bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracheobronchial Slough, a Potential Pathology in Endotracheal Tube Obstruction in Patients With Coronavirus Disease 2019 (COVID-19) in the Intensive Care Setting
Authors: Rubano Jerry A. , Jasinski Patrick T. , Rutigliano Daniel N. , Tassiopoulos Apostolos K. , Davis James E. , Beg Tazeen , Poovathoor Shaji , Bergese Sergio D. , Ahmad Sahar , Jawa Randeep S. , Vosswinkel James A. , Talamini Mark A.
Published: May 2020

Background:

A novel coronavirus (COVID-19) erupted in the latter part of 2019. The virus, SARS-CoV-2 can cause a range of symptoms ranging from mild through fulminant respiratory failure. Approximately 25% of hospitalized patients require admission to the intensive care unit, with the majority of those requiring mechanical ventilation. High density consolidations in the bronchial tree and in the pulmonary parenchyma have been described in the advanced phase of the disease. We noted a subset of patients who had a sudden, significant increase in peak airway, plateau and peak inspiratory pressures. Partial or complete ETT occlusion was noted to be the culprit in the majority of these patients.

Methods:

With institutional IRB approval, we examined a subset of our mechanically ventilated COVID-19 patients. All of the patients were admitted to one of our COVID-19 ICUs. Each was staffed by a board certified intensivist. During multidisciplinary rounds, all arterial blood gas (ABG) results, ventilator settings and ventilator measurements are discussed and addressed. ARDSNet Protocols are employed. In patients with confirmed acute occlusion of the endotracheal tube (ETT), acute elevation in peak airway and peak inspiratory pressures are noted in conjunction with desaturation. Data was collected retrospectively and demographics, ventilatory settings and ABG results were recorded.

Results:

Our team has observed impeded ventilation in intubated patients who are several days into the critical course. Pathologic evaluation of the removed endotracheal tube contents from one of our patients demonstrated a specimen consistent with sloughed tracheobronchial tissues and inflammatory cells in a background of dense mucin. Of 110 patients admitted to our adult COVID-19 ICUs, 28 patients required urgent exchange of their ETT.

Conclusion:

Caregivers need to be aware of this pathological finding, recognize, and to treat this aspect of the COVID-19 critical illness course, which is becoming more prevalent.
Leaning forward: Early arterial access promotes resuscitative endovascular balloon occlusion of the aorta utilization in battlefield casualties
Authors: Knipp Brian Scott , Needham Kenneth Eugene , Nguyen Phu Tan , Keville Meaghan Patricia , Brzuchalski Jason Thomas , Srivilasa Charlie , Lewis Clayton Jon , Betzold Richard David , DuBose Joseph Jeremy
Published: May 2020

Uncontrolled noncompressible torso hemorrhage remains a leading cause of potentially preventable death on the battlefield. The utilization of resuscitative endovascular balloon occlusion of the aorta (REBOA) has gained considerable traction in civilian and military trauma care. Establishment of arterial access remains the rate-limiting step in endovascular aortic occlusion. The decision to place arterial access, including size, location, and the appropriate clinician and scenario all must be considered to achieve the optimal patient outcome. This report is submitted by the Joint Medical Augmentation Unit, an elite surgical/resuscitation team that provides medical care in the most far-forward, austere environments in the special operations community. The authors highlight two cases where early arterial access, REBOA utilization, and massive blood transfusion with damage-control surgery were associated with patient survival. We also address the prehospital application of REBOA in battlefield trauma.

LEVEL OF EVIDENCE

Special Report, Level V
Preclinical Assessment of Autologous Tolerogenic Dendritic Cells From End-stage Renal Disease Patients
Authors: Bouchet-Delbos Laurence , Even Amandine , Varey Emilie , Saïagh Soraya , Bercegeay Sylvain , Braudeau Cécile , Dréno Brigitte , Blancho Gilles , Josien Régis , Cuturi Maria-Cristina , Moreau Aurélie
Published: May 2020

Background.

Kidney transplantation is the therapeutic of choice for patients with kidney failure. While immunosuppressive drugs can control graft rejection, their use is associated with increased infections and cancer, and they do not effectively control chronic graft rejection. Cell therapy is an attractive strategy to minimize the use of pharmacological drugs.

Methods.

We recently developed a protocol to generate human monocyte-derived autologous tolerogenic dendritic cells (ATDCs) from healthy volunteers. Herein, we transferred the ATDC manufacturing protocol to a Good Manufacturing Practice (GMP)–compliant facility. Furthermore, we compared the phenotype and in vitro functions of ATDCs generated from patients with end-stage renal disease to those generated from healthy volunteers.

Results.

We describe the critical steps for GMP-compliant production of ATDCs and define the quality criteria required to allow release of the cell products. Furthermore, we showed that ATDCs generated from healthy volunteers and patients with kidney failure display the same tolerogenic profile based on their phenotype, resistance to maturation, and ability to modulate T-cell responses.

Conclusions.

Together, these results allowed us to define the production process and the quality criteria for the release of ATDCs before their administration in patients receiving a kidney transplant.
Use of Culture to Reach Metabolically Adequate Beta-cell Dose by Combining Donor Islet Cell Isolates for Transplantation in Type 1 Diabetes Patients
Authors: Lee DaHae , Gillard Pieter , Hilbrands Robert , Ling Zhidong , Van de Velde Ursule , Jacobs-Tulleneers-Thevissen Daniel , Maleux Geert , Lapauw Bruno , Crenier Laurent , De Block Christophe , Mathieu Chantal , Pipeleers Daniel , Keymeulen Bart
Published: May 2020

Background.

Clinical islet transplantation is generally conducted within 72 hours after isolating sufficient beta-cell mass. A preparation that does not meet the sufficient dose can be cultured until this is reached after combination with subsequent ones. This retrospective study examines whether metabolic outcome is influenced by culture duration.

Methods.

Forty type 1 diabetes recipients of intraportal islet cell grafts under antithymocyte globulin induction and mycophenolate mofetil-tacrolimus maintenance immunosuppression were analyzed. One subgroup (n = 10) was transplanted with preparations cultured for ≥96 hours; in the other subgroup (n = 30) grafts contained similar beta-cell numbers but included isolates that were cultured for a shorter duration. Both subgroups were compared by numbers with plasma C-peptide ≥0.5 ng/mL, low glycemic variability associated with C-peptide ≥1.0 ng/mL, and with insulin independence.

Results.

The subgroup with all cells cultured ≥96 hours exhibited longer C-peptide ≥0.5 ng/mL (103 versus 48 mo; P = 0.006), and more patients with low glycemic variability and C-peptide ≥1.0 ng/mL, at month 12 (9/10 versus 12/30; P = 0.005) and 24 (7/10 versus 6/30; P = 0.007). In addition, 9/10 became insulin-independent versus 15/30 (P = 0.03). Grafts with all cells cultured ≥96 hours did not contain more beta cells but a higher endocrine purity (49% versus 36%; P = 0.03). In multivariate analysis, longer culture duration and older recipient age were independently associated with longer graft function.

Conclusions.

Human islet isolates with insufficient beta-cell mass for implantation within 72 hours can be cultured for 96 hours and longer to combine multiple preparations in order to reach the desired beta-cell dose and therefore result in a better metabolic benefit.
Cold War spy satellite images reveal long-term declines of a philopatric keystone species in response to cropland expansion
Authors: Munteanu Catalina , Kamp Johannes , Nita Mihai Daniel , Klein Nadja , Kraemer Benjamin M. , Müller Daniel , Koshkina Alyona , Prishchepov Alexander V. , Kuemmerle Tobias
Published: May 2020

Agricultural expansion drives biodiversity loss globally, but impact assessments are biased towards recent time periods. This can lead to a gross underestimation of species declines in response to habitat loss, especially when species declines are gradual and occur over long time periods. Using Cold War spy satellite images (Corona), we show that a grassland keystone species, the bobak marmot (
Marmota bobak
), continues to respond to agricultural expansion that happened more than 50 years ago. Although burrow densities of the bobak marmot today are highest in croplands, densities declined most strongly in areas that were persistently used as croplands since the 1960s. This response to historical agricultural conversion spans roughly eight marmot generations and suggests the longest recorded response of a mammal species to agricultural expansion. We also found evidence for remarkable philopatry: nearly half of all burrows retained their exact location since the 1960s, and this was most pronounced in grasslands. Our results stress the need for farsighted decisions, because contemporary land management will affect biodiversity decades into the future. Finally, our work pioneers the use of Corona historical Cold War spy satellite imagery for ecology. This vastly underused global remote sensing resource provides a unique opportunity to expand the time horizon of broad-scale ecological studies.
Behavioural syndromes shape evolutionary trajectories via conserved genetic architecture
Authors: Royauté Raphaël , Hedrick Ann , Dochtermann Ned A.
Published: May 2020

Behaviours are often correlated within broader syndromes, creating the potential for evolution in one behaviour to drive evolutionary changes in other behaviours. Despite demonstrations that behavioural syndromes are common, this potential for evolutionary effects has not been demonstrated. Here we show that populations of field crickets (
Gryllus integer
) exhibit a genetically conserved behavioural syndrome structure, despite differences in average behaviours. We found that the distribution of genetic variation and genetic covariance among behavioural traits was consistent with genes and cellular mechanisms underpinning behavioural syndromes rather than correlated selection. Moreover, divergence among populations' average behaviours was constrained by the genetically conserved behavioural syndrome. Our results demonstrate that a conserved genetic architecture linking behaviours has shaped the evolutionary trajectories of populations in disparate environments—illustrating an important way for behavioural syndromes to result in shared evolutionary fates.
Staphylococcus aureus nasal isolates may have the same genetic profile in atopic dermatitis paediatric patients and their close contacts
Authors: Cavalcante Fernanda Sampaio , Alvarenga Celina Vieira da Cunha Guedes , Saintive Simone , Dios Abad Eliane de , Carvalho Ferreira Dennis de , Netto dos Santos Kátia Regina
Published: May 2020

Atopic dermatitis (AD) is a chronic skin disease that affects up to 20 % of the paediatric population worldwide.

Staphylococcus aureus

colonizes anterior nares and can be transmitted in the home environment, aggravating AD. This study aimed to detect

S. aureus

from nares of AD patients and their family contacts, as well as to evaluate the antimicrobial resistance, virulence and clonality of these isolates. Among the 48 family groups investigated, 30 groups were selected, as both the child and his/her respective contact had methicillin-sensitive

S. aureus

(MSSA) (24 cases; 54 MSSA isolates) or methicillin-resistant

S. aureus

(MRSA) isolates (6 cases; 13 MRSA isolates). All MRSA isolates carried SCCmec IV.

S. aureus

carrying PVL genes were detected in 60 % of patients. Pulsed-field gel electrophoresis (PFGE) analysis was performed for 31 isolates from 15 family groups: all 6 with MRSA and 9 with MSSA isolates. Similar genotypic profiles between isolates from patients and their family contacts were noted in 10 (66.6 %) family groups, 5 (83.3 %) of the MRSA family groups and 5 (55.5 %) of the MSSA family groups, indicating that the pathogen was transmitted through family contacts.
Assessment of service availability and Infection prevention measures in hospitals of Nepal during the transition phase of COVID-19 case surge
Authors: Bhattarai Suraj , Dhungana Jaya , Ensor Tim , Shrestha Uttam Babu
Published: May 2020

As with other coronavirus-affected countries, Nepalese medical fraternity also expressed concerns regarding public health strategies of government and hospital readiness in response to upgoing case surge. To gauge such response, we assessed service availability and Infection prevention and control (IPC) status in 110 hospitals situated across seven provinces. An electronic survey was sent out to the frontline clinicians working on those hospitals between 24th March and 7th April 2020; one response per hospital was analyzed. Hospitals were divided into small, medium, and large based on the total number of beds (small:<=15; medium:16-50; large:>50), and further categorized into public, private, and mixed based on the ownership. Out of 110 hospitals, 81% (22/27) of small, 39% (11/28) of medium, and 33% (18/55) of large hospitals had not allocated isolation beds for COVID-19 suspects. All small, majority of medium (89%; 25/28), and 50% of large hospitals did not have a functional intensive care unit (ICU) at the time of study. Nasopharyngeal (NP)/throat swab kits were available in one-third (35/110), whereas viral transport media (VTM), portable fridge box, and refrigerator were available in one-fifth (20%) of hospitals. Only one hospital (large/tertiary) had a functional PCR machine. Except for General practitioners, other health cadres- crucial during pandemics, were low in number. On IPC measures, the supplies of simple face masks, gloves, and hand sanitizers were adequate in the majority of hospitals, however, N95-respirators, Filter masks, and PPE-suits were grossly lacking. Government COVID-19 support was unevenly distributed across provinces; health facilities in Province 2, Gandaki, and Province 5 received fewer resources than others. Our findings alert the Nepalese and other governments to act early and proactively during health emergencies and not wait until the disease disrupts their health systems. Other countries of similar economic levels may undertake similar surveys to measure and improve their pandemic response.
Predicting SARS-CoV-2 infection trend using technical analysis indicators
Authors: Paroli Marino , Sirinian Maria Isabella
Published: May 2020

COVID-19 pandemic is a global emergency caused by SARS-CoV-2 infection. Without efficacious drugs or vaccines, mass quarantine has been the main strategy adopted by governments to contain the virus spread. This has led to a significant reduction in the number of infected people and deaths and to a diminished pressure over the health care system. However, an economic depression is following due to the forced absence of worker from their job and to the closure of many productive activities. For these reasons, governments are lessening progressively the mass quarantine measures to avoid an economic catastrophe. Nevertheless, the reopening of firms and commercial activities might lead to a resurgence of infection. In the worst-case scenario, this might impose the return to strict lockdown measures. Epidemiological models are therefore necessary to forecast possible new infection outbreaks and to inform government to promptly adopt new containment measures. In this context, we tested here if technical analysis methods commonly used in the financial market might provide early signal of change in the direction of SARS-Cov-2 infection trend in Italy, a country which has been strongly hit by the pandemic. We conclude that technical analysis indicators can be usefully adopted to this aim.
PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response
Authors: Li Jie , Kaneda Megan M. , Ma Jun , Li Ming , Patel Kunal , Koga Tomoyuki , Sarver Aaron , Furnari Frank , Xu Beibei , Dhawan Sanjay , Ning Jianfang , Zhu Hua , Wu Anhua , You Gan , Jiang Tao , Venteicher Andrew S. , Rich Jeremy N. , Glass Christopher K. , Varner Judith A. , Chen Clark C.
Published: May 2020

Precision medicine in oncology leverages clinical observations of exceptional response. Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3Kγ, by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Significance Statement

Understanding the basis for exceptional responders represents a key pillar in the framework of precision medicine. In this study, we utilized distinct informatics platforms to analyze the expression profiles of clinically annotated tumor specimens derived from patients afflicted with glioblastoma, the most common form of primary brain cancer. These analyses converged on prognostic contributions from glioblastoma-associated microglia/macrophages. Glioblastoma-associated microglia secreted interleukin 11 (IL11) to activate a STAT3-MYC signaling axis in glioblastoma cells, facilitating resistance to the standard-of-care chemotherapy, temozolomide. Microglia recruitment and IL11 secretion were dependent on the myeloid specific phosphoinositide-3-kinase gamma isoform (PI3Kγ). Inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in specimens derived from exceptional responders, suggesting potential for clinical translation.
Reciprocal association between participation to a national election and the epidemic spread of COVID-19 in France: nationwide observational and dynamic modeling study.
Authors: Zeitoun Jean-David , Faron Matthieu , Manternach sylvain , Fourquet Jerome , Lavielle Marc , lefevre jeremie
Published: May 2020

Objective: To investigate possible reciprocal associations between the intensity of the COVID-19 epidemic in France and the level of participation at national elections.
Design: Observational study and dynamic modelling using a sigmoidal mixed effects model.
Setting: All hospitals where patients were admitted for COVID-19.
Participants: All admitted patients from March 18, 2020 to April 17, 2020.
Main outcome measures: Abstention and admission rate for COVID-19.
Results: Mean abstention rate in 2020 among departments was 52.5%+/-6.4 and had increased by a mean of 18.8% as compared with the 2014 election. There was a high degree of similarity of abstention between the two elections among the departments (p<0.001). Among departments with a high outbreak intensity before the election, those with a higher participation were not affected by a significantly higher number of COVID-19 admissions after the elections. The sigmoidal model fitted the data from the different departments with a high degree of consistency. The covariate analysis showed that a significant association between participation and number of admitted patients was observed for both elections (2020: B=-5.36, p<1e-9 and 2014: B=-3.15, p<1e-6) contradicting a direct specific causation of the 2020 election. Participation was not associated with the position of the inflexion point suggesting no effect in the speed of spread.
Conclusions: Our results suggest that the surrounding intensity of the COVID-19 epidemic in France did not have any local impact on citizens participation to a national election. The level of participation to the 2020 election had no impact on the spread of the pandemic.
The impact of COVID-19 on African American communities in the United States
Authors: Cyrus Elena , Clarke Rachel , Hadley Dexter , Bursac Zoran , Trepka Mary Jo , Devieux Jessy G , Bagci Ulas , Furr-Holden Debra , Coudray Makella S , Mariano Yandra , Kiplagat Sandra , Noel Ines , Ravelo Gira , Paley Michelle , Wagner Eric F
Published: May 2020

Importance: The novel Coronavirus Disease 2019 (COVID-19), declared a pandemic in March 2020, may present with disproportionately higher rates in underrepresented racial/ethnic minority populations in the United States, including African American communities who have traditionally been over-represented in negative health outcomes.
Study Objective: To understand the impact of the density of African American communities (defined as the percentage of African Americans in a county) on COVID-19 prevalence and death rate within the three most populous counties in each U.S. state and territory (n=152).
Design: An ecological study using linear regression was employed for the study.
Setting: The top three most populous counties of each U.S. state and territory were included in analyses for a final sample size of n=152 counties.
Participants: Confirmed COVID-19 cases and deaths that were accumulated between January 22, 2020 and April 12, 2020 in each of the three most populous counties in each U.S. state and territory were included.
Main outcome measures: Linear regression was used to determine the association between African American density and COVID-19 prevalence (defined as the percentage of cases for the county population), and death rate (defined as number of deaths per 100,000 population). The models were adjusted for median age and poverty.
Results: There was a direct association between African American density and COVID-19 prevalence; COVID-19 prevalence increased 5% for every 1% increase in county AA density (p<.01). There was also an association between county AA density and COVID-19 deaths, such; the death rate increased 2 per 100,000 for every percentage increase in county AA density (p=.02).
Conclusion: These study findings indicate that communities with a high African American density have been disproportionately burdened with COVID-19. Further study is needed to indicate if this burden is related to environmental factors or individual factors such as types of employment or comorbidities that members of these community have.
Management of large polyps in a colorectal cancer screening program with fecal immunochemical test: a population-based study
Authors: Denis Bernard , Gendre Isabelle , Perrin Philippe , Tuzin Nicolas , Pioche Mathieu
Published: May 2020

Objective

To analyze presentation, management and outcomes of large (≥ 20 mm) polyps (LPs) detected in a colorectal cancer (CRC) screening program using a fecal immunochemical test (FIT).

Design

Retrospective population-based study of all LPs detected in patients aged 50-74 years between 2015 and 2019 during FIT-positive colonoscopies within the screening program organized in Alsace (France).

Results

Among 13,633 FIT-positive colonoscopies, 1256 LPs (8.5% malignant and 51.8% non- pedunculated) were detected by 102 community gastroenterologists in 1164 patients (one in 12 colonoscopies). The sensitivity of optical diagnosis of malignancy was 54% for non-pedunculated and 27% for pedunculated T1 CRCs. Endoscopic resection rate was 82.7% [95% CI 80.3-84.9] for benign LPs (70.2% [95% CI 66.4-74.1] non-pedunculated, 95.2% [95% CI 93.4-97.1] pedunculated, p<0.001), varying from 0 to 100% depending on the endoscopist. It was correlated with cecal intubation (Pearson r = 0.49, p<0.01) and adenoma detection (r = 0.25, p=0.01) rates. Most endoscopists did not refer patients to more experienced endoscopists, so that 60 to 90% of 183 surgeries for benign LPs were unwarranted. Endoscopic resection was curative for 4.3% [95% CI 0.9-12.0] of non-pedunculated and 37.8% [95% CI 22.5-55.2] of pedunculated T1 CRCs. Overall, 22 endoscopic submucosal dissections had to be performed to avoid one surgery.

Conclusion

Compared with current recommendations, there is tremendous room for improvement of community endoscopy practices for the diagnosis and management of LPs. Detection and polypectomy competencies are correlated and highly variable among endoscopists. Endoscopic resection is curative in 83% of benign LPs and 16% of T1 CRCs.

WHAT IS KNOWN

➢

Endoscopic resection of large polyps is effective (success in > 90% of cases) and safe in tertiary care centers.

➢

Surgery for benign colorectal polyps is far from negligible in current practice.

WHAT IS NEW HERE

➢

One in 12 FIT-positive colonoscopies reveals a large polyp, that is 8 to 10 times more frequently than screening colonoscopies.

➢

In community practice, 4 of 5 benign large polyps only are removed endoscopically and 1 of 6 malignant large polyps cured endoscopically.

➢

Between 60% and 90% of surgeries for large benign polyps could be avoided if endoscopists having lesser polypectomy competency referred their patients to experienced endoscopists instead of surgeons.

➢

The benefit offered by endoscopic submucosal resection for the management of large polyps is marginal in community practice; here one surgery avoided for 22 endoscopic submucosal dissections performed.

➢

Detection and polypectomy competencies are correlated and highly variable among endoscopists.
Systematic and Statistical Review of COVID19 Treatment Trials
Authors: Siordia Juan Arturo , Bernaba Michael , Yoshino Kenji , Ulhaque Abid , Kumar Sooraj , Bernaba Mario , Bergin Edward
Published: May 2020

Objective: The following systematic review and meta-analysis compiles the current data regarding human controlled COVID-19 treatment trials. Methods: An electronic search of the literature compiled studies pertaining to human controlled treatment trials with COVID-19. Medications assessed included lopinavir/ritonavir, arbidol, hydroxychloroquine, favipiravir, and heparin. Statistical analyzes were performed for common viral clearance endpoints whenever possible. Results: Lopinavir/ritonavir showed no significant effect on viral clearance for COVID-19 cases (OR 0.95 [95% CI 0.50-1.83]). Hydroxychloroquine also showed no significant effect on COVID-19 viral clearance rates (OR 2.16 [95% CI 0.80-5.84]). Arbidol showed no seven-day (OR 1.63 [95% CI 0.76-3.50]) or 14-day viral (OR 5.37 [95% CI 0.35-83.30]) clearance difference compared to lopinavir/ritonavir. Review of literature showed no significant clinical improvement with lopinavir/ritonavir, arbidol, hydroxychloroquine, or remdesivir. Favipiravir showed quicker symptom improvement compared to lopinavir/ritonavir and arbidol. Heparin showed improvement with severe COVID-19 cases. Conclusion: Current medications do not show significant effect on COVID-19 viral clearance rates. Favipiravir shows favorable results compared to other tested medications. Heparin shows benefit for severe cases of COVID-19.
Evaluate the risk of resumption of business for the states of New York, New Jersey and Connecticut via a pre-symptomatic and asymptomatic transmission model of COVID-19
Authors: Tian Ting , Tan Jianbin , Jiang Yukang , Wang Xueqin , Zhang Heping
Published: May 2020

The United States has the highest number of confirmed cases of COVID-19 in the world. The early hot spot states were New York, New Jersey, and Connecticut. The workforce in these states was required to work from home except for essential services. It was necessary to evaluate an appropriate date for resumption of business since the premature reopening of the economy would lead to a broader spread of COVID-19, while the opposite situation would cause greater loss of economy. To reflect the real-time risk of the spread of COVID-19, it was crucial to evaluate the population of infected individuals before or never being confirmed due to the pre-symptomatic and asymptomatic transmissions of COVID-19. To this end, we proposed an epidemic model and applied it to evaluate the real-time risk of epidemic for the states of New York, New Jersey, and Connecticut. We used California as the benchmark state because California began a phased reopening on May 8, 2020. The dates on which the estimated numbers of unidentified infectious individuals per 100,000 for states of New York, New Jersey, and Connecticut were close to those in California on May 8, 2020, were June 1, 22, and 22, 2020, respectively. By the practice in California, New York, New Jersey, and Connecticut might consider reopening their business. Meanwhile, according to our simulation models, to prevent the resurgence of infections after reopening the economy, it would be crucial to maintain sufficient measures to limit the social distance after the resumption of businesses. This precaution turned out to be critical as the situation in California quickly deteriorated after our analysis was completed and its interventions after the reopening of business were not as effective as those in New York, New Jersey, and Connecticut.
The potential impact of the COVID-19 pandemic on tuberculosis: a modelling analysis
Authors: Cilloni Lucia , Fu Han , Vesga Juan F , Dowdy David , Pretorius Carel , Ahmedov Sevim , Nair Sreenivas A , Mosneaga Andrei , Masini Enos O , Suvanand Sahu , Arinaminpathy Nimalan
Published: May 2020

Background
Routine services for tuberculosis (TB) are being disrupted by stringent lockdowns against the novel SARS-CoV-2 virus. We sought to estimate the potential long-term epidemiological impact of such disruptions on TB burden in high-burden countries, and how this negative impact could be mitigated.

Methods
We adapted mathematical models of TB transmission in three high-burden countries (India, Kenya and Ukraine) to incorporate lockdown-associated disruptions in the TB care cascade. The anticipated level of disruption reflected consensus from a rapid expert consultation. We modelled the impact of these disruptions on TB incidence and mortality over the next five years, and also considered potential interventions to curtail this impact.

Results
Even temporary disruptions can cause long-term increases in TB incidence and mortality. We estimated that a 3-month lockdown, followed by 10 months to restore normal TB services, would cause, over the next 5 years, an additional 1.92 million TB cases (Crl 1.74 - 2.15) and 488,000 TB deaths (CrI 449 - 541 thousand) in India, 48,000 (33,400 - 72,320) TB cases and 16,800 deaths (11.9 - 21.9 thousand) in Kenya, and 9,100 (6,980 - 11,200) cases and 1,960 deaths (1,620 - 2,350) in Ukraine. However, any such negative impacts could be averted through supplementary 'catch-up' TB case detection and treatment, once restrictions are eased.

Interpretation
Lockdown-related disruptions can cause long-lasting increases in TB burden, but these negative effects can be mitigated with targeted interventions implemented rapidly once lockdowns are lifted.
A Real-Time Statistical Model for Tracking and Forecasting COVID-19 Deaths, Prevalence and Incidence
Authors: Syage Jack A.
Published: May 2020

Background: Pandemics do not occur frequently and when they do there is a paucity of forecasting tools that could help drive government responses to mitigate worst outcomes. Here we provide a forecasting model that is based on measurable variables and that strives for simplicity over complexity to obtain stable convergent forecasts of death, prevalence, incidence, and safe days for social easing.

Methods: We assume, based on prior pandemic data, that death rate rise and fall approximately follows a Gaussian distribution, which can be asymmetric, which we describe. By taking daily death data for foreign countries and U.S. states and fitting it to an appropriate Gaussian function provides an estimate of where in the cycle a particular population lies. From that time point one can integrate remaining time to obtain a final total death. By also using measured values for the time from infection to recovery or death and a mortality factor, the prevalence (active cases) and incidence (new cases) totals and rate curves can be constructed. It is also possible by setting a downward threshold on prevalence that an estimate of a minimum date to begin relaxing social restrictions may be considered.

Results: To demonstrate the model we chose the most severe hot-bed countries and U.S. states as a test-bed to evolve and improve our model and to compare with other models. The model can readily be applied to other countries by inputting data from public data bases. We also compare our forecasts to the University of Washington (UW) IHME model and are reassuringly similar yet show less variability on a weekly basis. The sum of squares for error (SSE) for international and U.S. states, respectively, that we track are: 26% and 26% for our model vs. 41% and 46% for the IHME model.

Conclusions: Our model appears closest to the UW IHME model; however, there are important differences and while both models forecast many of the same results of interest, each one offers unique benefits that the other does not. We believe that the model reported here excels for its simplicity, which makes the model easy to use.
Leveraging pleiotropy in genome-wide association studies in multiple traits with per trait interpretations
Authors: Taraszka Kodi , Zaitlen Noah , Eskin Eleazar
Published: May 2020

We introduce pleiotropic association test (PAT) for joint analysis of multiple traits using GWAS summary statistics. The method utilizes the decomposition of phenotypic covariation into genetic and environmental components to create a likelihood ratio test statistic for each genetic variant. Though PAT does not directly interpret which trait(s) drive the association, a per trait interpretation of the omnibus p-value is provided through an extension to the meta-analysis framework, m-values. In simulations, we show PAT controls the false positive rate, increases statistical power, and is robust to model misspecifications of genetic effect.

Additionally, simulations comparing PAT to two multi-trait methods, HIPO and MTAG show PAT having a 43.0% increase in the number of omnibus associations over the other methods. When these associations are interpreted on a per trait level using m-values, PAT has 52.2% more per trait interpretations with a 0.57% false positive assignment rate. When analyzing four traits from the UK Biobank, PAT identifies 22,095 novel associated variants. Through the m-values interpretation framework, the number of total per trait associations for two traits are almost tripled and are nearly doubled for another trait relative to the original single trait GWAS.
Developmental Normalization of Phenomics Data Generated by High Throughput Plant Phenotyping Systems
Authors: Lozano-Claros Diego , Meng Xiangxiang , Custovic Eddie , Deng Guang , Berkowitz Oliver , Whelan James , Lewsey Mathew G.
Published: May 2020

Background

Sowing time is commonly used as the temporal reference forArabidopsis thaliana(Arabidopsis) experiments in high throughput plant phenotyping (HTPP) systems. This relies on the assumption that germination and seedling establishment are uniform across the population. However, individual seeds have different development trajectories even under uniform environmental conditions. This leads to increased variance in quantitative phenotyping approaches. We developed the Digital Adjustment of Plant Development (DAPD) normalization method. It normalizes time-series HTPP measurements by reference to an early developmental stage and in an automated manner. The timeline of each measurement series is shifted to a reference time. The normalization is determined by cross-correlation at multiple time points of the time-series measurements, which may include rosette area, leaf size, and number.

Results

The DAPD method improved the accuracy of phenotyping measurements by decreasing the statistical dispersion of quantitative traits across a time-series. We applied DAPD to evaluate the relative growth rate inA. thalianaplants and demonstrated that it improves uniformity in measurements, permitting a more informative comparison between individuals. Application of DAPD decreased variance of phenotyping measurements by up to 2.5 times compared to sowing-time normalization. The DAPD method also identified more outliers than any other central tendency technique applied to the non-normalized dataset.
Sexually dimorphic roles for the type 2 diabetes-associatedC2cd4bgene in murine glucose homeostasis
Authors: Gharavy S. Neda Mousavy , Owen Bryn , Millership Steven J. , Chabosseau Pauline , Pizza Grazia , Martinez-Sanchez Aida , Tasoez Emirhan , Georgiadou Eleni , Hu Ming , Fine Nicholas H.F. , Jacobson David A. , Dickerson Matthew , Idevall-Hagren Olof , Montoya Alex , Kramer Holger , Mehta Zenobia , Withers Dominic J. , Ninov Nikolay , Gadue Paul J. , Cardenas-Diaz Fabian L. , Cruciani-Guglielmacci Céline , Magnan Christophe , Ibberson Mark , Leclerc Isabelle , Voz Marianne , Rutter Guy A.
Published: May 2020

Variants close to theVPS13C/C2CD4A/C2CD4Blocus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles forVPS13CandC2CD4Ain disease development, none has explored the role ofC2CD4B. Here, we show that systemic inactivation ofC2cd4bin mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. FemaleC2cd4bmice display unchanged body weight but abnormal glucose tolerance and defectivein vivo,but notin vitro,insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, maleC2cd4bnull mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation ofC2cd4ain mice, or in pancreatic β cell function at larval stages inC2cd4abnull zebrafish. These studies suggest thatC2cd4bmay act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles forC2CD4AorVPS13Cin the control of glucose homeostasis in man.
Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development
Authors: Geusz Ryan J. , Wang Allen , Chiou Joshua , Lancman Joseph J. , Wetton Nichole , Kefalopoulou Samy , Wang Jinzhao , Qiu Yunjiang , Yan Jian , Aylward Anthony , Ren Bing , Dong P Duc Si , Gaulton Kyle J. , Sander Maike
Published: May 2020

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genesLAMA1andCRB2. Knockdown oflama1orcrb2in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.
The role of intolerance of uncertainty in the acquisition and extinction of reward
Authors: Morriss Jayne , Biagi Nicolo , Lonsdorf Tina B. , Andreatta Marta
Published: May 2020

Individuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it remains unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a reward associative learning task with acquisition and extinction training phases (n= 58). Throughout the associative learning task, we recorded valence ratings (i.e. liking), skin conductance response (SCR) (i.e. sweating), and corrugator supercilii activity (i.e. brow muscle indicative or negative and positive affect) to learned reward and neutral cues. During acquisition training with partial reward reinforcement, higher IU was associated with greater corrugator supercilii activity to neutral compared to reward cues. IU was not related to valence ratings or SCR’s during the acquisition or extinction training phases. These preliminary results suggest that IU-related deficits during extinction may be limited to situations with threat. The findings further our conceptual understanding of IU’s role in the associative learning and extinction of reward, and in relation to the processing of threat and reward more generally.
In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor
Authors: Ariey-Bonnet Jeremy , Carrasco Kendall , Le Grand Marion , Hoffer Laurent , Betzi Stéphane , Feracci Mickael , Tsvetkov Philipp , Devred Francois , Collette Yves , Morelli Xavier , Ballester Pedro , Pasquier Eddy
Published: May 2020

The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used anin silicotarget prediction algorithm to investigate the mechanism of action of mebendazole, an anti-helminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cellsin vitro. Ourin silicoapproach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly up-regulated at the gene level in glioblastoma as compared to normal brain tissue. Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2 and MAPK14/p38α. Mebendazole could inhibit the activity of these kinasesin vitroin a dose-dependent manner, with a high potency against MAPK14. Its direct binding to MAPK14 was further validatedin vitroand inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases.

Significance Statement

This study provides a framework to investigate drug polypharmacology by rapidly identifying novel molecular targets of already-approved drugs. It unveils a new mechanism involved in the anticancer activity of anti-helminthic drug, mebendazole, which is currently being repurposed for the treatment of brain tumors. By helping to decipher the mechanism(s) of action of repurposed drugs in their new indications, this approach could contribute to the development of safer and more effective therapeutic strategies in oncology and beyond.
Choice activity stabilizes sensory representations and mediates sensorimotor associations in parietal cortex
Authors: Chang Ting-Yu , Doudlah Raymond , Kim Byounghoon , Sunkara Adhira , Lowe Meghan , Rosenberg Ari
Published: May 2020

Selecting actions which achieve desired goals often requires three-dimensional (3D) representations of the environment. Because the sensory epithelia cannot directly encode the world’s 3D spatial features, sensory signals must be converted into 3D representations. Here we investigated the relationships between the quality of 3D visual representations, choice-related activity, and motor-related activity in the parietal cortex of macaque monkeys using an eight-alternative 3D orientation discrimination task, visually guided saccade task, and laminar probe recordings. We found that choice activity was preferentially carried by caudal intraparietal area neurons with more robust 3D representations. Choice activity further stabilized the 3D representations, rather than attenuating information not directly relevant to the behavioral task (nuisance variables). An experience-dependent, sensorimotor association additionally aligned sensory and saccade direction preferences, particularly for neurons with choice activity. These findings reveal novel roles for choice activity in improving the fidelity of ecologically relevant object representations and mediating sensorimotor associations.
A singleton NLR of recent origin causes hybrid necrosis inArabidopsis thaliana
Authors: Barragan A. Cristina , Collenberg Maximilian , Wang Jinge , Lee Rachelle R.Q. , Cher Wei Yuan , Rabanal Fernando A. , Ashkenazy Haim , Weigel Detlef , Chae Eunyoung
Published: May 2020

Hybrid necrosis in plants arises from conflict between divergent alleles of immunity genes contributed by different parents, resulting in autoimmunity. We investigate a severe hybrid necrosis case inArabidopsis thaliana, where the hybrid does not develop past the cotyledon stage and dies three weeks after sowing. Massive transcriptional changes take place in the hybrid, including the upregulation of most NLR disease resistance genes. This is due to an incompatible interaction between the singleton TIR-NLR geneDANGEROUS MIX 10(DM10), which was recently relocated from a larger NLR cluster, and an unlinked locus,DANGEROUS MIX 11 (DM11). There are multipleDM10allelic variants in the globalA. thalianapopulation, several of which have premature stop codons. One of these, which has a truncated LRR domain, corresponds to theDM10risk allele. TheDM10locus and the adjacent genomic region in the risk allele carriers are highly differentiated from those in the non-risk carriers in the globalA. thalianapopulation, suggesting that this allele became geographically widespread only relatively recently. TheDM11risk allele is much rarer and found only in two accessions from southwestern Spain – a region from which theDM10risk haplotype is absent – indicating that the ranges ofDM10andDM11risk alleles may be non-overlapping.