted using the following terms (vasopressor OR vasoactive OR inotrope) AND (crystalloid OR colloid OR fluid) AND (sepsis) AND (shock OR septic shock) from 1965 to October 2020. A total of 1,022 citations were reviewed with only relevant clinical data extracted. While physiologic rationale provides a hypothetical foundation for interaction between fluid and vasopressor administration, few studies have sought to evaluate the clinical impact of this synergy. Current guidelines are not in alignment with the data available, which suggests a potential benefit from low-dose fluid administration and early vasopressor exposure. Future data must account for the impact of both of these pharmacotherapies when assessing clinical outcomes and should assess personalization of therapy based on the possible interaction.
Characteristics and Outcomes of Heart Transplant Recipients With Coronavirus-19 Disease in a High-volume Transplant Center
Authors: Marcondes-Braga Fabiana G. , Murad Ciro M. , Belfort Deborah S.P. , Dantas Rafael C.T. , Lira Maria Tereza S.S. , Aragão Carlos A.S. , Siciliano Rinaldo F. , Mangini Sandrigo , Seguro Luis Fernando B.C. , Campos Iáscara W. , Avila Mônica S. , Bello Mariana V.O. , dos Santos Fernanda B.A. , Strabelli Tânia M.V. , Gaiotto Fabio A. , Bacal Fernando
Published: March 2021

Background.

Heart transplant (HT) recipients may be at higher risk of acquiring SARS-CoV-2 infection and developing critical illness. The aim of this study is to describe characteristics and outcomes of HT recipients infected by SARS-COV-2, from a high-volume transplant center.

Methods.

We have described data of all adult HT recipients with confirmed coronavirus disease 2019 by RT-PCR in nasopharyngeal samples from April 5, 2020, to January 5, 2021. Outcomes and follow-up were recorded until February 5, 2021.

Results.

Forty patients were included. Twenty-four patients (60%) were men; the median age was 53 (40–60) y old; median HT time was 34 mo; and median follow-up time 162 d. The majority needed hospitalization (83%). Immunosuppressive therapy was reduced/withdrawn in the majority of patients, except from steroids, which were maintained. Seventeen patients (42.5%) were classified as having severe disease according to the ordinal scale developed by the World Health Organization Committee. They tended to have lower absolute lymphocyte count (P < 0.001) during follow-up when compared with patients with mild disease. Thirty-day mortality was 12.5%. However, a longer follow-up revealed increased later mortality (27.5%), with median time to death around 35 d. Bacterial nosocomial infections were a leading cause of death. Cardiac allograft rejection (10%) and ventricular dysfunction (12.5%) were also not negligible.

Conclusions.

Major findings of this study corroborate other cohorts’ results, but it also reports significant rate of later events, suggesting that a strict midterm surveillance is advisable to HT recipients with coronavirus disease 2019.
Bartonella quintana as a cause for prosthetic valve endocarditis and post-sternotomy mediastinitis
Authors: Plantinga Nienke L. , Vos Roemer J. , Georgieva Lyuba , Roescher Nienke
Published: March 2021

An otherwise healthy patient, with minimal clinical, biochemical and peroperative signs of infection, was diagnosed with

Bartonella quintana

prosthetic valve endocarditis by 16S PCR. The patient subsequently developed a post-sternotomy mediastinitis and

Bartonella quintana

was the only detected pathogen.

Bartonella quintana

can cause severe infections in individuals not classically at risk, and may be missed in the routine diagnostic work-up of endocarditis.
Entangled radicals may explain lithium effects on hyperactivity
Authors: Zadeh-Haghighi Hadi , Simon Christoph
Published: March 2021

It is known that bipolar disorder and its lithium treatment involve the modulation of oxidative stress. Moreover, it has been observed that lithium’s effects are isotope-dependent. Based on these findings, here we propose that lithium exerts its effects by influencing the recombination dynamics of a naturally occurring radical pair involving oxygen. We develop a simple model inspired by the radical-pair mechanism in cryptochrome in the context of avian magnetoreception and xenon-induced anesthesia. Our model reproduces the observed isotopic dependence in the lithium treatment of hyperactivity in rats. It predicts a magnetic-field dependence of the effectiveness of lithium, which provides one potential experimental test of our hypothesis. Our findings show that Nature might harness quantum entanglement for the brain’s cognitive processes.
Off-resonance saturation as an MRI method to quantify ferritin-bound iron in the post-mortem brain
Authors: Bossoni Lucia , Hegeman-Kleinn Ingrid , van Duinen Sjoerd G. , Vroegindeweij Lena H. P. , Langendonk Janneke G. , Hirschler Lydiane , Webb Andrew , van der Weerd Louise
Published: March 2021

Purpose

To employ an Off-Resonance Saturation (ORS) method to measure the ferritin-bound iron pool, which is an endogenous contrast agent which can give information on cellular iron status.

Methods

An ORS acquisition protocol was implemented on a 7T preclinical scanner and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland-Altman analysis on a ferritin-containing phantom. Ferritin-iron maps were obtained from post-mortem tissue of patients with neurological diseases characterized by brain iron accumulation, i. e. Alzheimer’s disease, Huntington’s disease and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were also obtained for comparison.

Results

In post-mortem tissue, the ferritin-iron contrast strongly co-localizes with histological iron staining, in all the cases. Quantitative iron values obtained via the ORS method are in agreement with literature.

Conclusions

Off-resonance saturation is an effective way to detect iron in grey matter structures, while mitigating for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of brain diseases characterized by brain iron accumulation and complement existing iron-sensitive parametric methods.
Recognition of familiar objects in tortoise hatchlings (Testudo spp.)
Authors: Damini Silvia , Stancher Gionata , Versace Elisabetta
Published: March 2021

Tortoises do not show parental care and live solitary except for the context of reproduction. Despite their limited need to interact with conspecifics, we previously observed that young tortoises, at their first experiences with conspecifics, can discriminate between familiar and unfamiliar conspecifics after just one encounter with another tortoise. Tortoise hatchlings ignored familiar conspecifics, while they first explored and then actively avoided unfamiliar conspecifics. It remains to be established whether the different reactions to unfamiliar and familiar individuals in tortoise hatchlings are reactions to novelty, or whether they are specific to the interactions with living animals. To test this, we familiarized one-month-old tortoise hatchlings with an object (a brown conevs. a blue sphere) and then tested them in a novel arena once with the familiar object and once with an unfamiliar one. To measure the reactions toward familiar and unfamiliar objects, we measured the distance between the tortoise and the object throughout the test. Differently from what happened with unfamiliar and familiar conspecifics, we found no difference in behavior toward familiar and unfamiliar objects. This shows that the different reactions toward familiar and unfamiliar conspecifics previously observed are specific for social interactions and are not a mere reaction to the novelty effect. The behavioral responses displayed by young tortoises for unfamiliar conspecifics, but not for unfamiliar objects, show the relevance of social behavior from the beginning of life, even for solitary species.
Contemporary clinical isolates ofStaphylococcus aureusfrom pediatric osteomyelitis patients display unique characteristics in a mouse model of hematogenous osteomyelitis
Authors: Roper Philip M , Eichelberger Kara R , Cox Linda , O’Connor Luke , Shao Christine , Ford Caleb A , Fritz Stephanie A , Cassat James E , Veis Deborah J
Published: March 2021

Osteomyelitis can result from the direct inoculation of pathogens into bone during injury or surgery, or from spread via the bloodstream, a condition called hematogenous osteomyelitis (HOM). HOM disproportionally affects children, and more than half of cases are caused byStaphylococcus (S.) aureus. Laboratory models of osteomyelitis mostly utilize direct injection of bacteria into the bone or the implantation of foreign material, and therefore do not directly interrogate the pathogenesis of pediatric hematogenous osteomyelitis. In this study, we inoculated mice intravenously and characterized resultant musculoskeletal infections using two strains isolated from adults (USA300-LAC and NRS384) and five new methicillin-resistantS. aureusisolates from pediatric osteomyelitis patients. All strains were capable of creating stable infections over five weeks, although the incidence varied. Micro-computed tomography (microCT) analysis demonstrated decreases in trabecular bone volume fraction but little effect on bone cortices. Histologic assessment revealed differences in the precise focus of musculoskeletal infection, with varying mixtures of bone-centered osteomyelitis and joint-centered septic arthritis. Whole genome sequencing of three new isolates demonstrated distinct strains, two within the USA300 lineage and one USA100 isolate. Interestingly, the USA100 strain showed a distinct predilection for septic arthritis, compared to the USA300 strains, including NRS384 and LAC, which more frequently led to osteomyelitis or mixed bone and joint infections. Collectively, these data outline the feasibility of using pediatric osteomyelitis clinical isolates to study the pathogenesis of HOM in murine models and lay the groundwork for future studies investigating strain-dependent differences in musculoskeletal infection.

Importance

The inflammation of bone tissue is called osteomyelitis, and more than half of cases are caused by an infection with the bacteriumStaphylococcus aureus. In children, the most common route of infection is hematogenous, wherein bacteria seed the bone from the bloodstream without another known site of infection. Although these infections pose a significant health problem, they are understudied in the laboratory because of a dearth of robust animal models. In this study, we utilized several previously uncharacterized clinical isolates ofS. aureusderived from children with bone infections to generate reproducible and stable musculoskeletal infection in mice with many features seen in human osteomyelitis, making them a valuable resource for future mechanistic and therapeutic studies.
A New Monocyte Epigenetic Clock Reveals Effects of Alcohol Consumption on Epigenetic Aging in Three Independent Cohorts
Authors: Liang Xiaoyu , Sinha Rajita , Justice Amy C. , Cohen Mardge H. , Aouizerat Bradley E. , Xu Ke
Published: March 2021

Background

Excessive alcohol consumption increases the risk of aging-related comorbidities and mortality. Assessing the impact of alcohol consumption on biological age is important for clinical decision-making and prevention. Evidence shows that alcohol alters monocyte function, and age is associated with DNA methylome and transcriptomic changes among monocytes. However, no monocyte-based epigenetic clock is currently available. In this study, we developed a new monocyte-based DNA methylation clock (MonoDNAmAge) by using elastic net regularization. The MonoDNAmAge was validated by benchmarking using epigenetic age acceleration (EAA) in HIV infection. Using MonoDNAmAge clock as well as four established clocks (i.e., HorvathDNAmAge, HannumDNAmAge, PhenoDNAmAge, GrimDNAmAge), we then evaluated the effect of alcohol consumption on biological aging in three independent cohorts (N=2,242).

Results

MonoDNAmAge, comprised of 186 CpG sites, was highly correlated with chronological age (rtraining=0.96, p<2.20E-16; rtesting=0.86, p=1.55E-141). The MonoDNAmAge clock predicted an approximately 10-year age acceleration from HIV infection in two cohorts. Quadratic regression analysis showed a nonlinear relationship between MonoDNAmAge and alcohol consumption in the Yale Stress Center Community Study (YSCCS,pmodel=4.55E-08,px2=7.80E-08) and in the Veteran Aging Cohort Study (VACS,pmodel=1.85E-02,px2=3.46E-02). MonoDNAmAge and light alcohol consumption showed a negative linear relationship in the Women’s Interagency HIV Study (WIHS,β=-2.63,px=2.82E-06). Heavy consumption increased EAAMonoDNAmAge up to 1.60 years in the VACS while light consumption decreased EAAMonoDNAmAge to 2.66 years in the WIHS. These results were corroborated by the four established epigenetic clocks.

Conclusions

We observed a nonlinear effect of alcohol consumption on epigenetic age that is estimated by a novel monocyte-based “clock” in three distinct cohorts, highlighting the complex effects of alcohol consumption on biological age.
Diverse arsenic-containing lipids in the surface ocean
Authors: Heal Katherine R. , Maloney Ashley E. , Ingalls Anitra E. , Bundy Randelle M.
Published: March 2021

Arsenic is present at nanomolar levels throughout the surface ocean, and microbes assimilate this toxic element due to its similarity to inorganic phosphorus. Although the concentration and characterization of dissolved arsenic has been a focus of ocean studies, the size of the particulate arsenic pool and its partitioning into organic molecules within the microbial community is not known. We measured the particulate pool of arsenic in five surface samples from the open ocean and determined the contribution of arsenic-containing lipids to this pool. Here we show that the accumulation of arsenic into lipids is a widespread phenomenon in the surface ocean. Particulate arsenic concentrations were 15 to 42 pmol L−1with 7–20% of the particulate arsenic pool in the form of arsenolipids. We characterized these arsenolipids and found that arsenosugar phospholipids dominated the arsenolipid pools in our samples with a minor component of arsenohydrocarbons and other unidentified lipids. A significant portion of the arsenosugar phospholipids (up to 35%) were present as previously undescribed mixed acyl ether lipids, suggesting a bacterial source.

Scientific significance statement

Marine microbes experience constant exposure to the toxic element arsenic. However, there are no baseline measurements of how much arsenic accumulates in microbial communities nor do we know the full spectrum of arsenic containing biomolecules produced in marine systems. In culture-based studies there is strong evidence that phytoplankton synthesize arsenic-containing lipids, but these lipids have not been observed in natural communities of marine microbes. Here we make measurements of bulk particulate arsenic at five sites in the surface open ocean and show that a significant portion of this particulate arsenic is present as complex arsenic-containing lipids. We characterize this arsenolipid pool chemically and quantitatively to show a variety of chemically distinct and quantitatively significant lipids that expand our understanding of marine arsenic biogeochemistry.

Data availability statement

Mass spectrometry data and its associated metadata will be available on Dryad with publication. Scripts for data processing and figure generation found on github athttps://github.com/kheal/particulate_As_data_analysis.
Noise Effect on the Temporal Patterns of Neural Synchrony
Authors: Zirkle Joel , Rubchinsky Leonid L
Published: March 2021

Neural synchrony in the brain is often present in an intermittent fashion, i.e., there are intervals of synchronized activity interspersed with intervals of desynchronized activity. A series of experimental studies showed that this kind of temporal patterning of neural synchronization may be very specific and may be correlated with behavior (even if the average synchrony strength is not changed). Prior studies showed that a network with many short desynchronized intervals may be functionally different from a network with few long desynchronized intervals as it may be more sensitive to synchronizing input signals. In this study, we investigated the effect of channel noise on the temporal patterns of neural synchronization. We employed a small network of conductance-based model neurons that were mutually connected via excitatory synapses. The resulting dynamics of the network was studied using the same time-series analysis methods as used in prior experimental and computational studies. While it is well known that synchrony strength generally degrades with noise, we found that noise also affects the temporal patterning of synchrony. Noise, at a sufficient intensity (yet too weak to substantially affect synchrony strength), promotes dynamics with predominantly short (although potentially very numerous) desynchronizations. Thus, channel noise may be one of the mechanisms contributing to the short desynchronization dynamics observed in multiple experimental studies.

Highlights

Channel noise alters the temporal pattern of intermittent neural synchrony

Noise may alter this pattern without significant change in average synchrony strength

The resulting patterning is similar to that observed in multiple experiments
Financial incentives facilitate the neural computation of prosocial decisions stronger in low empathic individuals
Authors: Iotzov Vassil , Saulin Anne , Kaiser Jochen , Han Shihui , Hein Grit
Published: March 2021

Financial incentives are commonly used to motivate behaviours. There is also evidence that incentives can decline the behaviour they are supposed to foster, for example, documented by a decrease in blood donations if a financial incentive is offered. Based on these findings, previous studies assumed that prosocial motivation is shaped by incentives. However, so far, there is no direct evidence showing an interaction between financial incentives and a specific prosocial motive. Combining drift-diffusion modelling and fMRI, we investigated the effect of financial incentives on empathy, i.e., one of the key motives driving prosocial decisions. In the empathy-alone condition, participants made prosocial decisions based on empathy, in the empathy-bonus condition, they were offered a financial bonus for prosocial decisions, in addition to empathy induction. On average, the bonus enhanced the information accumulation in empathy-based decision. On the neural level, this enhancement was related to the anterior insula, the same region that also correlated with empathy ratings. Moreover, the effect of the financial incentive on anterior insula activation was stronger the lower a person scored on empathy. These findings show that financial incentives enhance prosocial motivation in the absence of empathy but have little effect on high empathic individuals.
Optogenetic activation of striatal D1/D2 medium spiny neurons differentially engages downstream connected areas beyond the basal ganglia
Authors: Grimm Christina , Frässle Stefan , Steger Céline , von Ziegler Lukas , Sturman Oliver , Shemesh Noam , Bohacek Johannes , Stephan Klaas Enno , Razansky Daniel , Wenderoth Nicole , Zerbi Valerio
Published: March 2021

The basal ganglia (BG) are a group of subcortical nuclei responsible for motor control, motor learning and executive function. Central to BG function are striatal medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors. D1 and D2 MSNs are typically considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. While their opposite role is well documented for certain sensorimotor loops of the BG-thalamocortical network, it is unclear whether MSNs maintain a uniform functional role across the striatum and which influence they exert on brain areas outside the BG. Here, we addressed these questions by combining optogenetic activation of D1 and D2 MSNs in the mouse ventrolateral caudoputamen (vl CPu) with whole-brain functional MRI (fMRI) recordings. Neuronal excitation of either cell population in the vl CPu evoked distinct activity patterns in key regions of the BG-thalamocortical network including the pallidum, thalamus and motor cortex. Importantly, we report that striatal D1 and D2 MSN stimulation differentially engaged cerebellar and prefrontal regions. We characterised these long-range interactions by computational modelling of effective connectivity and confirmed that changes in D1 / D2 output drive functional relationships between regions within and beyond the BG. These results suggest a more complex functional organization of MSNs across the striatum than previously anticipated and provide evidence for the existence of an interconnected fronto - BG - cerebellar network modulated by striatal D1 and D2 MSNs.

Graphical Abstract
Should deep-sequenced amplicons become the new gold-standard for analysing malaria drug clinical trials?
Authors: Jones Sam , Kay Katherine , Hodel Eva Maria , Gruenberg Maria , Lerch Anita , Felger Ingrid , Hastings Ian
Published: March 2021

Background

Regulatory clinical trials are required to ensure the continued supply and deployment of effective antimalarial drugs. Patient follow-up in such trials typically lasts several weeks as the drugs have long half-lives and new infections often occur during this period. “Molecular correction” is therefore used to distinguish drug failures from new infections. The current WHO-recommend method for molecular correction uses length-polymorphic alleles at highly diverse loci but is inherently poor at detecting low density clones in polyclonal infections. This likely leads to substantial underestimates of failure rates, delaying the replacement of failing drugs with potentially lethal consequences. Deep sequenced amplicons (AmpSeq) substantially increase the detectability of low-density clones and may offer a new “gold standard” for molecular correction.

Methods

Pharmacological simulation of clinical trials was used to evaluate the suitability of AmpSeq for molecular correction. We investigated the impact of factors such as the number of amplicon loci analysed, the informatics criteria used to distinguish genotyping ‘noise’ from real low density signals, the local epidemiology of malaria transmission, and the potential impact of genetic signals from gametocytes.

Results

AmpSeq greatly improved molecular correction and provided accurate drug failure rate estimates. The use of 3 to 5 amplicons was sufficient, and simple, non-statistical, criteria could be used to classify recurrent infections as drug failures or new infections.

Conclusions

These results strongly endorse the deployment of AmpSeq as the standard for molecular correction in regulatory trials, with its potential extension into routine surveillance once the requisite technical support becomes established.
Is Destira My Destiny? Whether, When, and How to Join One's Small Family Business
Authors: Ward John L. , Zsolnay Carol
Published: March 2021

In mid-2012, after successful years in large public companies and obtaining an MBA, middle daughter Jen, 32, is trying to decide whether the time is right for her to enter her mother and sister's small family business to grow it further. Destira, Inc. was a designer/manufacturer of gymnastics wear for girls, headquartered in California. Donna Levy founded the company in 1990, after years of making leotards for her three daughters, who were competitive youth gymnasts, and getting requests from other parents to make the garments for their own children. In 2005, when Donna's oldest daughter, Jodi, joined Destira, Donna gave her a 50 percent equity stake. Between then and year-end 2011, the pair grew the revenues from $550,000 to $1.06 million, increased the number of outlets carrying the brand, upgraded the internal accounting/operations software, and added an online direct-to-customer retail business. The case shows realistic considerations for the individual, family, and business when evaluating whether or not to commit to join the family enterprise.
Aura: Designing Strategy and Status in Saudi Arabia
Authors: Smith Ned , Meyer Andrea
Published: March 2021

This case gives students the opportunity to explore the concept of organizational status as a competitive asset. CEO Noura Abdullah of Saudi furniture retailer Aura founded her company as a middle-market furniture and home goods store offering affordable yet design-savvy products. By many accounts, both tangible and intangible, Aura had been a success. By late 2014, Aura had drawn considerable attention from several high-status Saudi wedding planners and media outlets, including Harper's Bazaar Interiors, Elle Decor, and Martha Stewart Weddings. This attention yielded unusually strong conversion rates (the percentage of visitors to the store who made a purchase). Foot traffic, on the other hand, remained unexpectedly low, leading Abdullah to wonder whether the high-status affiliations had unintentionally signaled to mid-market consumers that they would not be able to afford Aura's products, keeping such customers away. Students will decide, along with Abdullah, how to handle this unique “problem” as Aura enters a growth phase to other Saudi and Middle Eastern markets.
Lie, Cheat, and Steel: Governance and Scandal at ThyssenKrupp
Authors: Shein James B. , Meagher Evan , Darcy Matt , Mitra Abhishek , Willich Barrett
Published: March 2021

On March 7, 2013, ThyssenKrupp Group CEO Heinrich Hiesinger was shocked to receive a resignation letter from Gerhard Cromme, chairman of the company's supervisory board.

Hiesinger had been CEO since 2010. Early in his tenure, ThyssenKrupp incurred massive losses from disastrous steel investments and faced allegations of colluding with other companies to fix prices in its railway steel operations. As a result, Hiesinger had been forced to dismiss three executive board members, one for violating company policy. After a supervisory board member also was dismissed for violating company policy, the company's offices were raided in an investigation of price-fixing in steel contracts to the automotive industry.

Cromme had been sharply criticized by shareholders and analysts as an impediment to the cultural, strategic, and governance changes Hiesinger was trying to make to address the scandals at ThyssenKrupp, but for months he defiantly had resisted calls for his removal. With no warning, he resigned without naming a successor or creating a plan to select one.

Now that he no longer needed to deal with the distractions created by Cromme's presence, Hiesinger was free to finalize a plan to address the defects in ThyssenKrupp's governance.
OurCrowd: Growing a Crowdfunding Platform in a VC World
Authors: Markovich Sarit , Meagher Evan
Published: March 2021

This case features the challenges of a startup in the crowdfunding space in 2015 as its leadership assesses potential sources of growth for the company s future. Founded in Israel in 2012 by a renowned venture capitalist, OurCrowd was a venture capital crowdfunding platform that strove to connect high-growth startups raising capital with accredited private investors from around the world. Its value proposition was to democratize an inefficient market for private equity that had historically been dominated by a small number of highly connected venture capital firms (VCs). The case asks students to put themselves in the shoes of OurCrowd s head of investor community as he prepares for a meeting with the company s board of directors to discuss potential strategies for growth: Should the company partner with the incumbent VCs it initially sought to disrupt, emphasize marketing its Portfolio Reserve fund, strive to provide its investors and investees with higher value-added services, target a broader swath of investors by aggressively marketing the platform in international markets, or attempt to go up-market and pursue increasingly larger deals with later-stage companies? Through assessing these options and discussing this case, students will learn about incentive problems in two-sided markets as well as how different types of crowdfunding platforms create value for users.
The U‐shaped pattern of size‐dependent mortality and its correlated factors in a subtropical monsoon evergreen forest
Authors: Lu Ruiling , Qiao Yang , Wang Jing , Zhu Chen , Cui Erqian , Xu Xiaoni , He Yi , Zhao Zexuan , Du Ying , Yan Liming , Shen Guochun , Yang Qingsong , Wang Xihua , Xia Jianyang
Published: March 2021

Tree mortality is an important ecological process influencing multiple functions of forest ecosystems. Previous studies have shown two basic size–mortality patterns, including a competition‐driven declining and a disturbance‐driven increasing mortality rate with tree size. Subtropical forests, which have a high species diversity and subject to frequent monsoon disturbances, are widely distributed in eastern Asia. However, the tree size–mortality pattern in the mature subtropical forests remains unclear.

Here we analysed patterns of size‐dependent mortality from tree species to forest community using a 5‐year inventory data from 117 species and 163,612 individuals in a 20‐ha forest dynamic plot in a mature subtropical monsoon evergreen forest in eastern China. To explain the spatial variability in mortality patterns, two major biotic drivers (competition and tree size) and multiple local‐scale environmental factors were further analysed.

Our results showed that tree size was the best predictor of tree mortality at the scales of both species and community. A species‐level analysis identified four size–mortality patterns that are shaped by species‐specific attributes such as maximum size and life form. For 27 out of 92 species that comprised 59% of tree individuals, the relationship between size and mortality exhibited a U‐shaped pattern of a first decline followed by an increase. An overall community‐scale size‐dependent mortality also showed a U‐shaped pattern.

Tree mortality was also influenced by the competition and environmental conditions, but the relative importance varied widely across tree sizes and species. The competition showed significant correlations with the mortality of small trees while the effect of environmental conditions on mortality was strongest for large trees. A principal component analysis showed that a combination of biotic and abiotic factors explained 42.3% of the spatial variation in mortality at large sizes.

Synthesis. Our results reveal four identifiable size‐dependent mortality patterns that differ across diverse species, jointly leading to a U‐shaped size–mortality pattern at the community level. This finding calls for the need to establish the details of every potential size–mortality pattern with consideration of the different effects of biotic and abiotic factors on tree mortality of specific size.