bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Sepsis-2 (Systemic Inflammatory Response Syndrome Based) to Sepsis-3 (Sequential Organ Failure Assessment Based) Definitions—A Multicenter Retrospective Study*
Authors: Engoren Milo , Seelhammer Troy , Freundlich Robert E. , Maile Michael D. , Sigakis Matthew J. G. , Schwann Thomas A.
Published: July 2020

Objectives:

Recently, the definition of sepsis has changed from a physiologic derangement (Sepsis-1 and -2) to organ dysfunction (Sepsis-3) based. We sought to determine the concordance between the different sepsis phenotypes and how that affected mortality.

Design:

Retrospective, multicenter study.

Setting:

Three academic medical centers.

Patients:

29,459 patients who had suspected infection, defined as obtaining blood cultures and receiving antibiotics: 18,183 (62%) had either Sepsis-2 or Sepsis-3.

Measurements and Main Results:

Kappa was used to show agreement between phenotypes. Conditional logistic regression was used to create models of associations between factors and phenotypes and between factors and mortality. About 12,981 patients had Sepsis-2; 12,043 had Sepsis-3; and 6,841 patients had both Sepsis-2 and Sepsis-3. Fifty-three percent of Sepsis-2 patients also had Sepsis-3, whereas 57% of Sepsis-3 patients also had Sepsis-2. Agreement between the two phenotypes was poor: kappa = 0.213 ± 0.006. Mortality was 6% in patients with only Sepsis-2, 10% with only Sepsis-3, and 18% in patients who had both phenotypes. Combining the variables in Sepsis-2 and Sepsis-3 improved the discrimination (C-statistic = 0.742 ± 0.005, p < 0.001) of mortality.

Conclusions:

We found that Sepsis-2 and Sepsis-3-based sepsis diagnoses represent separate phenotypes with poor agreement. Patients who have both phenotypes are at increased risk of mortality compared with having either phenotype alone. Inclusion of both systemic inflammatory response syndrome and Sequential Organ Failure Assessment criteria in the same model improves the discrimination of mortality.
Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria
Authors: Ouma Benson J. , Ssenkusu John M. , Shabani Estela , Datta Dibyadyuti , Opoka Robert O. , Idro Richard , Bangirana Paul , Park Gregory , Joloba Moses L. , Kain Kevin C. , John Chandy C. , Conroy Andrea L.
Published: July 2020

Objectives:

Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors.

Design:

Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children.

Setting:

Mulago National Referral Hospital in Kampala, Uganda.

Subjects:

Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months.

Interventions:

None.

Measurements and Main Results:

Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β –0.42, 95% CI, –0.69 to –0.15, p = 0.002; children ≥ 5, β –0.39, 95% CI, –0.67 to –0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau).

Conclusions:

These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.
Folliculocystic and Collagen Hamartoma: A Distinct Hamartoma Associated With Tuberous Sclerosis Complex
Authors: Cardona Rocio , Cancel-Artau Karina J. , Carrasquillo Osward Y. , Martin-Garcia Rafael F.
Published: July 2020

Tuberous sclerosis complex (TSC) is a neurocutaneous disease characterized by cutaneous and extracutaneous hamartomas. Dermatologic evaluation is critical for early diagnosis because mucocutaneous manifestations account for 4 of 11 major and 3 of 6 minor diagnostic criteria. Folliculocystic and collagen hamartoma (FCCH) is a recently described entity associated with TSC. We herein describe the case of a 28-year-old woman with a history of TSC who presented with a scalp lesion present since childhood. Physical examination revealed a solitary, well-circumscribed exophytic tumor over the occipital scalp measuring 9 × 8 cm and covered with comedones and cyst-like structures. Biopsy of the lesion demonstrated thickening of the collagen bundles throughout the dermis, concentric perifollicular and perivascular fibrosis, an increased number of dilated vessels, and keratin-filled cysts lined by the infundibular epithelium. Clinicopathologic correlation was diagnostic for FCCH. The patient was referred for surgical excision. In addition, we review 11 other cases of FCCH previously reported in the literature.
Unusual Presentations of Primary and Metastatic Adenoid Cystic Carcinoma Involving the Skin
Authors: Collins Katrina , Prieto Victor G. , Aung Phyu P.
Published: July 2020

Adenoid cystic carcinoma (ACC) is most commonly seen in the salivary glands but may occur at other sites. Primary or metastatic involvement of the skin is unusual. We report 2 cases of ACC with unusual presentation. In the first case, a 55-year-old woman presented with a cutaneous lesion on the right shin, and final pathology showed ACC. An extracutaneous origin was excluded by clinical and imaging studies. In the second case, a 49-year-old woman presented with a nodule on the breast, and biopsy confirmed high-grade ACC (>30% solid areas). She underwent lumpectomy and subsequent mastectomy after recurrence. Sixteen months after the initial diagnosis of ACC of the breast, distant metastases at multiple sites, including the skin, were identified. This report will increase awareness of these rare presentations of cutaneous ACC and allow correct diagnosis and appropriate management of such cases.
Coronavirus (COVID-19) Infection–Induced Chilblains: A Brisk Perieccrine Inflammatory Response
Authors: Wargo Jeffrey J. , Weir Nathan M. , Shamma H. Nicholas
Published: July 2020

The varying cutaneous and pathological manifestations of coronavirus 2 (SARS-CoV-2 or COVID-19) may have prognostic implications. Acral ischemic findings present with a hypercoagulable state in critically ill COVID-19 patients. Pathologically confirmed varicella-like exanthem and perniosis COVID-19 cases have correlated with paucisymptomatic and asymptomatic patients in previous reports. We present the second case of biopsy-proven COVID-19 infection–induced chilblains (pernio) in a paucisymptomatic patient with a brisk perieccrine lymphocytic response. Based on an antecedent pathological study, we know coronavirus particles have been seen in the eccrine gland associated with a brisk peri-inflammatory response. The prominent perieccrine inflammation is helpful in the diagnosis of COVID-19 infections. Currently, nonischemic pathological findings correlate with a good prognosis based on the paucisymptomatic or asymptomatic nature of their disease courses. Patients presenting with suspected COVID-19 infection–induced chilblains who are paucisymptomatic or asymptomatic should be isolated and immediately tested with polymerase chain reaction (PCR) testing (as there is a delay in diagnosis based on the poor sensitivity of the current rapid test). We continue to stress the importance of early diagnosis and quarantining to prevent spread to the older and immunocompromised patients.
The Impact of Vaccination Efforts on the Spatiotemporal Patterns of the Hepatitis A Outbreak in Michigan, 2016–2018
Authors: Brouwer Andrew F. , Zelner Jonathan L. , Eisenberg Marisa C. , Kimmins Lynsey , Ladisky Macey , Collins Jim , Eisenberg Joseph N. S.
Published: July 2020

Background:

The United States is currently experiencing the largest hepatitis A virus (HAV) outbreak since the introduction of a vaccine in 1996. More than 31,000 cases have been reported since 2016. Although HAV had largely been considered a foodborne pathogen in recent years, this outbreak has been spread primarily through person-to-person transmission in urban settings and has been associated with homelessness and substance use. Michigan was one of the first states to report an outbreak, with 910 reported cases between August 2016 and December 2018.

Methods:

We analyzed surveillance and vaccination data from Michigan using a disease transmission model to investigate how vaccine timing and coverage influenced the spatiotemporal patterns of the outbreak, distinguishing between Southeast Michigan, where the outbreak began, and the rest of the state.

Results:

We estimated that vaccination had little impact in Southeast Michigan (3% cases averted [95% confidence interval (CI) = 1%, 8%]) but had a substantial impact in the rest of the state, preventing a larger outbreak (91% cases averted [95% CI = 85%, 97%]) lasting several more years.

Conclusions:

Our results emphasize the value of targeting populations where local transmission is not yet sustained rather than populations where transmission is already waning. Simulation modeling can aid in proactive rather than reactive decision-making and may help direct the response to outbreaks emerging in other states. See video abstract: http://links.lww.com/EDE/B704.
Prospective Association Between Manganese in Early Pregnancy and the Risk of Preeclampsia
Authors: Liu Tiange , Hivert Marie-France , Rifas-Shiman Sheryl L. , Rahman Mohammad L. , Oken Emily , Cardenas Andres , Mueller Noel T.
Published: July 2020

Background:

Manganese, an essential micronutrient, has been found in lower concentrations among women with preeclampsia in cross-sectional and case–control studies without establishment of a temporal relationship.

Methods:

We evaluated the prospective association of manganese (in red blood cells) in first trimester of pregnancy with incidence of preeclampsia (ascertained by reviewing medical records) among 1,312 women in eastern Massachusetts (Project Viva, 1999–2002). We used log-binomial regression to examine the manganese–preeclampsia relationship, adjusting for maternal age, race/ethnicity, parity, prepregnancy body mass index, blood pressure, and hematocrit.

Results:

The median (25th, 75th percentile) manganese concentrationin red blood cells was 16.2 ng/g (13.1, 20.4) and 48 (4%) women developed preeclampsia. We observed an inverse dose–response relationship between manganese and preeclampsia. Compared with women in the lowest tertile, women in the middle manganese tertile had 0.81 times the risk of preeclampsia (95% CI: 0.43, 1.5) and those in the highest tertile had 0.50 (95% CI: 0.25, 0.99) times the risk.

Conclusions:

Our results provide insight into a potentially modifiable way to prevent preeclampsia.
Porcine Urinary Bladder Extracellular Matrix for Treatment of Periocular Skin Defects
Authors: Law James J. , Baker Laura X. , Chen Qingxia , Mawn Louise A. , Barahimi Behin , Kupcha Anna C. , Alford Mark A. , Sobel Rachel K.
Published: July 2020

Purpose:

To describe the experience of 4 oculoplastic surgeons with porcine bladder matrix for periocular anterior lamella and donor site skin defects either as stand-alone treatment or in conjunction with other reconstructive procedures. The authors hypothesized that defect size and location influence the requirement for additional matrix treatments or ancillary procedures.

Methods:

Following the Institutional Review Board approval, the authors conducted a retrospective review of 17 patients treated with porcine bladder matrix at 2 oculoplastic practices between 2016 and 2018. Powdered matrix was applied to the skin defect and overlaid with a matrix sheet. Subsequent rounds of matrix treatment or other reconstructive procedures were performed as necessary. Defect size and location were correlated to the number of ancillary matrix treatments or surgical procedures via univariate analysis.

Results:

Twenty-five sites (21 primary and 4 donor) in 17 individuals (8–95 years, M = 58.8 years, 10 males) were treated with porcine bladder matrix. All wounds healed successfully. Additional matrix treatments were administered at 5 sites. Ancillary procedures were performed for 7 sites. Upper lid involvement and larger defect size tended to require additional ancillary procedures (p = 0.006), while lower eyelid and other periocular defects required fewer procedures (p < 0.001).

Conclusion:

Porcine bladder matrices are useful adjuncts to healing periocular anterior lamella defects in various settings. Such repairs are useful in nonsurgical candidates, but must take into account varying levels of complexity based on lesion location. Smaller defects are more conducive to application of matrices as stand-alone treatment, while larger or upper eyelid defects often require additional procedures.
The Ophthalmology Surgical Competency Assessment Rubric for External Dacryocystorhinostomy Surgery
Authors: Juniat Valerie , Saleh George M. , Naik Milind , Nerad Jeffrey , Gauba Vinod , Devoto Martin H. , Pakdel Farzad , Golnik Karl C.
Published: July 2020

Purpose:

The International Council of Ophthalmology (ICO) is currently developing a series of standardized, internationally validated, teaching tool for key ophthalmic surgical procedures called the Ophthalmology Surgical Competency Assessment Rubrics (OSCARs). This study aims to develop an OSCAR for external dacryocystorhinostomy (ExDCR).

Methods:

An international panel of content experts, representing Argentina, India, U.A.E., United Kingdom, and the U.S.A. was established and worked to develop the rubric using a range of online collaboration tools. The team used the standardized OSCAR template as a baseline, developing explicit behavioral descriptors (the behavior and performance expected for each step) that were reviewed and modified with successive models. Learners were scored on a modified 4-point Dreyfus scale of skill acquisition (novice, beginner, advanced beginner, competent) with the removal of the expert domain. The tool was then reviewed by a secondary panel of international content experts, representing Brazil, India, Iran, Singapore, United Kingdom, and the U.S.A.

Results:

The final OSCAR ExDCR tool was developed in alignment with the ICO-OSCAR standard. Nineteen agreed and weighted stems were produced. Specific comments with regards to the parameters and wording were incorporated to formulate the final rubric, which was internationally agreed and demonstrated face and content validity.

Conclusions:

The OSCAR ExDCR is skill and behavior based, has ICO agreed standards for assessment, and provides learners with specific targets for improvement. Although the OSCAR tool has face and content validity, further development could better elucidate its precise role.
Nerve Sheath Myxoma Involving the Medial Rectus Muscle: A Case Report
Authors: Mora-Cantallops Arnau , Won-Kim Hae-Ryung , Navarro-Cantero Antonia , Martínez-San-Millán Juan , Sales-Sanz Marco
Published: July 2020

A 63-year-old man reported a 2-year history of painless OS proptosis. The first MRI, performed in the institution of origin, resulted in a diagnosis of hemangioma versus orbital pseudotumor. Examination revealed proptosis and mild chemosis. Ancillary tests were normal, and oral prednisone was initiated without remarkable changes. Later, an incisional biopsy identified the lesion as an intramuscular myxoma of the left rectus, and a new MRI was ordered. It described a fusiform thickening of the medial rectus with and exophytic growth below the inferior rectus and upward toward the superior oblique. Due to the localization of the lesion, a combined transcaruncular and swinging eyelid approach with a lateral orbitotomy was performed. Histopathological examination revealed a proliferation of stromal origin composed of myxoid matrix with fusocellular and stellate-shaped cells. Cells were S-100, CD34, and CD56 positive and negative for epithelial membrane antigen, CD68, CD10, actin, and desmin. Results were consistent with a left medial rectus nerve sheath myxoma.
Factors Associated With Physician Empowerment and Well-being at an Academic Medical Center
Authors: Yakes Elizabeth Ann , Dean Stephanie , Labadie Robert F. , Byrne Daniel , Estrada Cristina , Thompson Reid , Kendall James , Yarbrough Mary
Published: July 2020

Objective:

This study reports an institutional approach to rapidly measure burnout and gather physicians’ opinions on workplace factors that empower well-being.

Methods:

In July 2017, physicians at Vanderbilt University Medical Center were invited to participate in a two-question survey measuring self-reported burnout and providing an opportunity to describe structures that empower well-being. Free-text responses were analyzed and a linear regression model assessed factors associated with well-being.

Results:

A total of 1135 physicians responded (43.3% response rate) with a mean well-being score of 56 (scale 0 to 100). Higher scores were associated with clinical fellow status (P = 0.002), male sex (P = 0.008), less allocation of time to clinical care (P < 0.001), and not commenting on “leadership” and “autonomy” in the free-text response.

Conclusions:

Brief surveys collecting perspectives on well-being can help employers identify high-risk groups and provide a roadmap for institutional change.
Fecal microbial transplant for inflammatory bowel disease
Authors: Claytor Jennifer D. , El-Nachef Najwa
Published: July 2020

Purpose of review

The purpose of this brief review is to investigate the current utility of fecal microbial transplantation (FMT) to ameliorate dysbiosis contributing to inflammatory bowel disease pathogenesis.

Recent findings

Increasing data from randomized, controlled trials support a role for multiple FMT administrations in the induction of remission and even as a maintenance therapy in mild-to-moderate Ulcerative Colitis. Small series and one small randomized controlled trial among patients with Crohn's Disease and with pouchitis continue to produce conflicting clinical results and microbial profile data on the host and donor levels. It is not clear whether patients with Crohn's disease are more susceptible to disease flare after FMT. Novel FMT delivery systems, including oral, and early-intensity colonoscopic devices, are under investigation.

The allure of minimizing the risks and cost of long-term immunosuppression via modulation of patient microbiota remains enticing, and the most recent randomized controlled data in ulcerative colitis reveals acceptable clinical remission rates. However, prior to wide adoption of FMT within the inflammatory bowel disease treatment armamentarium, large clinical trials identifying biomarkers of treatment success, ensuring safety across all indications, and cultivating optimized donor and host selection are needed.
Trigeminal Neuralgia With Extraoral Trigger Zone Successfully Treated With Intraoral Injections of Botulinum Toxin: A Case Report
Authors: Dinan John E. , Smith Alexander , Hawkins James M.
Published: July 2020

Trigeminal neuralgia is a pain condition that is frequently misdiagnosed and challenging to manage. We present the case of a patient with trigeminal neuralgia with multiple misdiagnoses and poorly managed pain. Despite the presence of trigger zones both inside and outside her mouth, complete symptom resolution was ultimately achieved through onabotulinumtoxinA injections, delivered solely intraorally.
The Effects of Education About Urinary Incontinence on Nurses' and Nursing Assistants' Knowledge, Attitudes, Continence Care Practices, and Patient Outcomes
Authors: Ostaszkiewicz Joan , Tomlinson Emily , Hunter Kathleen
Published: July 2020

The aims of this systematic review were to describe, critique, and summarize research about the effects of education about urinary incontinence on nurses' and nursing assistants' knowledge and attitudes toward urinary incontinence, their continence care practices, and patient outcomes. We searched key electronic databases (PsycINFO, MEDLINE, CINAHL, Web of Science, and Cochrane Library) for full-text primary research articles written in the English language and published between January 1990 and October 2018. Studies were included if they described a controlled or uncontrolled trial of an education program for nurses or nursing assistants about urinary incontinence and evaluated the effects of the program on either knowledge, attitudes, practice, or patient outcomes. Data were extracted about the aim, design, sample and setting, trial methods, intervention, outcomes of interest, and findings. Quality appraisal was conducted using a mixed-methods appraisal tool. Results are presented in tabular format and reported descriptively. Nineteen studies met inclusion criteria; most were set in the United States or the UK. All trials that evaluated the effects on knowledge reported improvements; however, the effects of education on attitudes were mixed as were the effects of education on continence care practices. Eleven of the 19 studies reported the statistical effect of education on patient outcomes. Uncontrolled trials reported improvements in nursing home residents' and community-dwelling patients' continence status, but this effect was not observed in a large controlled trial. Similarly, 2 studies set in inpatient rehabilitation found no significant differences in patient continence outcomes following an educational intervention targeted to nurses.
Compliance to Individualized Recommendations Based on an Evidence-Based Algorithm for Behavioral Management of Lower Urinary Tract Symptoms
Authors: Gammie Andrew
Published: July 2020

PURPOSE:

The aim of this study was to evaluate patient compliance to individualized recommendations for self-management of fluid intake, bladder irritants, and timing of fluid consumption.

DESIGN:

Single-group, before-after pilot study.

SUBJECTS AND SETTING:

The sample comprised 22 patients (17 male and 5 females, mean age 62 years, age range 27-84 years). The study setting was the uroflow clinic at Southmead Hospital, Bristol, UK, a tertiary level referral hospital for complex evaluation and treatment of urological patients.

METHODS:

Patients were given a bladder diary to complete after 2 weeks, which was compared with the bladder diary they had originally brought to clinic, to see whether the advice was followed. The bladder diary used required the patient to document the times and volumes of urination over a period of 3 days, magnitude of urinary urgency felt at the time, along with fluid intake timing, amount, and type of beverage. The study was not designed to measure changes in symptoms, but observed changes recorded in the bladder diaries are reported.

RESULTS:

All 6 of the 22 participants who were advised to increase the volume of fluid intake complied, with an increased average intake of a mean of 520 mL (range 100-1450 mL). Similarly, one participant advised to reduce fluid intake decreased their fluid intake by 1800 mL per day. Thirteen out of 16 patients (81%) who were advised to remove caffeine, alcohol, or artificial sweeteners from their diet complied, indicated by no bladder irritant being recorded on their bladder diary. Nine out of 12 patients (75%) advised to reduce fluid intake in the evenings complied, decreased fluid intake after 6 pm by an average of 240 mL (range 100-550 mL less).

CONCLUSIONS:

A majority of participants given fluid intake advice that is specific to their symptoms and lifestyle complied with recommendations. Simple guidance could usefully be given to patients before they are referred to specialist urological care or undergo urodynamic testing.
Does Lockdown Decrease the Protective Role of Ultraviolet-B (UVB) Radiation in Reducing COVID-19 Deaths?
Authors: Moozhipurath Rahul Kalippurayil , Kraft Lennart
Published: July 2020

Background

Nations are imposing unprecedented measures at large-scale to contain the spread of COVID-19 pandemic. Recent studies indicate that measures such as lockdowns may have slowed down the growth of COVID-19. However, in addition to substantial economic and social costs, these measures also limit the exposure to Ultraviolet-B radiation (UVB). Emerging observational evidence indicate the protective role of UVB and vitamin D in reducing the severity and mortality of COVID-19 deaths. In this observational study, we empirically outline the independent protective roles of lockdown and UVB exposure as measured by ultraviolet index (UVI), whilst also examining whether the severity of lockdown is associated with a reduction in the protective role.

Methods

We apply a log-linear fixed-effects model to a panel dataset of 162 countries over a period of 108 days (n=6049). We use the cumulative number of COVID-19 deaths as the dependent variable and isolate the mitigating influence of lockdown severity on the association between UVI and growth-rates of COVID-19 deaths from time-constant country-specific and time-varying country-specific potentially confounding factors.

Findings

After controlling for time-constant and time-varying factors, we find that a unit increase in UVI and lockdown severity are independently associated with 17% [-1.8 percentage points] and 77% [-7.9 percentage points] decline in COVID-19 deaths growth rate, indicating their respective protective roles. However, the widely utilized and least severe lockdown (recommendation to not leave the house) already fully mitigates the protective role of UVI by 95% [1.8 percentage points] indicating its downside.

Interpretation

We find that lockdown severity and UVI are independently associated with a slowdown in the daily growth rates of cumulative COVID-19 deaths. However, we find consistent evidence that increase in lockdown severity is associated with a significant reduction in the protective role of UVI in reducing COVID-19 deaths. Our results suggest that lockdowns in conjunction with adequate exposure to UVB radiation might have provided even more substantial health benefits, than lockdowns alone. For example, we estimate that there would be 21% fewer deaths on average with sufficient UVB exposure while people were recommended not to leave their house. Therefore, our study outlines the importance of considering UVB exposure, especially while implementing lockdowns and may support policy decision making in countries imposing such measures.
Diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of COVID-19 in the United States
Authors: Afshordi Niayesh , Holder Benjamin , Bahrami Mohammad , Lichtblau Daniel
Published: July 2020

The SARS-CoV-2 pandemic has caused significant mortality and morbidity worldwide, sparing almost no community. As the disease will likely remain a threat for years to come, an understanding of the precise influences of human demographics and settlement, as well as the dynamic factors of climate, susceptible depletion, and intervention, on the spread of localized epidemics will be vital for mounting an effective response. We consider the entire set of local epidemics in the United States; a broad selection of demographic, population density, and climate factors; and local mobility data, tracking social distancing interventions, to determine the key factors driving the spread and containment of the virus. Assuming first a linear model for the rate of exponential growth (or decay) in cases/mortality, we find that population-weighted density, humidity, and median age dominate the dynamics of growth and decline, once interventions are accounted for. A focus on distinct metropolitan areas suggests that some locales benefited from the timing of a nearly simultaneous nationwide shutdown, and/or the regional climate conditions in mid-March; while others suffered significant outbreaks prior to intervention. Using a first-principles model of the infection spread, we then develop predictions for the impact of the relaxation of social distancing and local climate conditions. A few regions, where a significant fraction of the population was infected, show evidence that the epidemic has partially resolved via depletion of the susceptible population (i.e., “herd immunity”), while most regions in the United States remain overwhelmingly susceptible. These results will be important for optimal management of intervention strategies, which can be facilitated using our online dashboard.
Data From the COVID-19 Epidemic in Florida Suggest That Younger Cohorts Have Been Transmitting Their Infections to Less Socially Mobile Older Adults
Authors: Harris Jeffrey E.
Published: July 2020

We analyzed the daily incidence of newly reported COVID-19 cases among adults aged 20-39 years, 40-59 years, and 60 or more years in the sixteen most populous counties of the state of Florida from March 1 through June 27, 2020. In all 16 counties, an increase in reported COVID-19 case incidence was observed in all three age groups soon after the governor-ordered Full Phase 1 reopening went into effect. Trends in social mobility, but not trends in testing, track case incidence. Data on hospitalization do not support the hypothesis that the observed increase in case incidence was merely the result of liberalization of testing criteria. Parameter estimates from a parsimonious two-group heterogeneous SIR model strongly support the hypothesis that younger persons, having first acquired their infections through increasing social contact with their peers, then transmitted their infections to older, less socially mobile individuals. Without such cross-infection, an isolated epidemic among older people in Florida would be unsustainable.
Role of pharmacist during the COVID-19 pandemic: a scoping review
Authors: Visacri Marília Berlofa , Figueiredo Isabel Vitória , de Mendonça Lima Tácio
Published: July 2020

Background

Since the start of the new Coronavirus (COVID-19) outbreak in December 2019, pharmacists worldwide are playing a key role adopting innovative strategies to minimize the adverse impact of the pandemic.

Objectives

To identify and describe core services provided by the pharmacist during the COVID-19 pandemic.

Methods

A literature search was performed in MEDLINE, Embase, Scopus, and LILACS for studies published between December 1st, 2019 and May 20th, 2020 without language restriction. Studies that reported services provided by pharmacists during the COVID-19 pandemic were included. Two independent authors performed study selection and data extraction with a consensus process. The pharmacist’s intervention identified in the included studies were described based on key domains in the DEPICT v.2.

Results

A total of 1,189 records were identified, of which 11 studies fully met the eligibility criteria. Most of them were conducted in the United States of America (n=4) and China (n=4). The most common type of publication were letters (n=4) describing the workplace of the pharmacist in hospitals (n=8). These findings showed the different roles of pharmacists during the COVID-19 pandemic, such as disease prevention and infection control, adequate storage and drug supply, patient care and support for healthcare professionals. Pharmacists’ interventions were mostly conducted for healthcare professionals and patients (n=7), through one-to-one contact (n=11), telephone (n=6) or video conference (n=5). The pharmacists’ main responsibility was to provide drug information for healthcare professionals (n=7) as well as patient counseling (n=8).

Conclusions

A reasonable number of studies that described the role of the pharmacists during the COVID-19 pandemic were found. All studies reported actions taken by pharmacists, although without providing a satisfactory description. Thus, future research with more detailed description as well as an evaluation of the impact of pharmacist intervention is needed in order to guide future actions in this and-or other pandemic.
OmpK36 and TraN facilitate conjugal transfer of theKlebsiella pneumoniaecarbapenem resistance plasmid pKpQIL
Authors: Low Wen Wen , Wong Joshua LC , Peña Alejandro , Seddon Chloe M , Costa Tiago RD , Beis Konstantinos , Frankel Gad
Published: July 2020

We investigated the mechanism of conjugal transfer of the endemicKlebsiella pneumoniaecarbapenem resistance plasmid, pKpQIL. Transfer efficiency of this plasmid was found to be dependent on the expression of the major outer membrane porin, OmpK36, in recipient cells. We also found that conjugal uptake is reduced in recipients expressing an OmpK36 isoform associated with the globally pervasiveK. pneumoniaeST258 clade (OmpK36ST258). This reduction was attributed to a glycine-aspartate insertion in loop 3 of OmpK36ST258, which constricts the pore by 26%. Deletion offinO, which encodes an RNA-binding protein, derepressed transfer of pKpQIL and enabled visualisation of the conjugation pilus and OmpK36-dependent conjugation in real time. While deletion oftraNabolished pKpQIL conjugation, substitutingtraNin pKpQIL with its homologue from R100-1 circumvented OmpK36 dependency. These results suggest that OmpK36 in recipientK. pneumoniaeand the pKpQIL-encoded TraN in donor bacteria cooperate to facilitate plasmid transfer. This is the first report since 1998 to suggest a novel recipient cell receptor for IncF plasmid transfer and supports the idea that TraN mediates receptor specificity for plasmids belonging to this incompatibility group.
USH2A is a skin end-organ protein necessary for vibration sensing in mice and humans
Authors: Schwaller Fred , Bégay Valérie , García-García Gema , Taberner Francisco J. , Moshourab Rabih , McDonald Brennan , Docter Trevor , Kühnemund Johannes , Ojeda-Alonso Julia , Paricio-Montesinos Ricardo , Lechner Stefan G. , Poulet James F.A. , Millan Jose M. , Lewin Gary R.
Published: July 2020

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive vibration-sensing neurons are associated with Meissner’s corpuscles and Pacinian corpuscles1. Such end-organ structures have been recognized for more than 160 years, but their exact functions have remained a matter of speculation. Here we examined the role of USH2A in touch sensation in humans and mice. TheUSH2Agene encodes a transmembrane protein with a very large extracellular domain. PathogenicUSH2Amutations cause Usher syndrome associated with hearing loss and visual impairment2. We show that patients with biallelic pathogenicUSH2Amutations also have profound impairments in vibrotactile touch perception. Similarly, mice lacking the USH2A protein showed severe deficits in a forepaw vibrotactile discrimination task. Forepaw rapidly-adapting mechanoreceptors (RAMs) recorded fromUsh2a−/−mice innervating Meissner’s corpuscles showed profound reductions in their vibration sensitivity. However, the USH2A protein was not expressed in sensory neurons, but was found in specialized terminal Schwann cells in Meissner’s corpuscles. Loss of this large extracellular tether-like protein in corpuscular end-organs innervated by RAMs was sufficient to reduce the vibration sensitivity of mechanoreceptors. Thus, USH2A expressed in corpuscular end-organs associated with vibration sensing is required to properly perceive vibration. We propose that cells within the corpuscle present a tether-like protein that may link to mechanosensitive channels in sensory endings to facilitate small amplitude vibration detection essential for the perception of fine textured surfaces.
Single-cell sequencing of human iPSC-derived cerebellar organoids shows recapitulation of cerebellar development
Authors: Nayler Samuel , Agarwal Devika , Curion Fabiola , Bowden Rory , Becker Esther B.E.
Published: July 2020

Current protocols for producing cerebellar neurons from human pluripotent stem cells (hPSCs) are reliant on animal co-culture and mostly exist as monolayers, which have limited capability to recapitulate the complex arrangement of the brain. We developed a method to differentiate hPSCs into cerebellar organoids that display hallmarks of in vivo cerebellar development. Single-cell profiling followed by comparison to an atlas of the developing murine cerebellum revealed transcriptionally-discrete populations encompassing all major cerebellar cell types. Matrigel encapsulation altered organoid growth dynamics, resulting in differential regulation of cell cycle, migration and cell-death pathways. However, this was at the expense of reproducibility. Furthermore, we showed the contribution of basement membrane signalling to both cellular composition of the organoids and developmentally-relevant gene expression programmes. This model system has exciting implications for studying cerebellar development and disease most notably by providing xeno-free conditions, representing a more biologically relevant and therapeutically tractable culture setting.
Organic dust induced mitochondrial dysfunction could be targeted via cGAS-STING or mitochondrial NOX-2 inhibition
Authors: Massey Nyzil , Shrestha Denusha , Bhat Sanjana Mahadev , Kondru Naveen , Charli Adhithiya , Karriker Locke A. , Kanthasamy Anumantha G. , Charavaryamath Chandrashekhar
Published: July 2020

Organic dust (OD) exposure in animal production industries poses serious respiratory and other health risks. OD consists of microbial products and particulate matter and OD exposure induced respiratory inflammation is under intense investigation. However, the effect of OD exposure on brain largely remains unknown. Recently, we have shown that OD exposure of brain microglial cells induces an inflammatory phenotype with the release of mitochondrial DNA (mt-DNA). Therefore, we tested a hypothesis that OD-exposure induced secreted mt-DNA signaling drives the inflammation. OD samples were collected from commercial swine operations and a filter sterilized OD extract (ODE) was prepared. Mouse (C57BL/6) microglial cell line was treated with medium or ODE (5%) for 48 hours along with either PBS or mitoapocynin (MA, 10 μM, NOX-2 inhibitor). Microglia treated with control or anti-STING siRNA were exposed to medium or ODE. Next, mouse (C57BL/6) pups were euthanized under an approved protocol, organotypic brain slice cultures (BSCs) were prepared and exposed to medium or ODE with or without MA treatment daily for five days. Culture supernatant, cell pellets and mt-free cytosolic fractions were processed to quantify mt-superoxide, mt-DNA, cytochrome C, TFAM, mitochondrial stress markers and mt-DNA induced signaling via cGAS-STING and TLR9. Data were analyzed using one-way ANOVA and post-hoc tests. A p value of ≤ 0.05 was considered significant. ODE exposure increased the mt-superoxide formation andMA treatment decreased the ODE-induced mt-DNA release into cytosol. ODE exposure increased the cytochrome C and TFAM levels. ODE increased MFN1/2 and PINK1 but not DRP1 and MA treatment decreased the MFN2 expression. MA treatment decreased the ODE-exposure induced mt-DNA signaling via cGAS-STING and TLR9. Anti-STING siRNA decreased the ODE-induced increase in IRF3, IFN-β and Iba1 expression. In BSCs, MA-treatment decreased the ODE induced TNF-α, IL-6 and MFN1. Taken together, OD exposure induced mt-DNA signaling could be curtailed through mitochondrial NOX-2 inhibition or STING suppression to reduce neuroinflammation.
Early data on the performance of a combined SARS-CoV-2 spike-nucleocapsid antibody lateral flow device compared to a nucleocapsid-only device
Authors: Linares Christian A. , Ryan Felicity , Moses Samuel E.
Published: July 2020

The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Genetic architecture of host proteins interacting with SARS-CoV-2
Authors: Pietzner Maik , Wheeler Eleanor , Carrasco-Zanini Julia , Raffler Johannes , Kerrison Nicola D. , Oerton Erin , Auyeung Victoria P.W. , Luan Jian’an , Finan Chris , Casas Juan P. , Ostroff Rachel , Williams Steve A. , Kastenmüller Gabi , Ralser Markus , Gamazon Eric R. , Wareham Nicholas J. , Hingorani Aroon D. , Langenberg Claudia
Published: July 2020

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid ‘in silico’ assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting incis(MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at theABOlocus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).
A Glu-Glu-Tyr sequence in the cytoplasmic tail of the M2 protein renders IAV susceptible to restriction of HA-M2 association in primary human macrophages
Authors: Bedi Sukhmani , Haag Amanda , Ono Akira
Published: July 2020

Influenza A virus (IAV) assembly at the plasma membrane is orchestrated by at least five viral components including hemagglutinin (HA), neuraminidase (NA), matrix (M1), the ion channel M2, and viral ribonucleoprotein (vRNP) complexes although particle formation itself requires only HA and/or NA. While these five viral components are expressed efficiently in primary human monocyte-derived macrophages (MDM) upon IAV infection, this cell type does not support efficient HA-M2 association and IAV particle assembly at the plasma membrane. The defects in HA-M2 association and particle assembly are specific to MDM and not observed in a monocytic cell line differentiated into macrophage-like cells. Notably, both these defects can be reversed upon disruption of the actin cytoskeleton. In the current study, we sought to examine whether M2 contributes to particle assembly in MDM and to identify a viral determinant involved in the MDM-specific and actin-dependent suppression of IAV assembly. An analysis using correlative fluorescence and scanning electron microscopy showed that an M2-deficient virus fails to form budding structures at the cell surface even after F-actin is disrupted, indicating that M2 is essential for virus particle formation at the MDM surface. Notably, proximity ligation analysis revealed that single amino acid substitution in a Glu-Glu-Tyr sequence (residues 74-76) in the M2 cytoplasmic tail allows HA-M2 association to occur efficiently even in MDM with intact actin cytoskeleton. This phenotype did not correlate with known phenotypes of the M2 substitution mutants regarding M1 interaction or vRNP packaging in epithelial cells. Overall, our study identifies a viral determinant for susceptibility to cytoskeleton-dependent regulation in MDM and hence, sheds light on the molecular mechanism behind the MDM-specific restriction of IAV assembly.

Importance

Non-permissive cell types that are unable to support viral replication serve as important tools for identification of host factors that either block viral replication (restriction factors) or support viral replication in permissive cell types (co-factors). We previously identified the MDM as a cell type that is non-permissive to IAV assembly, likely due to a block in HA-M2 association. In the current study, we determined that the IAV M2 protein is necessary for virus particle formation in MDM but also renders the virus susceptible to the MDM-specific suppression of virus assembly. We identified a specific amino acid motif in the M2 cytoplasmic tail, disruption of which allows M2 to associate with HA even in MDM. Our findings strongly support the possibility that the MDM-specific defect in HA-M2 association is due to the presence of a restriction factor(s) in MDM, which likely interacts directly with the M2 cytoplasmic domain, rather than indirectly through other internal viral components, and thereby prevents M2 from associating with HA.
High-frequency stimulation of ventral CA1 neurons reduces amygdala activity and inhibits fear
Authors: Graham Jalina , D’Ambra Alexa , Jung Se Jung , Vishwakarma Nina , Venkatesh Rasika , Parigi Abhijna , Antzoulatos Evan G. , Fioravante Diasynou , Wiltgen Brian J.
Published: July 2020

The hippocampus can be divided into distinct segments that make unique contributions to learning and memory. The dorsal hippocampus supports cognitive processes like spatial learning and navigation while the ventral hippocampus regulates emotional behaviors related to fear, anxiety and reward. In the current study, we determined how pyramidal cells in ventral CA1 respond to spatial cues and aversive stimulation during a context fear conditioning task. We also examined the effects of high and low frequency stimulation of these neurons on defensive behaviors. Similar to previous work in the dorsal hippocampus, we found that cells in ventral CA1 expressed high-levels of c-Fos in response to a novel spatial environment. Surprisingly, however, the number of activated neurons did not increase when the environment was subsequently paired with footshock. This was true even in the subpopulation of ventral CA1 pyramidal cells that send direct projections to the amygdala. When these cells were stimulated at high-frequencies (20-Hz), we observed feedforward inhibition of basal amygdala neurons and impaired expression of context fear. In contrast, low-frequency stimulation (4-Hz) did not inhibit principal cells in the amygdala and produced a slight increase in fear generalization. Similar results have been reported in dorsal CA1. Therefore, despite the clear differences between the dorsal and ventral hippocampus, CA1 neurons in each segment appear to make similar contributions to context fear conditioning.