bluuebunny/crossref_metadata_2025 huggingface dataset:
Likelihood of Bacterial Infection in Patients Treated With Broad-Spectrum IV Antibiotics in the Emergency Department*
Authors: Shappell Claire N. , Klompas Michael , Ochoa Aileen , Rhee Chanu
Published: May 2021

OBJECTIVES:

Best practice guidelines and quality metrics recommend immediate antibiotic treatment for all patients with suspected sepsis. However, little is known about how many patients given IV antibiotics in the emergency department are ultimately confirmed to have bacterial infection.

DESIGN, SETTING, AND PATIENTS:

We performed a retrospective study of adult patients who presented to four Massachusetts emergency departments between June 2015 and June 2018 with suspected serious bacterial infection, defined as blood cultures drawn and broad-spectrum IV antibiotics administered. Structured medical record reviews were performed on a random sample of 300 cases to determine the post hoc likelihood of bacterial infection, categorized as definite, likely, unlikely, or definitely none.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Among the 300 patients with suspected serious bacterial infections, mean age was 68 years (sd 18), median hospital length of stay was 5 days (interquartile range, 3–8 d), 45 (15%) were admitted directly to ICU, and 14 (5%) died in hospital. Overall, 196 (65%) had definite (n = 115; 38%) or likely (n = 81; 27%) bacterial infection, whereas 104 (35%) were unlikely (n = 55; 18%) or definitely not infected (n = 49; 16%). Antibiotic treatment durations differed by likelihood of infection (median 15 days for definite, 9 for likely, 7 for unlikely, and 3 for definitely not infected). The most frequent post hoc diagnoses in patients with unlikely or definitely no bacterial infection included viral infections (28%), volume overload or cardiac disease (9%), drug effects (9%), and hypovolemia (7%). The likelihoods of infection were similar in the subset of 96 cases in whom emergency department providers explicitly documented possible or suspected sepsis and in the 45 patients admitted from the emergency department to the ICU.

CONCLUSIONS:

One third of patients empirically treated with broad-spectrum antibiotics in the emergency department are ultimately diagnosed with noninfectious or viral conditions. These findings underscore the difficulty diagnosing serious infections in the emergency department and have important implications for guidelines and quality measures that compel immediate empiric antibiotics for all patients with possible sepsis.
Clinical significance of CCNE1 copy number gain in acral melanoma patients
Authors: Wu Xiaowen , Yan Junya , Yu Jiayi , Cheng Zhiyuan , Guo Qian , Kong Yan , Guo Jun
Published: May 2021

Copy number variations are frequently observed in cell cycle–related genes in acral melanoma. However, the clinical significance of copy number gain of CCNE1 in acral melanoma has not been fully elucidated. In this study, 490 acral melanoma samples were examined for CCNE1 copy number using the QuantiGenePlex DNA Assay. Correlation between CCNE1 copy number and acral melanoma patients’ clinicopathologic features were analyzed using Chi-squared test. The impact of CCNE1 copy number on patients’ progression-free survival (PFS) and overall survival (OS) probability were analyzed using Kaplan–Meier analysis. The impact of CCNE1 copy number on patients’ median PFS after receiving chemotherapy was also evaluated. The results showed that CCNE1 copy number gain was observed in 28.30% of patients, with 3.16% of patients carrying both CCNE1 copy number gain and BRAF mutation and 4.34% of patients carrying both CCNE1 copy number gain and NRAS mutation. The median PFS time for patients with CCNE1 copy number gain was shorter than that of patients without CCNE1 copy number gain (17.0 vs. 27.0 months, P = 0.002).In the cohort that received chemotherapy (n = 82), the median PFS time for patients with CCNE1 copy number gain was shorter than that of patients without CCNE1 copy number gain (4.8 vs. 7.4 months, P = 00.006). CCNE1 copy number gain was an independent prognostic marker for acral melanoma patients’ PFS. Our study indicates that CCNE1 copy number gain is frequent in acral melanoma and may be a biomarker to predict acral melanoma patients’ outcomes after receiving chemotherapy.
Storage solutions to improve grafts preservation and longevity in coronary artery bypass grafting surgery: hype or hope?
Authors: Eqbal Adam , Gupta Saurabh , Bisleri Gianluigi
Published: May 2021

Purpose of review

Saphenous vein grafts (SVGs) remain the most-commonly used conduits for coronary artery bypass grafting (CABG).

Significant rates of vein graft failure (VGF) remain a limitation of their use as this diminishes the long-term benefits of CABG. The choice of intraoperative SVGs preservation solution is believed to have an impact on graft patency; however, the superiority of one solution over the others remains in question.

Recent findings

In the present review, we describe the pathophysiological mechanisms underlying the different phases of VGF. We also reviewed the most recent literature comparing and evaluating the efficacy of various storage solutions. These include heparinized saline, autologous heparinized blood, buffered solutions, and crystalloid cardioplegia.

It is clear that the composition of the SVGs storage solution has an impact on vessel wall structure and function. There is a lack of translational and clinical research on the topic; thus, conclusions cannot be drawn regarding the superiority of one solution over the others in terms of VGF. Future research needs to be conducted to address this gap in the literature in order to make meaningful evidence-based recommendations on intraoperative graft storage.
Review new concepts in pharmacotherapy for peripheral arterial disease
Authors: Kotalczyk Agnieszka , Vallabhaneni Srinivasa Rao , Lip Gregory Y.H.
Published: May 2021

Purpose of review

To provide an overview of new concepts in the pharmacotherapy of patients with peripheral artery disease (PAD).

Recent findings

Modern therapeutic strategies for patients with PAD include specific symptom management and multidisciplinary prevention of cardiovascular events. Low-dose rivaroxaban in combination with aspirin improves outcomes compared with aspirin monotherapy among patients with PAD. Other novel concepts include the use of bosentan, vorapaxar or sildenafil among symptomatic patients with PAD. Likewise, lipid-lowering therapy reduces the risk of major cardiovascular and limb events.

Personalized management, identification of risk factors and shared-decision making are crucial in improving the best medical therapy for patients with PAD. Further studies are needed to assess the long-term safety and efficacy of novel strategies in real-world patients.
A double-edged sword: The effects of social network ties on job satisfaction in primary care organizations
Authors: Yuan Christina T. , Lai Alden Yuanhong , Benishek Lauren E. , Marsteller Jill A. , Mahabare Darshan , Kharrazi Hadi , Dy Sydney M.
Published: May 2021

Background

Social ties between health care workers may be an important driver of job satisfaction; however, research on this topic is limited.

Purpose

We used social network methods to collect data describing two types of social ties, (a) instrumental ties (i.e., exchange of advice that enables work) and (b) expressive ties (i.e., exchange of social support), and related those ties to workers’ job satisfaction.

Methodology

We surveyed 456 clinicians and staff at 23 primary care practices about their social networks and workplace attitudes. We used multivariable linear regression to estimate the relationship between an individual’s job satisfaction and two network properties: (a) eigenvector centrality (a measure of the importance of an individual in a network) and (b) ego network density (a measure of the cohesiveness of an individual’s network). We examined this relationship for both instrumental and expressive ties.

Results

Individuals who were more central in the expressive network were less satisfied in their job, b = −0.40 (0.19), p < .05, whereas individuals who had denser instrumental networks were more satisfied in their job, b = 0.49 (0.21), p < .05.

Conclusion

Workplace relationships affect worker well-being. Centrality in an expressive network may require greater emotional labor, increasing workers’ risk for job dissatisfaction. On the other hand, a dense instrumental network may promote job satisfaction by strengthening workers’ access to full information, supporting competence and confidence.

Practice Implications

Efforts to increase job satisfaction should consider both the positive and negative effects of social networks on workers’ sense of well-being.
Safety and Antibody Kinetics of COVID-19 Convalescent Plasma for the Treatment of Moderate to Severe Cases of SARS-CoV-2 Infection in Pediatric Patients
Authors: Arrieta Antonio , Galvis Alvaro E. , Morphew Tricia , Ehwerhemuepha Louis , Osborne Stephanie , Enriquez Claudia , Imfeld Karen , Hoang Janet , Nieves Delma , Ashouri Negar , Singh Jasjit , Nugent Diane
Published: May 2021

Background:

Therapies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its life-threatening respiratory infection coronavirus disease 2019 (COVID-19) have been evaluated, including COVID-19 convalescent plasma (CCP). Multiple large reports of CCP treatment in adults exist. Pediatric data on CCP safety and efficacy are limited.

Methods:

Single-center prospective, open-label trial looking at safety, antibody kinetics and outcomes of CCP (10 mL/kg, max 1 unit) treatment for COVID-19 in hospitalized pediatric patients with moderate to severe disease or at high-risk for serious illness.

Results:

Thirteen patients were enrolled. No infusion-related adverse events occurred. No hematologic or metabolic adverse events were noted during hospitalization or at 3-weeks. Ten patients had clinical improvement by day 7 (WHO eight-category ordinal severity scale for COVID-19). Following CCP, anti-SARS-CoV-2 anti-nucleocapsid IgG increased significantly at 24 hours and high levels were sustained at 7- and 21-days. Transient IgM response was noted. Twelve patients (92.3%) were discharged home, 9 (75%) by day 7 post-CCP. One remained on invasive ventilatory support 42 days after CCP and was eventually discharged to an intermediate care facility. The single patient death was retrospectively confirmed to have had brain death before CCP.

Conclusion:

CCP was well tolerated in pediatric patients, resulted in rapid antibody increase, and did not appear to interfere with immune responses measured at 21 days. More pediatric data are necessary to establish the efficacy of CCP, but our data suggest benefit in moderate to severe COVID-19 when used early. Other immunologic or antiviral interventions may be added as supported by emerging data.
Bioelectric impedance analysis for body composition measurement and other potential clinical applications in critical illness
Authors: Moonen Hanneke Pierre Franciscus Xaverius , Van Zanten Arthur Raymond Hubert
Published: May 2021

Purpose of review

Insight into body composition is of great value in the ICU. Bioelectric impedance analysis (BIA) is the most applicable bedside technique. However, bioimpedance has not been validated in the critically ill, and the interpretation of the measurements poses challenges. This review discusses the potential clinical applications of BIA and explores caveats and solutions to its use in the intensive care setting.

Recent findings

A correlation is repeatedly found between raw impedance parameters, fluid ratios, overhydration, and adverse outcome of critical illness. However, cut-off and reference values remain elusive. Experience with BIA-guided fluid management in the ICU is limited. BIA-derived muscle mass appears a promising biomarker for sarcopenia, correlating well with CT-analysis. Body cell mass and fat-free mass provide potential use in estimation of metabolic rate, protein requirements and pharmacokinetics. Several methods of reducing bias in BIA parameters in critical illness require validation.

There are currently too many uncertainties and discrepancies regarding interpretation of bioimpedance in critical illness, to justify therapeutic consequences. However, there are several promising areas of research, concerning some of the most urgent clinical problems in intensive care, emphasizing the need to evaluate further the use and interpretation of bioimpedance in the intensive care setting.
Adverse events of systemic immune-based combination therapies in the first-line treatment of patients with metastatic renal cell carcinoma: systematic review and network meta-analysis
Authors: Quhal Fahad , Mori Keiichiro , Remzi Mesut , Fajkovic Harun , Shariat Shahrokh F. , Schmidinger Manuela
Published: May 2021

Purpose of review

To compare the safety profiles of systemic immune checkpoint inhibitor-based combination therapies that were evaluated in the first-line setting of the management of patients with advanced or metastatic renal cell carcinoma (mRCC).

Recent findings

Six phase III randomized control trials comparing first-line immune-based combination therapies to sunitinib in previously untreated patients with mRCC. Network meta-analyses were conducted to compare treatment-related adverse events (TRAEs), treatment discontinuation, and treatment-related mortality.

Lenvatinib plus pembrolizumab was associated with the highest likelihood of grade ≥3 TRAEs, and treatment discontinuation rates. Nivolumab plus ipilimumab was associated with the lowest rates of grade ≥3 TRAEs. However, it was associated with a higher likelihood of endocrine-related adverse events (AEs). A higher likelihood of high-grade diarrhea was associated with pembrolizumab plus axitinib and avelumab plus axitinib. All combinations showed low rates of hematological AEs.
Neurosyphilis Surveillance: Exploring the Use of Multiple Data Sources to Better Understand Morbidity in California
Authors: Burghardt Nicole Olson , Nelson Lauren N. , Tang Eric C. , Plotzker Rosalyn E. , Jacobson Kathleen , Murphy Ryan D.
Published: May 2021

Accurate reporting of neurosyphilis diagnoses is important to quantify and monitor severe outcomes associated with infection of Treponemal pallidum. This analysis compared the demographic distribution of neurosyphilis diagnoses in sexually transmitted disease surveillance data with administrative hospital data in the California Project Area from 2016 to 2018. Although neurosyphilis morbidity was similar, significant differences were noted by sex, age group, race/ethnicity, and region. Both sexually transmitted disease surveillance and administrative hospital data may be imperfect systems to understand the true morbidity of neurosyphilis.
Fibrinolytic Impairment and Mortality in Pediatric Septic Shock: A Single-Center Prospective Observational Study*
Authors: Tuan Ta Anh , Ha Nguyen Thi Thu , Xoay Tran Dang , My Tran Thi Kieu
Published: May 2021

OBJECTIVES:

Fibrinolytic shutdown is associated with poor prognosis in adult sepsis, but data in the pediatric population are sparse. This study aimed to identify the association between impaired fibrinolysis and mortality in pediatric septic shock.

DESIGN:

A prospective, observational study conducted between August 2019 and August 2020.

SETTING:

PICU at a pediatric tertiary hospital in Hanoi, Vietnam.

PATIENTS:

Fifty-six pediatric patients who met septic shock criteria were enrolled.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Conventional coagulation tests and rotational thromboelastometry were performed at diagnosis. The fibrinolytic activity on extrinsic pathway thromboelastometry was negatively correlated with the Vasoactive-Inotropic Score at 24 hours post-PICU admission, peak lactate level during the first 24 hours, Pediatric Logistic Organ Dysfunction-2 score, and Pediatric Risk of Mortality-III score (all p < 0.05). Compared with patients with nonovert disseminated intravascular coagulation, dysfunction of less than two organs, and who survived, patients with overt disseminated intravascular coagulation, dysfunction of greater than two organs, and who died showed significantly lower fibrinolytic activity, represented by significantly higher lysis indexes (%) and lower maximum lysis (%) (all p < 0.05). The threshold values for prediction of mortality were lysis index 60 minutes greater than 97.5 (area under the curve = 0.86; sensitivity = 73%; specificity = 90%), maximum lysis less than 6.5 (area under the curve = 0.83; sensitivity = 73%; specificity = 87%), and lysis index 45 minutes greater than 99.5 (area under the curve = 0.83; sensitivity = 73%; specificity = 85%). Hypofibrinolysis was associated with prolonged PICU length of stay in survivors and with early mortality in nonsurvivors.

CONCLUSIONS:

Fibrinolytic shutdown in pediatric septic shock is associated with an increase in disease severity and mortality. This highlights the need for further investigations regarding whether fibrinolytic therapy improved the outcome of pediatric septic shock.
Intraoperative Hypoxia Independently Associated With the Development of Acute Kidney Injury Following Bilateral Orthotopic Lung Transplantation
Authors: Knight Joshua , Hill Adam , Melnyk Vladyslav , Doney Luke , D’Cunha Jonathan , Kenkre Tanya , Subramaniam Kathirvel , Howard-Quijano Kimberly
Published: May 2021

Background.

Acute kidney injury (AKI) is a common postoperative complication in bilateral orthotopic lung transplant (BOLTx) recipients, but the contribution of intraoperative variables is not well defined. The authors hypothesized that intraoperative hypotension as well as hypoxia and vasopressor use would be associated with the development of postoperative AKI after BOLTx in patients without pre-existing renal dysfunction.

Methods.

The authors performed a retrospective analysis of patients undergoing BOLTx at a single center between 2013 and 2017. Intraoperative variables of hemodynamics included duration of mean arterial pressure <55, <60, and <65 mm Hg; duration of oxygen saturation <90%; and vasoactive-inotropic score (VIS). Associations between the occurrence of AKI and intraoperative hypotension, hypoxemia, and VIS were evaluated while controlling for significant confounding variables.

Results.

AKI occurred in 177 (72%) of 245 patients in postoperative days 1–7. Notable significant differences in univariate analyses included cumulative mechanical support time, maximum VIS, peripheral oxygen saturation <90% for >15 min, total minutes oxygen saturation <90%, and surgery duration in minutes. There was no significant difference in intraoperative hypotension measured as a duration >15 min for mean arterial pressure <55, <60, or <65 mm Hg. Multivariate logistic regression revealed preoperative creatinine (Odds ratio [OR], 7.77; confidence interval [CI], 1.96-30.83; P = 0.004), surgery duration (OR, 1.004; CI, 1.002-1.007; P = 0.002), and oxygen saturation (OR, 2.06; CI, 1.01-4.24; P = 0.049) <90% for >15 min to be independently associated with AKI.

Conclusions.

This study revealed that >15 min of intraoperative hypoxia was independently associated with postoperative AKI after BOLTx.
Update on alpha-synuclein-based biomarker approaches in the skin, submandibular gland, gastrointestinal tract, and biofluids
Authors: Andréasson Mattias , Svenningsson Per
Published: May 2021

Purpose of review

There is a need for objective diagnostic and prognostic biomarkers in Parkinson's disease (PD), partly given the expected increase in clinical trials aimed at demonstrating a disease-modifying effect in early disease. Alpha-synuclein (α-syn) plays a decisive role in the pathogenesis of PD. Here, we review recent publications exploring established and novel methodologies to detect α-syn species in tissues and biofluids.

Recent findings

Using immunohistochemistry (IHC), recent studies have focused on the detection of phosphorylated α-syn (p-α-syn) in cutaneous nerve fibers, reporting varying sensitivity and high specificity for the diagnosis of PD. A predilection for p-α-syn depositions in cutaneous autonomic nerve fibers has emerged, possibly contrasting with other synucleinopathies.

Novel studies utilizing the seeding propensity of pathological α-syn have generated encouraging results with regard to diagnostic performance in both tissues and biofluids including skin, submandibular gland, and cerebrospinal fluid.

Detection of neuronal p-α-syn in skin punch biopsies remains a promising minimally invasive diagnostic tool in PD. Seeding assays have emerged as a new method with its diagnostic potential warranting replication in further studies from various tissues and biofluids. Longitudinal studies employing both IHC and seeding assays are needed to identify possible biomarkers of disease progression.
Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank Study
Authors: Papier Keren , Knuppel Anika , Perez-Cornago Aurora , Watts Eleanor L. , Tong Tammy YN , Schmidt Julie A , Allen Naomi , Key Timothy J , Travis Ruth C
Published: May 2021

Background

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort.

Methods

Study participants were 318 749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006-2010), and re-measured in 12 334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias.

Results

After correction for multiple testing (P<0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration=1.12, 95% CI, 1.08-1.16), and inversely associated with varicose veins (0.90, 0.85-0.95), cataracts (0.97, 0.95-0.99), diabetes (0.92, 0.90-0.95), and iron deficiency anaemia (0.90, 0.86-0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality.

Conclusions

Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

Key messages

Evidence on the association between circulating insulin-like growth factor-I (IGF-I) and risk of many common, non-cancer health outcomes in the general population is relatively limited.

This study used an outcome-wide approach to prospectively examine associations of circulating IGF-I with risk of 25 common conditions in a large, prospective cohort of over 300,000 UK adults.

Our study showed that circulating IGF-I is associated with risks of several common diseases and conditions; IGF-I was positively associated with carpal tunnel syndrome and inversely associated with varicose veins, cataracts, diabetes, and iron deficiency anaemia.

Further research is needed to evaluate whether these differences in risk may reflect causal relationships.
A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is Absent in Horseshoe Bats
Authors: Wickenhagen Arthur , Sugrue Elena , Lytras Spyros , Kuchi Srikeerthana , Turnbull Matthew L , Loney Colin , Herder Vanessa , Allan Jay , Jarmson Innes , Cameron-Ruiz Natalia , Varjak Margus , Pinto Rute M , Stewart Douglas G , Swingler Simon , Noerenberg Marko , Greenwood Edward J D , Crozier Thomas W M , Gu Quan , Clohisey Sara , Wang Bo , Maranhão Costa Fabio Trindade , Santana Monique Freire , de Lima Ferreira Luiz Carlos ,   ISARIC4C investigators, Da Silva Filho Joao Luiz , Marti Matthias , Stanton Richard J , Wang Eddie C Y , Castello-Palomares Alfredo , Ho Antonia , Baillie Kenneth , Jarrett Ruth F , Robertson David L , Palmarini Massimo , Lehner Paul J , Rihn Suzannah J , Wilson Sam J
Published: May 2021

Cell autonomous antiviral defenses can inhibit the replication of viruses and reduce transmission and disease severity. To better understand the antiviral response to SARS-CoV-2, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that while some people can express a prenylated OAS1 variant, that is membrane-associated and blocks SARS-CoV-2 infection, other people express a cytosolic, nonprenylated OAS1 variant which does not detect SARS-CoV-2 (determined by the splice-acceptor SNP Rs10774671). Alleles encoding nonprenylated OAS1 predominate except in people of African descent. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response. Remarkably, approximately 55 million years ago, retrotransposition ablated the OAS1 prenylation signal in horseshoe bats (the presumed source of SARS-CoV-2). Thus, SARS-CoV-2 never had to adapt to evade this defense. As prenylated OAS1 is widespread in animals, the billions of people that lack a prenylated OAS1 could make humans particularly vulnerable to the spillover of coronaviruses from horseshoe bats.
Insect attraction to the six major types of traditional-style, residential light bulbs and implications for insect survival and light pollution
Authors: Justice Michael J. , Justice Teresa C.
Published: May 2021

Artificial light at night can affect the behavior and survival of the arthropods attracted to it. Most light pollution research focuses on high-wattage street lamps, but lower-wattage lamps used to illuminate porches, paths, façades, and backyards vastly outnumber street lamps. Thus, residential consumers could potentially have an enormous influence on artificial light ecologies by their choice of lamp. This study compared insect attraction to the six major types of traditional-style, residential light bulb: incandescent, CFL, halogen, warm color temperature LED, cool color temperature LED, and the yellow “bug” lights marketed as reducing insect attraction. The bulbs were alternately used in a baffle-funnel light trap from early spring through late fall, and capture rates were determined for the orders of insects. Incandescent bulbs produced the highest trap captures; the warm color temperature LED bulb produced the fewest, even fewer than the yellow “bug” light. The yellow “bug” light attracted more Dermaptera (Leach) than the other bulbs. The data support a recommendation of LED bulbs, especially those with a warm color temperature, to minimize the effects of night lighting on insect behavior and mortality. Further, the use of yellow “bug” lights, in contrast to their marketing, could attract earwigs and other minor pests.
Superiority of serum NFL in predicting Multiple Sclerosis severity
Authors: Kosa Peter , Masvekar Ruturaj , Komori Mika , Phillips Jonathan , Ramesh Vighnesh , Varosanec Mihael , Sandford Mary , Bielekova Bibiana
Published: May 2021

Objective

Serum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. While sNFL correlates with cerebrospinal fluid NFL (cNFL), 40-60% of variance remains unexplained. Assuming that for diseases of the central nervous system (CNS), such as multiple sclerosis (MS), the cNFL better reflects CNS injury, our goal was to develop and validate adjustment of sNFL for relevant confounders, to strengthen cNFL-sNFL correlations.

Methods

We used 1,378 matched cNFL-sNFL pairs divided into training and validation cohort with matching data on 11 confounders, neuroexam, and magnetic resonance imaging (MRI). The effect of confounders on cNFL-sNFL relationship was tested using multiple linear regression (MLR) model. Propensity score matching was used to identify effect of spinal cord damage on sNFL levels.

Results

In the training cohort (n=898) we correlated 11 confounders with the residuals from cNFL-sNFL linear regression. Four non-overlapping confounders explaining highest proportion of variance (12%: age, 8.7%: blood urea nitrogen, 3%: alkaline phosphatase, and 3.9%: weight) were used in MLR model. The model strengthened the cNFL-sNFL correlation from R2 = 0.52 to 0.64 in the independent validation cohort and strengthened correlation of adjusted sNFL with number of contrast-enhancing lesions (from R2 0.11 to 0.18). However, only sNFL, but not cNFL correlated with MS severity outcomes. Using propensity score matching, we demonstrated that subjects with proportionally higher sNFL to cNFL levels have significantly higher clinical and radiological evidence of spinal cord injury.

Interpretation

Superiority of sNFL likely resides in the release of NFL from axons of lower motor or dorsal ganglia neurons directly to blood.
Community-level face mask usage in Boston, MA
Authors: McLane Meera , Casey Sharon M. , Gallagher Allison , Ohemeng-Tinyase Maame Akosua , Yosif Sabina , Chaparala Sree Ramya , Lincoln Sarah , Murray Eleanor J.
Published: May 2021

What is already known about this topic?

Community-level face mask use is encouraged as an important preventive measure against COVID-19 transmission, and evidence suggests that jurisdictions which implement face mask mandates see a subsequent decline in COVID incidence.

What is added by this report?

In the Greater Boston area when a face mask mandate is in effect, 95% of people observed were wearing some type of face covering. Most of which were wearing fabric/cloth coverings (51%) or single use surgical masks (40%). Of those wearing a face covering, 85% were appropriately fitted. Indoor locations have higher adherence of appropriately worn face masks, compared to outdoor locations.

What are the implications for public health practice?

Adherence with face mask mandates was very high, but many individuals wore fabric face masks with unknown filtration efficacy. In addition, it was common for individuals to mis-wear, adjust, or remove their masks. Public health policies requiring mask use should include messaging about appropriate type and best practices for use.
Perigenual and Subgenual Anterior Cingulate Afferents Converge on Common Pyramidal Cells in Amygdala Subregions of the Macaque
Authors: Kelly EA , Thomas VK , Indraghanty A , Fudge JL
Published: May 2021

The subgenual (sgACC) and pregenual (pgACC) anterior cingulate are important afferents of the amygdala, with different cytoarchitecture, connectivity, and function. The sgACC is associated with arousal mechanisms linked to salient cues, while the pgACC is engaged in conflict decision-making, including in social contexts. After placing same-size, small volume tracer injections into sgACC and pgACC of the same hemisphere in male Macaques, we examined anterogradely labeled fiber distribution to understand how these different functional systems communicate in the main amygdala nuclei at both mesocopic and cellular levels. The sgACC has broad-based termination patterns. In contrast, the pgACC has a more restricted pattern which was always nested in sgACC terminals. Terminal overlap occurred in subregions of the accessory basal and basal nuclei, which we termed ‘hotspots’. In triple-labeling confocal studies, the majority of randomly selected CAMKIIα (+) cells (putative amygdala glutamatergic neurons) in ‘hotspots’ received dual contacts from the sgACC and pgACC. The ratio of dual contacts occurred over a surprisingly narrow range, suggesting a consistent, tight balance of afferent contacts on postsynaptic neurons. Large boutons, which are associated with greater synaptic strength, were approximately 3 times more frequent on sgACC versus pgACC axon terminals in ‘hotspots’, consistent with a fast ‘driver’ function. Together, the results reveal a nested interaction in which pgACC (’conflict/social monitoring’) terminals converge with the broader sgACC (’salience’) terminals at both the mesoscopic and cellular level. The pre-synaptic organization in ‘hotspots’ suggest that shifts in arousal states can rapidly, and flexibly influence decision-making functions in the amygdala.

Significance statement

The subgenual (sgACC) and perigenual cingulate (pgACC) have distinct structural and functional characteristics and are important afferent modulators of the amygdala. The sgACC is critical for arousal, while the pgACC mediates conflict-monitoring, including in social contexts. Using dual tracer injections in the same monkey, we found that sgACC inputs broadly project in the main amygdala nuclei, whereas pgACC inputs were more restricted and nested in zones containing sgACC terminals (‘hotspots’). The majority of CAMKIIα + (excitatory) amygdala neurons in ‘hotspots’ received converging contacts, which were tightly balanced. pgACC and sgACC afferent streams are therefore highly interdependent in these specific amygdala subregions, permitting ‘internal arousal’ states to rapidly shape responses of amygdala neurons involved in conflict and social monitoring networks.
Comparing host module activation patterns and temporal dynamics in infection by influenza H1N1 viruses
Authors: Nudelman Irina , Kudrin Daniil , Nudelman German , Deshpande Raamesh , Hartmann Boris M. , Kleinstein Steven H. , Myers Chad L. , Sealfon Stuart C. , Zaslavsky Elena
Published: May 2021

Influenza is a serious global health threat that shows varying pathogenicity among different virus strains. Understanding similarities and differences among activated functional pathways in the host responses can help elucidate therapeutic targets responsible for pathogenesis. To compare the types and timing of functional modules activated in host cells by four influenza viruses of varying pathogenicity, we developed a new DYNAmic MOdule (DYNAMO) method that addresses the need to compare functional module utilization over time. This integrative approach overlays whole genome time series expression data onto an immune-specific functional network, and extracts conserved modules exhibiting either different temporal patterns or overall transcriptional activity. We identified a common core response to influenza virus infection that is temporally shifted for different viruses. We also identified differentially regulated functional modules that reveal unique elements of responses to different virus strains. Our work highlights the usefulness of combining time series gene expression data with a functional interaction map to capture temporal dynamics of the same cellular pathways under different conditions. Our results help elucidate conservation of the immune response both globally and at a granular level, and provide mechanistic insight into the differences in the host response to infection by influenza strains of varying pathogenicity.
Naturally enhanced neutralizing breadth to SARS-CoV-2 after one year
Authors: Wang Zijun , Muecksch Frauke , Schaefer-Babajew Dennis , Finkin Shlomo , Viant Charlotte , Gaebler Christian , Hoffmann Hans-Heinrich , Barnes Christopher O. , Cipolla Melissa , Ramos Victor , Oliveira Thiago Y. , Cho Alice , Schmidt Fabian , da Silva Justin , Bednarski Eva , Aguado Lauren , Yee Jim , Daga Mridushi , Turroja Martina , Millard Katrina G. , Jankovic Mila , Gazumyan Anna , Zhao Zhen , Rice Charles M. , Bieniasz Paul D. , Caskey Marina , Hatziioannou Theodora , Nussenzweig Michel C.
Published: May 2021

Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naïve individuals2,5-8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.
Assessing chromatin relocalization in 3D using the patient rule induction method
Authors: Segal Mark R.
Published: May 2021

Three dimensional (3D) genome architecture is critical for numerous cellular processes, including transcription, while certain conformation-driven structural alterations are frequently oncogenic. Inferring 3D chromatin configurations has been advanced by the emergence of chromatin conformation capture assays, notably Hi-C, and attendant 3Dreconstructionalgorithms. These have enhanced understanding of chromatin spatial organization and afforded numerous downstream biological insights. Until recently,comparisonsof 3D reconstructions between conditions and/or cell types were limited to prescribed structural features. However,multiMDS, a pioneering approach developed by Rieber and Mahony (2019) that performs joint reconstruction and alignment, enables quantification of all locus-specific differences between paired Hi-C data sets. By subsequently mapping these differences to the linear (1D) genome the identification ofrelocalizationregions is facilitated through use of peak calling in conjunction with continuous wavelet transformation. Here, we seek to refine this approach by performing the search for significant relocalization regions in terms of the 3D structures themselves, thereby retaining the benefits of 3D reconstruction and avoiding limitations associated with the 1D perspective. The search for (extreme) relocalization regions is conducted using thepatient rule induction method(PRIM). Considerations surrounding orienting structures with respect to compartmental and principal component axes are discussed, as are approaches to inference and reconstruction accuracy assessment. Illustration makes recourse to comparisons between four different cell types.
SARS-CoV-2 B.1.617.2 Delta variant replication, sensitivity to neutralising antibodies and vaccine breakthrough
Authors: Mlcochova Petra , Kemp Steven , Dhar Mahesh Shanker , Papa Guido , Meng Bo , Mishra Swapnil , Whittaker Charlie , Mellan Thomas , Ferreira Isabella , Datir Rawlings , Collier Dami A. , Albecka Anna , Singh Sujeet , Pandey Rajesh , Brown Jonathan , Zhou Jie , Goonawardne Niluka , Marwal Robin , Datta Meena , Sengupta Shantanu , Ponnusamy Kalaiarasan , Radhakrishnan Venkatraman Srinivasan , Abdullahi Adam , Charles Oscar , Chattopadhyay Partha , Devi Priti , Caputo Daniela , Peacock Tom , Wattal Chand , Goel Neeraj , Satwik Ambrish , Vaishya Raju , Agarwal Meenakshi ,   The Indian SARS-CoV-2 Genomics Consortium (INSACOG),   The CITIID-NIHR BioResource COVID-19 Collaboration,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Mavousian Antranik , Lee Joo Hyeon , Bassi Jessica , Silacci-Fegni Chiara , Saliba Christian , Pinto Dora , Irie Takashi , Yoshida Isao , Hamilton William L. , Sato Kei , James Leo , Corti Davide , Piccoli Luca , Bhatt Samir , Flaxman Seth , Barclay Wendy S. , Rakshit Partha , Agrawal Anurag , Gupta Ravindra K.
Published: May 2021

The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha).In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
Elastic energy savings and active energy cost in a simple model of running
Authors: Schroeder Ryan T. , Kuo Arthur D.
Published: May 2021

The energetic economy of running benefits from tendon and other tissues that store and return elastic energy, thus saving muscles from costly mechanical work. The classic “Spring-mass” computational model successfully explains the forces, displacements and mechanical power of running, as the outcome of dynamical interactions between the body center of mass and a purely elastic spring for the leg. Conversely, the Spring-mass model does not include active muscles and cannot explain the metabolic energy cost of running. Here we add explicit actuation and dissipation to the Spring-mass model, resulting in substantial active (and thus costly) work for running on level ground and up or down slopes. Dissipation is modeled as modest energy losses (5% of total mechanical energy for running at 3 m · s-1) from hysteresis and foot-ground collisions, that must be restored by active work each step. Even with substantial elastic energy return (59% of positive work, comparable to empirical observations), the active work could account for most of the metabolic cost of human running (about 68%, assuming human-like muscle efficiency). We also introduce a previously unappreciated energetic cost for rapid production of force, that helps explain the relatively smooth ground reaction forces of running, and why muscles might also actively perform negative work. Although elastic return is key to energy savings, there are still losses that require restorative muscle work, which can cost substantial energy during running.

Author Summary

Running is an energetically economical gait whereby the legs bounce like pogo sticks. Leg tendons act elastically to store and return energy to the body, thus saving the muscles from costly work with each running step. Although elasticity is known to save energy, it does not explain why running still requires considerable effort, and why the muscles still do any work at all. We use a simple computational model to demonstrate two possible reasons why. One is that small amounts of energy are lost when the leg collides with the ground and when the tendons are stretched, and muscles must restore that energy during steady running. A second reason is that muscles may perform work to avoid turning on and off rapidly, which may be even more energetically costly. The resulting muscle work, while small, may actually explain most of the energetic cost of running. Economy may be gained from elasticity, but running nonetheless requires muscles to do active work.
Astrocyte plasticity ensures continued endfoot coverage of cerebral blood vessels and integrity of the blood brain barrier, with plasticity declining with normal aging
Authors: Mills William A. , Jiang Shan , Martin Joelle , Woo AnnaLin M. , Bergstresser Matthew , Kimbrough Ian F. , Sontheimer Harald
Published: May 2021

Astrocytes extend endfeet that enwrap the vasculature. Disruptions to this association in disease coincide with breaches in blood-brain barrier (BBB) integrity, so we asked if the focal ablation of an astrocyte is sufficient to disrupt the BBB. 2Phatal ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. This occurred prior to endfoot retraction in young mice yet occurred with significant delay in aged animals. Laser-stimulating replacement astrocytes showed them to induce constrictions in pre-capillary arterioles indicating that replacement astrocytes are functional. Inhibition of EGFR and pSTAT3 significantly reduced astrocyte replacement post-ablation yet without perturbations to BBB integrity. Identical endfoot replacement following astrocyte cell death due to reperfusion post-stroke supports the conclusion that astrocyte plasticity ensures continual vascular coverage so as to retain the BBB. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells and may represent a novel therapeutic target for vessel recovery post-stroke.
An intranasal vaccine durably protects against SARS-CoV-2 variants in mice
Authors: Hassan Ahmed O. , Shrihari Swathi , Gorman Matthew J. , Ying Baoling , Yuan Dansu , Raju Saravanan , Chen Rita E. , Dmitriev Igor P. , Kashentseva Elena , Adams Lucas J. , Shi Pei-Yong , Fremont Daved H. , Curiel David T. , Alter Galit , Diamond Michael S.
Published: May 2021

SARS-CoV-2 variants that attenuate antibody neutralization could jeopardize vaccine efficacy and the end of the COVID-19 pandemic. We recently reported the protective activity of a single-dose intranasally-administered spike protein-based chimpanzee adenovirus-vectored vaccine (ChAd-SARS-CoV-2-S) in animals, which has advanced to human trials. Here, we assessed its durability, dose-response, and cross-protective activity in mice. A single intranasal dose of ChAd-SARS-CoV-2-S induced durably high neutralizing and Fc effector antibody responses in serum and S-specific IgG and IgA secreting long-lived plasma cells in the bone marrow. Protection against a historical SARS-CoV-2 strain was observed across a 100-fold vaccine dose range and over a 200-day period. At 6 weeks or 9 months after vaccination, serum antibodies neutralized SARS-CoV-2 strains with B.1.351 and B.1.1.28 spike proteins and conferred almost complete protection in the upper and lower respiratory tracts after challenge. Thus, in mice, intranasal immunization with ChAd-SARS-CoV-2-S provides durable protection against historical and emerging SARS-CoV-2 strains.