bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Intellectual Function After Traumatic Brain Injury in Very Young Children
Authors: Crowe Louise M. , Catroppa Cathy , Babl Franz E. , Godfrey Celia , Anderson Vicki
Published: November 2020

Objective:

To investigate long-term intellectual function following a traumatic brain injury (TBI) in early childhood and to identify the contribution of injury and environment to outcome.

Participants:

Fifty children younger than 3 years with a diagnosis of accidental TBI were recruited through a pediatric hospital emergency department. Children with TBI were compared with a group (n = 33) of typically developing children (TDC) matched on demographics.

Design:

Longitudinal, single-site, case-control study.

Measures:

Children completed intellectual assessments (IQ) at 4.5 to 5.5 years of age (average 3.5 years after TBI) and at 7.5 to 9 years of age (average 6.5 years after TBI). Information on injury and environmental predictors of outcome was collected.

Results:

IQ scores for all groups were in the average range; however, children with TBI of any severity had lower scores than TDC at both time points. There was some suggestion of children with TBI achieving lower verbal IQ scores over time than TDC. IQ scores were predicted by family environment, not injury characteristics.

Conclusions:

A TBI in early childhood is associated with lower IQ scores that persist several years postinjury. Socioeconomic status is an influential factor on IQ at 6.5 years post-TBI.
miRNAs as Potential Biomarkers for Traumatic Brain Injury: Pathway From Diagnosis to Neurorehabilitation
Authors: Herrold Amy A. , Kletzel Sandra L. , Foecking Eileen M. , Saban Karen L. , Przybycien–Szymanska Magdalena M. , Zilliox Michael , Bhaumik Dulal , Lange Dustin , Radke Jay R. , Salinas Ilse , Bender Pape Theresa L.
Published: November 2020

Background:

Biomarkers that can advance precision neurorehabilitation of the traumatic brain injury (TBI) are needed. MicroRNAs (miRNAs) have biological properties that could make them well suited for playing key roles in differential diagnoses and prognoses and informing likelihood of responsiveness to specific treatments.

Objective:

To review the evidence of miRNA alterations after TBI and evaluate the state of science relative to potential neurorehabilitation applications of TBI-specific miRNAs.

Methods:

This scoping review includes 57 animal and human studies evaluating miRNAs after TBI. PubMed, Scopus, and Google Scholar search engines were used.

Results:

Gold standard analytic steps for miRNA biomarker assessment are presented. Published studies evaluating the evidence for miRNAs as potential biomarkers for TBI diagnosis, severity, natural recovery, and treatment-induced outcomes were reviewed including statistical evaluation. Growing evidence for specific miRNAs, including miR21, as TBI biomarkers is presented.

Conclusions:

There is evidence of differential miRNA expression in TBI in both human and animal models; however, gaps need to be filled in terms of replication using rigorous, standardized methods to isolate a consistent set of miRNA changes. Longitudinal studies in TBI are needed to understand how miRNAs could be implemented as biomarkers in clinical practice.
Effects of Continuous Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome on Corneal Morphological Characteristics
Authors: Chalkiadaki Evangelia , Andreanos Konstantinos , Karmiris Efthymios , Mani Aikaterini , Kastanakis Emmanouil , Amfilochiou Anastasia , Papaconstantinou Dimitrios , Koutsandrea Chrysanthi , Georgalas Ilias
Published: November 2020

Purpose:

To evaluate the effects of continuous positive airway pressure (CPAP) therapy on corneal endothelial morphometry and pachymetry in patients with obstructive sleep apnea–hypopnea syndrome (OSAHS).

Methods:

This prospective, observational study included patients with OSAHS who were evaluated right before and after the commencement of CPAP treatment. Each patient underwent a detailed ophthalmologic examination and assessment of their corneal endothelium with a noncontact specular microscope (Tomey EM-3000; Tomey Corp). Endothelial cell density, coefficient of variation of cell area (CV), hexagonal cell appearance ratio (%Hex), and central corneal thickness were measured. The post-CPAP results were compared with the results of a control group. The differences in the corneal parameters between pre- and post-CPAP therapy of the OSAHS group were correlated with the pretreatment polysomnography results.

Results:

Twenty-seven distinct eyes of 27 patients recently diagnosed with OSAHS and 30 eyes of 30 healthy individuals were used for the statistical analysis. The mean age of patients with OSAHS was 54.2 ± 11.8 years, and after 9.6 months (range 3–18 mo) of good adherence to CPAP treatment, their CV values, indicating polymegathism, decreased from 41.7 ± 8.7 to 38.3 ± 5.8 (P = 0.04), whereas %Hex, indicating pleomorphism, increased from 45.8% ± 8.2% to 48.4% ± 6.6% (P = 0.008). Their post-CPAP corneal parameters did not differ significantly from those of the control group (P > 0.05). A significant positive correlation was observed between the decrease in CV and the duration of the treatment (Rs = 0.566, P = 0.002), as well as the pre-CPAP nonrapid eye movement (NREM) sleep percentage (Rs = 0.459, P = 0.02). A negative correlation was noted between the decrease in CV and the percentage of rapid eye movement (REM) sleep (Rs = −0.459, P = 0.02).

Conclusions:

Better oxygenation during sleep, resulting from increased CPAP adherence, had a significant influence on corneal endothelium, providing an improvement in corneal polymegathism and pleomorphism, with a potential return of CV and %Hex to their normal values. Greater improvement in polymegathism was observed in patients with greater proportion of NREM sleep.
Association Between Proportion of Workday Treating COVID-19 and Depression, Anxiety, and PTSD Outcomes in US Physicians
Authors: Gainer Danielle M. , Nahhas Ramzi W. , Bhatt Nita V. , Merrill Autumnn , McCormack Julie
Published: November 2020

Objective:

The primary objective of this cross-sectional study was to examine the association between time spent treating patients with Coronavirus disease 2019 (COVID-19) and levels of depression, anxiety, and posttraumatic stress disorder (PTSD) in US physicians.

Methods:

The authors conducted an anonymous online survey of US physicians. Linear regression was used to test the association between proportion of day treating COVID-19 and symptoms of depression, anxiety, and PTSD.

Results:

In a sample of 1724 US physicians, proportion of day treating COVID-19 was positively and significantly associated with depression, anxiety, and PTSD scores (P < 0.001 for each).

Conclusions:

Mental health resources should be provided to physicians who treat COVID-19 because the proportion of day treating COVID-19 is associated with depression, anxiety, and PTSD outcomes.
Knowledge, attitudes, and Expectations of Medical Staff Toward Medical Error Management Policies in Humanitarian Medicine: A Qualitative Study
Authors: Biquet Jean-Marc , Schopper Doris , Sprumont Dominique , Michel Philippe
Published: November 2020

Background

Patient safety, a major component of quality of care, is now an attribute of health care systems in developed countries at least. Although there is ever more research on this subject in developed countries, humanitarian medicine, mainly implemented in resource-poor countries, has yet to structure its own set of policies and strategies on patient safety and the management of medical errors.

Objectives

We assessed the knowledge, attitudes, and expectations of medical humanitarian staff regarding the development of policies and strategies related to patient safety and medical error management in medical humanitarian action.

Methods

We conducted 36 semistructured interviews with international medical and paramedical staff active in 6 medical humanitarian organizations after having interviewed the medical directors or the person in charge of quality of care and the legal advisors. Interviews were transcribed verbatim and subjected to a thematic analysis.

Results

The interviews confirmed the current absence of clear investments in dealing with safety risks in the selected medical humanitarian organizations. The difficulties experienced by medical staff in reporting medical errors such as blame culture, lack of training, and absence of leadership committed on patient safety are nonspecific. Other arguments are related to the specific conditions of humanitarian settings: coexistence of different medical culture, absence of international or local regulations or external pressures, and great diversity of activities and contexts.

Conclusions

Interviewed staff expressed high expectations of receiving guidance from their organizations and support to adopt clear patient safety and medical error management policies adapted to their complex operational and clinical realities.
Implementing Patient and Family Involvement Interventions for Promoting Patient Safety: A Systematic Review and Meta-Analysis
Authors: Giap Thi-Thanh-Tinh , Park Myonghwa
Published: November 2020

Objective

The aims of the study were to evaluate and to quantify the effects of patient and family involvement (PFI) interventions on patient safety by synthesizing the available global data.

Methods

Four databases were searched to identify relevant studies that have assessed the impact of PFI on patient safety up to March 2019. Reference lists of potential selected articles were also used to identify additional relevant studies. Effect sizes (ESs) were calculated using random and fixed effects models. Statistical heterogeneity was measured using the I
2 test.

Results

Twenty-two studies met the review criteria. The meta-analysis showed that PFI were beneficial in significantly reducing adverse events (ES = −0.240, P < 0.001), decreasing the length of hospital stay (ES = −0.122, P < 0.001), increasing patient safety experiences (ES = 0.630, P = 0.007), and improving patient satisfaction (ES = 0.268, P = 0.004). However, the PFI interventions did not significantly enhance the perception of patient safety (ES = 0.205, P = 0.09) or the quality of life (ES = 0.057, P = 0.61). Moreover, moderate-to-high heterogeneity was found for all impacts except adverse events (I
2 = 0%) and length of hospital stay (I
2 = 35%). A funnel plot indicated a low degree of publication bias for the adverse event outcome.

Conclusions

The synthesized evidence in this review demonstrates the benefits of PFI for promoting patient safety. However, further studies should extend the research scope to fill the existing gaps for both the type of PFI interventions and the patient safety outcomes.
Catastrophic Human Error in Assisted Reproductive Technologies: A Systematic Review
Authors: Nesbit Carleigh , Blanchette Porter Misty , Esfandiari Navid
Published: November 2020

Objective

Assisted reproductive technologies (ARTs) are complex processes with multiple and diverse opportunities for human error. Errors in ART are thought to be rare, but can have devastating consequences for patients and their offspring. The objectives of this article are to review known cases of human error in the ART laboratory and suggest preventative strategies.

Methods

We performed a systematic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using PubMed and Google Scholar databases. Studies were eligible for inclusion if they involved known cases of unintentional human error in the ART laboratory. Only full-text articles in English were included. References of the resulted studies were considered for inclusion.

Results

A total of 420 articles were screened and 37 articles were selected for inclusion. These largely included case reports and reviews in the medical and legal literature. Twenty-two adverse events due to human error in the ART laboratory were identified. Eight of these adverse events were the result of the insemination with the wrong sperm, 6 errors lead to the transfer of the wrong embryo, 3 lead to an error in preimplantation genetic testing, and 5 adverse events lead to the failure of gamete and embryo cryostorage.

Conclusions

Since the advent of ART, there have been reports of catastrophic events occurring secondary to human error in the laboratory to include incidents of unintended parentage, and have resulted in the loss of embryos and gametes through cryostorage failure. Proposed solutions include the stringent implementation and adherence to safety protocols, adequate laboratory staffing and training, and novel methods for specimen labeling and tracking. Of utmost importance is having knowledge of these errors and the ability to determine cause so that future events can be prevented.
Labio-facial Necrotizing Fasciitis in a Young Patient
Authors: Lança Maria Leticia de Almeida , Trento Guilherme dos Santos , Santos José Cleveilton dos , Navarro Claudia Maria , Pereira-Filho Valfrido Antônio
Published: November 2020

Necrotizing fasciitis (NF) is an infection of the deeper tissues that results in progressive destruction of muscle fascia and overlying subcutaneous fat. It has a fast and destructive course. Moreover, it is related to immunosuppression and could be fatal. The aim of this study is to report a clinical case of a young patient, without immunosuppression, who developed NF evolution due to an erroneous diagnosis of abscess at the beginning of the disease. Patient was submitted to broad-spectrum antibiotic therapy and aggressive surgical treatment. Adequate treatment led to a satisfactory evolution in a short period of time. Early recognition and adequate treatment are essential for a favorable prognosis.
Lithium for Carbamazepine-Induced Syndrome of Inappropriate Antidiuretic Hormone
Authors: Pham Vicky M. , White Jennifer M. , Gunther Steven R. , Stewart Jonathan T.
Published: November 2020

Objectives

To examine the effectiveness of low-dose lithium carbonate for managing carbamazepine-induced hyponatremia.

Methods

Single case study in an 88 year old man with bipolar illness and vascular dementia who had failed to respond to other mood stabilizers.

Results

The patient had developed hyponatremia on two separate occasions when treated with carbamazepine. Introduction of low-dose lithium resulted in prompt normalization of serum sodium levels, which was maintained for the subsequent 8 weeks.

Conclusions

Carbamazepine may sometimes be the best or only viable treatment option for patients with bipolar illness or other conditions. When its use is complicated by syndrome of inappropriate ADH, dose reduction and fluid restriction are the simplest options but, if ineffective, addition of lithium may be a feasible, albeit somewhat complicated, alternative.
Stationary frequencies and mixing times for neutral drift processes with spatial structure
Authors: McAvoy Alex , Adlam Ben , Allen Benjamin , Nowak Martin A.
Published: November 2020

We study a general setting of neutral evolution in which the population is of
finite, constant size and can have spatial structure. Mutation leads to
different genetic types (traits), which can be discrete or continuous. Under
minimal assumptions, we show that the marginal trait distributions of the
evolutionary process, which specify the probability that any given individual
has a certain trait, all converge to the stationary distribution of the mutation
process. In particular, the stationary frequencies of traits in the population
are independent of its size, spatial structure and evolutionary update rule, and
these frequencies can be calculated by evaluating a simple stochastic process
describing a population of size one (i.e. the mutation process itself). We
conclude by analysing mixing times, which characterize rates of convergence of
the mutation process along the lineages, in terms of demographic variables of
the evolutionary process.
Validation of immunoaffinity-HPLC/PDA method for microvitamin
(biotin and cobalamins) analysis in marine resources and
products
Authors: Park Ye-Eun , Nam Ki-Ho , Kim Yeon-Kye , Chun Jiyeon
Published: November 2020

Given that Korea is surrounded by water on three sides, fishery resources are
abundant and consumed nationwide. To assess the dietary intake of
micronutrients, reliable analysis should be performed. However, there is no
verified method for the analysis of vitamins B7 and B12 in
fishery resources. In this study, the immunoaffinity-high performance liquied
chromatography (HPLC)/photodiode array-detector (PDA) was validated and applied
to analyze microvitamins B7 (biotin) and B12 (cobalamins)
in fishery producus. The specificity of the immunoaffinity-HPLC/PDA method was
good for biotin and cyanocobalamin. The analytical quantitation limits for
biotin and cyanocobalamin were 0.028 and 0.014 μg/100 g, respectively.
The recovery of vitamins B7 and B12 ranged from
99.0% to 101.3%, indicating a good accuracy. The repeatability (CV
3.6%-3.8%) and reproducibility (CV 4.9%-6.1%) of
immunoaffinity-HPLC/PDA assay for vitamins B7 and B12 were
acceptable, indicating good precision. Vitamins B7 (1.06 to 10.55
μg/100 g) and B12 (0.36 to 36.13 μg/100 g) were
detected in all fishery products (n=28) including 4 fish, 3 crustaceans, 3
marine algae, 3 cephalopods, 4 shellfish, 3 others and 8 products. The highest
vitamin B7 and B12 contents were found in gazami crabs and
ark shells, respectively. In conclusion, our data could be used for establishing
national vitamin database on Korean fishery resources.
Evaluation of antibacterial and antioxidant activities of Sacha
inchi (Plukenetia volubilis L.) leaf from
Myanmar
Authors: Jang Miran , You SoHyeon , Kim Gun-Hee
Published: November 2020

The comparative study evaluated the antioxidant and antimicrobial activities of
Sacha inchi (Plukenetia volubilis L.) leaf extracts from
Mandalay and Yangon, Myanmar. The total polyphenol and flavonoid contents were
higher in Sacha inchi extracts from Yangon (97.84 and 89.60 mg/g, respectively)
than in those from Mandalay (71.27 and 60.81 mg/g, respectively). Both DPPH and
ABTS radical scavenging activities and FRAP values were higher in Sacha inchi
from Yangon, than Mandalay. A clear zone formed aroundallpaperdiscs placed on a
plate coated with pathogenic bacteria indicated antibacterial activity of Sacha
inchi extracts. Time-kill curves showed that the growth of all tested strains
was inhibited by incubation with Sacha inchi extracts for 24 h. The MIC50 and
MIC100 were 6.25-2,000 and 125-5,000 μg/mL for eleven and eight tested
strains. All measurement methods showed that the antibacterial activity was
superior for Sacha inchi from Yangon compared with Mandalay. The more effective
antioxidant and antimicrobial activities of Sacha inchi from Yangon were
ascribed to the higher abundance of functional phenolics and flavonoids.
The effect of Cudrania tricuspidata fruit vinegar
on LPS-induced inflammation in 3T3-L1 adipocytes
Authors: Park Se-Eun , Yeo Soo Hwan , Kim Seung
Published: November 2020

Cudrania tricuspidata fruit has anti-inflammatory and
anti-obesity effects. The present study aimed to determine the effect of
C. tricuspidata fruits vinegar (CFV) on lipopolysaccharide
(LPS)-induced adipocytes inflammation in 3T3-L1 adipocytes. The differentiation
of 3T3-L1 adipocytes was induced by dexamethasone (DEX),
3-isobutyl-1-methylxanthine (IBMX) and insulin. Differentiated 3T3-L1 adipocytes
were incubated with CFV followed by LPS treatment. The secretion of tumor
necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte
chemoattractant protein-1 (MCP-1) were measured using ELISA. The expression of
toll-like receptor 4 (TLR4), myeloid differentiation primary response 88
(MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6) and nuclear
factor kappa B (NF-κB) were measured by western blotting. The results
showed that CFV dose-dependently inhibited lipid droplet generation and
LPS-induced TNF-α, IL-6 and MCP-1 production in the adipocytes. CFV
inhibited NF-κB activation, and the LPS-induced expression of TLR4,
MyD88, and TRAF6. These results indicated that CFV inhibits the LPS-induced
inflammatory response in adipocytes by inhibiting TLR4 signaling, including
NF-κB pathways.
The impacts of COVID-19 mitigation on dengue virus transmission: a modelling study
Authors: Cavany Sean M , España Guido , Vazquez-Prokopec Gonzalo M , Scott Thomas W , Perkins T Alex
Published: November 2020

Background

The COVID-19 pandemic has induced unprecedented reductions in human mobility and social contacts throughout the world. Because dengue virus (DENV) transmission is strongly driven by human mobility, behavioral changes associated with the pandemic have been hypothesized to impact dengue incidence. By discouraging human contact, COVID-19 control measures have also disrupted dengue vector control interventions, the most effective of which require entry into homes.

Method

We used an agent-based model with a realistic treatment of human mobility and vector control to investigate how and why dengue incidence could differ under a lockdown scenario with a proportion of the population sheltered at home.

Result

We found that a lockdown in which 70% of the population sheltered at home led to a small average increase in cumulative DENV infections of up to 10%, depending on the time of year lockdown occurred. Lockdown had a more pronounced effect on the spatial distribution of DENV infections, with higher incidence under lockdown in regions with high mosquito abundance. Transmission was also more focused in homes following lockdown. The proportion of people infected in their own home rose from 54% under normal conditions to 66% under lockdown, and the household secondary attack rate rose from 0.109 to 0.128, a 17% increase. When we considered that lockdown measures could disrupt regular, city-wide vector control campaigns, the increase in incidence was more pronounced than with lockdown alone, especially if lockdown occurred at the optimal time for vector control.

Discussion

Our results indicate that an unintended outcome of COVID-19 control measures may be to adversely alter the epidemiology of dengue. This observation has important implications for an improved understanding of dengue epidemiology and effective application of dengue vector control. When coordinating public health responses during a syndemic, it is important to monitor multiple infections and understand that an intervention against one disease may exacerbate another.
Public perceptions of non-adherence to COVID-19 measures by self and others in the United Kingdom
Authors: Williams Simon N , Armitage Christopher J. , Tampe Tova , Dienes Kimberly
Published: November 2020

OBJECTIVE

To explore the perceptions of non-adherence to COVID-19 policy measures by self and others in the UK, focusing on perceived reasons for non-adherence.

DESIGN

Qualitative study comprising 12 online focus groups conducted between 25th September and 13th November 2020.

SETTING

Online video-conferencing

PARTICIPANTS

51 UK residents aged 18 and above, reflecting a range of ages, genders and race/ethnicities.

RESULTS

Participants reported seeing an increase in non-adherence in others and identified a number of challenges to their own adherence to measures. Thematic analysis identified six main themes related to participants’ reported reasons for non-adherence in self and others: (1) Alert fatigue (2) Inconsistent rules (3) Lack of trust in government (4) Helplessness (5) Resistance and rebelliousness (6) Reduced perception of risk and the prospect of a vaccine. Participants also raised concerns that adherence would be impacted by a desire to socialise over Christmas. Two forms of non-adherence were observed: overt rule- breaking and subjective rule interpretation.

CONCLUSIONS

Adherence may be improved by: less frequent and clearer information on COVID-19 to reduce alert fatigue; implementing a more unified set of measures within and across countries in the UK; role modelling good adherence by authority figures; exploring ways to mitigate the impact that events like Christmas vaccine ‘breakthroughs’ may have on reducing adherence.
Fighting COVID-19 with Flexible Testing: Models and Insights
Authors: Yu Jiali , Shen Zuo-Jun (Max)
Published: November 2020

Increasing testing capacities plays a substantial role in safely reopening the economy and avoiding a new wave of COVID-19. Pooled testing can expand testing capabilities by pooling multiple individual samples, but it also raises accuracy concerns. In this study, we propose a flexible testing strategy that adopts pooled testing or individual testing according to epidemic dynamics. We identify the prevalence threshold between individual and pooled testing by modeling the expected number of tests per confirmed case. Incorporating an epidemic model, we show pooled testing is more effective in containing epidemic outbreaks and can generate more reliable test results than individual testing because the reliability of test results is relevant to both testing methods and prevalence. Our study is the first to evaluate the interplay between pooled testing and a rapidly evolving outbreak to the best of our knowledge. Our results allay accuracy concerns about pooled testing and provide theoretical supports to empirical studies.
Estimating COVID-19 Virus Prevalence from Records of Testing Rate and Test Positivity
Authors: Everts Arnout JW
Published: November 2020

Introduction

PCR testing for COVID-19 is not done at random but selectively on suspected cases. This paper presents a method to estimate a “genuine Virus Prevalence” by quantifying and removing the bias related to selective testing.

Methods

Data used are from nine (9) neighbouring countries in Western Europe that record similar epidemic trends despite differences in Testing Rate. Regression analysis is used to establish a relationship of declining Test Positivity with increased Testing Rate. By extrapolating this trend to an “infinitely complete” Testing Rate, an unbiased Test Positivity or “genuine Virus Prevalence” is computed. Via pairing of “genuine Virus Prevalence” with Excess-Deaths, a “genuine Infection Fatality Rate (IFR) is also derived.

Results

Peak levels of “genuine Virus Prevalence” were around 0.5 to 2% during the 1st epidemic “wave” (week 10 to week 20) and are approaching similar levels in the ongoing 2nd “wave” (week 34 onward). “Genuine Virus Prevalence” estimates are close to reported Seroprevalence in the studied countries with a correlation coefficient of 0.58. “Genuine” IFR is found comparable to closed-community model IFR. Finally, results of community mass-testing in Slovakia are within the estimated range of “genuine Virus Prevalence”.

Conclusions

Estimates of “genuine Virus Prevalence” benchmark favourably to other indications of virus prevalence suggesting the estimation method is robust and potentially deployable beyond this initial dataset of countries. “Genuine Virus Prevalence” curves suggest that during the 1st epidemic “wave”, curve flattening and waning happened at very modest levels of infection spread, either naturally or facilitated by government measures.
Sustained expression of inflammatory monocytes and activated T cells in COVID-19 patients and recovered convalescent plasma donors
Authors: Singh Ravinder , Bajpai Meenu , Yadav Pushpa , Maheshwari Ashish Kumar , Kumar Suresh , Agrawal Sonal , Kumar Jayesh , Md Islam , Mars Jaswinder Singh , Ramakrishna Gayatri , Sarin Shiv K , Trehanpati Nirupma
Published: November 2020

Intense monocyte activation and infiltration into the target tissues is the main mechanism of lung injury in SARS CoV2 infection. A reduction in the degree and nature of such cellular responses is expected following recovery. We aimed to investigate the immune responses in severe Covid-19 patients and recovered patients.

Methods

Severe COVID-19 patients (n=34) at Lok Nayak Hospital, New Delhi and COVID-19 recovered patients (n=15) from mild disease and considered for convalescent plasma (COPLA) donation at Institute of Liver and Biliary Sciences (ILBS), New Delhi were recruited. We performed a multiplex cytokine bead assay in plasma and detailed multicolour flow cytometric analysis in peripheral blood of both groups and outcomes were compared in both groups and with healthy controls (n=10).

Results

A significant increase in inflammatory markers [MIP1-a, MIP3a, MCP1, MIF, MMP12, ITAC, VEGF-A, and leptin] was observed in severe patients. Non-survivors additionally showed increased IL-6 levels. Despite the sustained expression of MIPs, the recovered patients showed a surge in MCSF and IL-18 levels. Both the groups had increased CCR2, CX3CR1 positive monocytes, low CD8 T cells, APRIL and BAFFR+ve B cells compared with healthy subjects. In conclusion, patients who have recovered and considered for COPLA donations still have compromised immunity with sustained expression of inflammatory monocytes and activated T cells.
Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites -Trichuris muris,Brugia malayi,Heligmosomoides polygyrusandSchistosoma mansoni
Authors: Partridge Frederick A , Bataille Carole JR , Forman Ruth , Marriott Amy E , Forde-Thomas Josephine , Häberli Cécile , Dinsdale Ria L , O’Sullivan James DB , Willis Nicky J , Wynne Graham M , Whiteland Helen , Archer John , Steven Andrew , Keiser Jennifer , Turner Joseph D , Hoffmann Karl F , Taylor Mark J , Else Kathryn J , Russell Angela J , Sattelle David B
Published: November 2020

Nine hundred million people are infected with the soil-transmitted helminthsAscaris lumbricoides(roundworm), hookworm, andTrichuris trichiura(whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility ofex vivo Trichuris muris.Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity againstBrugia malayiandHeligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematodeSchistosoma mansoni,a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.

Author summary

Around a billion people are infected by the soil transmitted helminthsAscaris,hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and againstSchistosoma mansoni,a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.
SEMITONES: Single-cEll Marker IdentificaTiON by Enrichment Scoring
Authors: Vlot Anna Hendrika Cornelia , Maghsudi Setareh , Ohler Uwe
Published: November 2020

Identification of markers is an essential step in single-cell analytic. Current marker identification strategies typically rely on cluster assignments of cells. Cluster assignment, in particular of development data, is non-trivial, potentially arbitrary and commonly relies on prior knowledge. Yet, cluster uncertainty is not commonly taken into account. In response, we present SEMITONES, a principled method for cluster-free marker identification. We showcase its application on healthy haematopoiesis data as 1) a robust alternative to highly variable gene selection, 2) for marker gene and regulatory region identification, and 3) for the construction of co-enrichment networks that reveal regulators of cell identity.
A Hybrid Cellular-Heterogeneous Catalyst Strategy for the Production of Olefins from Glucose
Authors: Wang Zhen Q. , Song Heng , Hara Noritaka , Park Dae Sung , Kumar Gaurav , Min Yejin , Dauenhauer Paul J. , Chang Michelle C. Y.
Published: November 2020

Living systems provide a promising approach to chemical synthesis, having been optimized by evolution to convert renewable carbon sources such as glucose to an enormous range of small molecules. However, a large number of synthetic structures can still be difficult to obtain solely from cells, such as unsubstituted hydrocarbons. In this work, we demonstrate the use of a hybrid cellular-heterogeneous catalytic strategy to produce olefins from glucose, using a selective hydrolase to generate an activated intermediate that is readily deoxygenated. Using a new family of iterative thiolase enzymes, we have genetically engineered a microbial strain that produces 4.3 ± 0.4 g L−1of fatty acid from glucose with 86% captured as 3-hydroxyoctanoic and 3-hydroxydecanoic acids. This 3-hydroxy substituent serves as a leaving group enabling heterogeneous tandem decarboxylation-dehydration routes to olefinic products on Lewis acidic catalysts without the additional redox input required for enzymatic or chemical deoxygenation of simple fatty acids.
The human cytomegalovirus protein UL116 interacts with the viral ER resident glycoprotein UL148 and promotes the incorporation of gH/gL complexes into virions
Authors: Siddiquey Mohammed N.A. , Schultz Eric P. , Yu Qin , Amendola Diego , Vezzani Giacomo , Yu Dong , Maione Domenico , Lanchy Jean-Marc , Ryckman Brent J. , Merola Marcello , Kamil Jeremy P.
Published: November 2020

Heterodimers of glycoproteins H (gH) and L (gL) comprise a basal element of the viral membrane fusion machinery conserved across herpesviruses. In human cytomegalovirus (HCMV), a glycoprotein encoded byUL116noncovalently assembles onto gH at a position similar to that occupied by gL, forming a heterodimer that is incorporated into virions. However, physiological roles for UL116 or its complex with gH remain to be identified. Here, we show that UL116 promotes the expression of gH/gL complexes and is required for the efficient production of infectious cell-free virions.UL116-nullmutants show a 10-fold defect in production of infectious cell-free virions from infected fibroblasts and epithelial cells. This defect is accompanied by reduced expression of the two disulfide-linked gH/gL complexes that play crucial roles in viral entry: the heterotrimer of gH/gL with glycoprotein O (gO) and the pentameric complex of gH/gL with UL128, UL130, and UL131. Furthermore, gH/UL116 complexes comprise a substantial constituent of virions since an abundant gH species not covalently linked to other glycoproteins, which has long been observed in the literature, is readily detected from wild-type but notUL116-nullvirions.

Interestingly, UL116 co-immunoprecipitates with UL148, a viral ER resident glycoprotein previously shown to attenuate ER-associated degradation (ERAD) of gO, and we observe elevated levels of UL116 inUL148-nullvirions.

Collectively, our findings suggest that UL116 may serve as a chaperone for gH to support the assembly, maturation, and incorporation of gH/gL complexes into virions.

IMPORTANCE

HCMV is a betaherpesvirus that causes dangerous opportunistic infections in immunocompromised patients, as well as in the immune-naive fetus and preterm infants. The potential of the virus to enter new host cells is governed in large part by two alternative viral glycoprotein H (gH) / glycoprotein L (gL) complexes that play important roles in entry: gH/gL/gO and gH/gL/UL128-131. A recently identified virion gH complex, comprised of gH bound to UL116, adds a new layer of complexity to the mechanisms that contribute to HCMV infectivity. Here, we show that UL116 promotes the expression of gH/gL complexes, and that UL116 interacts with the viral ER-resident glycoprotein UL148, a factor that supports the expression of gH/gL/gO. Overall, our results suggest that UL116 is a chaperone for gH. These findings have important implications for understanding of HCMV cell tropism as well as for the development of vaccines against the virus.
Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis
Authors: Xu Jian , Converse Paul J. , Upton Anna M. , Mdluli Khisimuzi , Fotouhi Nader , Nuermberger Eric L.
Published: November 2020

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations inRv0678that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greaterin vitropotency than BDQ, including againstRv0678mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-typeM. tuberculosisH37Rv and an isogenicRv0678mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.
Regular universal screening for SARS-CoV-2 infection may not allow reopening of society after controlling a pandemic wave
Authors: Bootsma MCJ , Kretzschmar ME , Rozhnova G , Heesterbeek JAP , Kluytmans JAJW , Bonten MJM
Published: November 2020

Background

To limit societal and economic costs of lockdown measures, public health strategies are needed that control the spread of SARS-CoV-2 and simultaneously allow lifting of disruptive measures. Regular universal random screening of large proportions of the population regardless of symptoms has been proposed as a possible control strategy.

Methods

We developed a mathematical model that includes test sensitivity depending on infectiousness for PCR-based and antigen-based tests, and different levels of onward transmission for testing and non-testing parts of the population. Only testing individuals participate in high-risk transmission events, allowing more transmission in case of unnoticed infection. We calculated the required testing interval and coverage to bring the effective reproduction number due to universal random testing (Rrt) below 1, for different scenarios of risk behavior of testing and non-testing individuals.

Findings

With R0 = 2.5, lifting all control measures for tested subjects with negative test results would require 100% of the population being tested every three days with a rapid test method with similar sensitivity as PCR-based tests. With remaining measures in place reflecting Re = 1.3, 80% of the population would need to be tested once a week to bring Rrt below 1. With lower proportions tested and with lower test sensitivity, testing frequency should increase further to bring Rrt below 1. With similar Re values for tested and non-tested subjects, and with tested subjects not allowed to engage in higher risk events, at least 80% of the populations needs to test every five days to bring Rrt below. The impact of the test-sensitivity on the reproduction number is far less than the frequency of testing.

Interpretation

Regular universal random screening followed by isolation of infectious individuals is not a viable strategy to reopen society after controlling a pandemic wave of SARS-CoV-2. More targeted screening approaches are needed to better use rapid testing such that it can effectively complement other control measures.

Funding

RECOVER (H2020-101003589) (MJMB), ZonMw project 10430022010001 (MK, HH), FCT project 131_596787873 (GR). ZonMw project 91216062 (MK)
Salivary CGRP as diagnostic and migraine attack phase monitor biomarker: CGRP (in)dependent attacks
Authors: Alpuente Alicia , Gallardo Victor J , Asskour Laila , Caronna Edoardo , Torres-Ferrus Marta , Pozo-Rosich Patricia
Published: November 2020

Objective

To assess saliva as a substrate to measure CGRP by comparing interictal levels of CGRP in patients with episodic migraine and controls; and to evaluate saliva CGRP temporal profile during migraine attacks.

Methods

This prospective observational study included women with episodic migraine and healthy controls. Participants collected daily saliva samples for 30 consecutive days and 3 additional ones during migraine attacks. 4 timepoints were considered: interictal (72h headache-free), preictal (PRE-24h before the attack), ictal (0h,2h,8h), postictal (POST-24h after the attack). CGRP levels were quantified by ELISA.

Results

35 women (22 patients, 13 controls) were included. Statistically significant differences were found in interictal salivary levels of CGRP between patients and controls (median[IQR]: 98.0 [86.7] vs. 42.2 [44.7] pg/mL; p=0.010). An increase in CGRP levels during migraine attacks was detected (median[IQR]: preictal 113.5 [137.8], 0h 164.6 [204.5], 2h 101.7 [159.1], 8h 82.6 [166.2], postictal 79.6 [124.3] pg/ml; p<0.001). Patients were classified as having CGRP-dependent (80.0%) and non-CGRP dependent migraine attacks (20.0%) according to the magnitude of change between preictal and ictal phase (0h). Accompanying symptoms were different depending on the type of attack. In the longitudinal analysis, we observed that the amount of CGRP measured during attacks were phase dependent and it was influenced by the frequency of monthly headache days (p=0.02).

Interpretation

Patients with episodic migraine have higher interictal salivary levels of CGRP than controls. These levels usually increase during a migraine attack, however, not every attack is CGRP-dependent, which in turn, might explain different underline pathophysiology and response to acute and preventive treatment.
Biomarkers of lesion severity in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION)
Authors: Guo Yan , Mehrabian Zara , Johnson Mary A. , Miller Neil R. , Henderson Amanda D. , Hamlyn John , Bernstein Steven L.
Published: November 2020

The rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION) is similar in many of its pathophysiological responses to clinical NAION. However, little is known of the parameters associated with rNAION induction severity and if pre- or early post-induction biomarkers can be identified that enable prediction of lesion severity and ultimate loss of retinal ganglion cells (RGCs). Adult male Sprague-Dawley outbred rats were evaluated for various parameters including physiological characteristics (heart rate, respiratory rate, temperature, hematocrit), optic nerve head (ONH) appearance, pre- and post-induction mean diameter, and intravenous fluorescein and indocyanine green angiographic patterns of vascular leakage at 5 hours post-induction, performed using a spectral domain-optical coherence tomography (SD-OCT) instrument. These parameters were correlated with ultimate RGC loss by Brn3a (+) immunohistology. RGC loss also was correlated with the relative level of laser exposure. The severity of ONH edema 2d, but not 5hr, post induction was most closely associated with the degree of RGC loss, revealing a threshold effect, and consistent with a compartment syndrome where a minimum level of capillary compression within a tight space is responsible for damage. RGC loss increased dramatically as the degree of laser exposure increased. Neither physiological parameters nor the degree of capillary leakage 5hr post induction were informative as to the ultimate degree of RGC loss. Similar to human NAION, the rNAION model exhibits marked variability in lesion severity. Unlike clinical NAION, pre-induction ONH diameter likely does not contribute to ultimate lesion severity; however, cross-sectional ONH edema can be used as a biomarker 1-2d post-induction to determine randomization of subjects prior to inclusion in specific neuroprotection or neuroregeneration studies.
Everything you wanted to know about Mayaro virus but were afraid to ask: Characterization and lifecycle of Mayaro virus in vertebrate and invertebrate cellular backgrounds
Authors: Pujhari Sujit , Brustolin Marco , Heu Chan C. , Smithwick Ronald , Larrosa Mireia , Hafenstein Susan , Rasgon Jason L.
Published: November 2020

Mayaro virus (MAYV) is an emerging new world alphavirus (genusAlphavirus, familyTogaviridae)that causes acute multiphasic febrile illness, skin rash, polyarthritis, and occasional severe clinical phenotypes. The virus lifecycle alternates between invertebrate and vertebrate hosts. Here we characterize the replication features, cell entry, life cycle, and virus-related cell pathology of MAYV using vertebrate and invertebratein vitromodels. Electron dense clathrin-coated pits in infected cells, and reduced viral production in the presence of dynasore, ammonium chloride, and bafilomycin, indicates that viral entry occurs through pH-dependent endocytosis. Increase in FITC-dextran uptake (an indicator of macropinocytosis) in MAYV-infected cells, and dose-dependent infection inhibition by 5-(N-ethyl-N-isopropyl) amiloride (a macropinocytosis inhibitor), indicated that macropinocytosis is an additional entry mechanism of MAYV in vertebrate cells. Acutely infected vertebrate and invertebrate cells formed cytoplasmic or membrane-associated extracytoplasmic replication complexes. Mosquito cells showed modified hybrid cytoplasmic vesicles that supported virus replication, nucleocapsid production, and maturation. Mature virus particles were released from cells by both exocytosis and budding from the cell membrane. MAYV replication was cytopathic and associated with induction of apoptosis by the intrinsic pathway, and later by the extrinsic pathway in infected vertebrate cells. Given that MAYV is expanding its geographical existence as a potential public health problem, this study lays the foundation of biological understanding valuable for therapeutic and preventive interventions.