bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronavirus Disease 2019 (COVID-19) Transmission in the United States Before Versus After Relaxation of Statewide Social Distancing Measures
Authors: Tsai Alexander C , Harling Guy , Reynolds Zahra , Gilbert Rebecca F , Siedner Mark J
Published: September 2020

Background

Weeks after issuing social distancing orders to suppress severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and reduce growth in cases of severe coronavirus disease 2019 (COVID-19), all US states and the District of Columbia partially or fully relaxed these measures.

Methods

We identified all statewide social distancing measures that were implemented and/or relaxed in the United States between 10 March and 15 July 2020, triangulating data from state government and third-party sources. Using segmented linear regression, we estimated the extent to which relaxation of social distancing affected epidemic control, as indicated by the time-varying, state-specific effective reproduction number (Rt).

Results

In the 8 weeks prior to relaxation, mean Rt declined by 0.012 units per day (95% confidence interval [CI], −.013 to −.012), and 46/51 jurisdictions achieved Rt < 1.0 by the date of relaxation. After relaxation of social distancing, Rt reversed course and began increasing by 0.007 units per day (95% CI, .006–.007), reaching a mean Rt of 1.16. Eight weeks later, the mean Rt was 1.16 and only 9/51 jurisdictions were maintaining an Rt < 1.0. Parallel models showed similar reversals in the growth of COVID-19 cases and deaths. Indicators often used to motivate relaxation at the time of relaxation (eg, test positivity rate <5%) predicted greater postrelaxation epidemic growth.

Conclusions

We detected an immediate and significant reversal in SARS-CoV-2 epidemic suppression after relaxation of social distancing measures across the United States. Premature relaxation of social distancing measures undermined the country’s ability to control the disease burden associated with COVID-19.
Estrogen Deficiency and Colonic Function: Surgical Menopause and Sex Differences in Angiotensin and Dopamine Receptor Interaction
Authors: Garrido-Gil Pablo , Rodriguez-Perez Ana I , Lage Lucia , Labandeira-Garcia Jose L
Published: September 2020

The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin–angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin–angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.
National Profiles of Coronavirus Disease 2019 Mortality Risks by Age Structure and Preexisting Health Conditions
Authors: Verdery Ashton M , Newmyer Lauren , Wagner Brandon , Margolis Rachel
Published: September 2020

Background and Objectives

Although individual age and preexisting health conditions are well-documented risk factors for coronavirus disease 2019 (COVID-19) mortality, it is unclear whether these 2 factors capture unique dimensions of risk for epidemic severity at the national level. In addition, no studies have examined whether national distributions of these factors are associated with epidemic experiences to date.

Research Design and Methods

Drawing on surveys of older adults from 42 countries and estimated case fatality ratios by age and preexisting health conditions, we document and compare national profiles of COVID-19 mortality risks among older adults. We develop 2 measures of national risk profiles: one based on age structures and another based on distributions of preexisting health conditions. Our analysis compares these constructs and documents their associations with national COVID-19 mortality rates.

Results

National profiles of COVID-19 mortality risk based on age structure and preexisting health conditions are moderately uncorrelated, capturing different aspects of risk. Both types of national risk profiles correlate meaningfully with countries’ COVID-19 mortality experiences to date.

Discussion and Implications

Measures of population age structure are readily available for every country in the world, while cross-national measures of older adult population health are more limited. In the COVID-19 crisis, these factors give different pictures of the countries with high and low risks of COVID-19 mortality. Moreover, our results suggest that both types of national risk profiles based on population health reflect current COVID-19 mortality severity in several countries, highlighting the need for more cross-national comparative data on older adult population health.
The Limit Point of the Pentagram Map and Infinitesimal Monodromy
Authors: Aboud Quinton , Izosimov Anton
Published: September 2020

The pentagram map takes a planar polygon $P$ to a polygon $P^{\prime }$ whose vertices are the intersection points of the consecutive shortest diagonals of $P$. The orbit of a convex polygon under this map is a sequence of polygons that converges exponentially to a point. Furthermore, as recently proved by Glick, coordinates of that limit point can be computed as an eigenvector of a certain operator associated with the polygon. In the present paper, we show that Glick’s operator can be interpreted as the infinitesimal monodromy of the polygon. Namely, there exists a certain natural infinitesimal perturbation of a polygon, which is again a polygon but in general not closed; what Glick’s operator measures is the extent to which this perturbed polygon does not close up.
A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting
Authors: Hicks Sarah M , Pohl Kai , Neeman Teresa , McNamara Hayley A , Parsons Kate M , He Jin-shu , Ali Sidra A , Nazir Samina , Rowntree Louise C , Nguyen Thi H O , Kedzierska Katherine , Doolan Denise L , Vinuesa Carola G , Cook Matthew C , Coatsworth Nicholas , Myles Paul S , Kurth Florian , Sander Leif E , Mann Graham J , Gruen Russell L , George Amee J , Gardiner Elizabeth E , Cockburn Ian A ,   SARS-CoV-2 Testing in Elective Surgery Collaborators
Published: September 2020

Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been hampered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay–based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0–1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Translating an evidence-based clinical pathway into shareable CDS: developing a systematic process using publicly available tools
Authors: Michel Jeremy J , Flores Emilia J , Dutcher Lauren , Mull Nikhil K , Tsou Amy Y
Published: September 2020

Objective

To develop a process for translating semi-structured clinical decision support (CDS) into shareable, computer-readable CDS.

Materials and Methods

We developed a systematic and transparent process using publicly available tools (eGLIA, GEM Cutter, VSAC, and the CDS Authoring Tool) to translate an evidence-based clinical pathway (CP) into a Clinical Quality Language (CQL)-encoded CDS artifact.

Results

We produced a 4-phase process for translating a CP into a CQL-based CDS artifact. CP content was extracted using GEM into discrete clinical concepts, encoded using standard terminologies into value sets on VSAC, evaluated against workflows using a wireframe, and finally structured as a computer readable CDS artifact using CQL. This process included a quality control step and intermediate products to support transparency and reuse by other CDS developers.

Discussion

Translating a CP into a shareable, computer-readable CDS artifact was accomplished through a systematic process. Our process identified areas of ambiguity and gaps in the CP, which generated improvements in the CP. Collaboration with clinical subject experts and the CP development team was essential for translation. Publicly available tools were sufficient to support most translation steps, but expression of certain complex concepts required manual encoding.

Conclusion

Standardized development of CDS from a CP is feasible using a systematic 4-phase process. CPs represent a potential reservoir for developers of evidence-based CDS. Aspects of CP development simplified portions of the CDS translation process. Publicly available tools can facilitate CDS development; however, enhanced tool features are needed to model complex CDS statements.
Validation Study of BioSystems® Y15 Histamine Dehydrogenase Kit for the Detection of Histamine in Fish and Fishery Products: AOAC Performance Tested MethodSM 072001
Authors: Tobeña Andreu , Dueñas Sabina , Boix Mercè
Published: September 2020

Background

BioSystems has developed a histamine kit for automated procedure, through the use of a Y15 analyzer, for quantification of histamine in fish and fishery products.

Objective

Validate the method under the specific guidelines of the AOAC Research Institute Performance Tested MethodSM (PTM) program.

Method

Samples are extracted with boiling water. The enzymatic method is based on histamine dehydrogenase that catalyzes the oxidation of histamine in the presence of an electron mediator that reduces a dye that is measured at 420 nm. The increase of absorbance is proportional to the histamine concentration. Dispensing of reagents and sample, absorbance readings, calibration, and calculation of results are performed automatically in the analyzer BioSystems Y15.

Results

The linearity ranges from 0 to 200 mg/kg (r2 > 0.99). The LOQ is 10 mg/kg in all the matrixes. Recoveries range from 75 to 107% at concentrations from 5 to 200 mg/kg, with repeatability precision values between 0.8 and 5.5%. Comparisons with the HPLC reference method shows a good correlation. Cross-reactivity of the assay is negligible for all biogenic amines tested except for agmatine (6.3%). Product consistency was verified by validating lot-to-lot variations and variations within the same lot. Shelf life was verified by real-time stability testing during 40 months at 2–8°C. No differences in histamine detection were observed in robustness testing, in which minor changes are introduced to the assay protocol.

Conclusions

The automated, simple, and rapid BioSystems Y15 Histamine Dehydrogenase Kit has been successfully validated.

Highlights

The method is qualified for PTM certification No. 072001.
Insights into the Decontamination of Cocaine-Positive Hair Samples
Authors: Erne Robert , Baumgartner Markus R , Kraemer Thomas
Published: September 2020

A highly discussed step in hair sample preparation for forensic analytics is the applied decontamination. The here presented investigations aim to gain insight and give recommendations on how to conduct this decontamination for the analysis of cocaine consumption in hair. Key insights were gained from the investigation of cocaine consumer hair, which was artificially contaminated in a humid atmosphere with 13C6 labelled cocaine and from cocaine powder contaminated hair. Several decontamination protocols were investigated, whereby the usage of a decontamination protocol consisting of multiple short repetitive washes allowed to visualize the wash out of (13C6-) cocaine. Multiple methanol washes proved to be an efficient and simple decontamination approach. Our findings showed that decontamination protocols can successfully wash out recent cocaine contaminations. They were observed to be rather quickly washed out, whereas cocaine from consumption or “older” cocaine contaminations were shown to eliminate both at a constant rate (from inner hair compartments). Thus, the usage of decontamination protocols to differentiate between consumption and contamination was shown to be limited. As contamination can happen any time at any level, only the application of elaborated decision trees, based on cocaine metabolite ratios and thresholds, can provide the distinction between consumption and contamination. Thus, the authors highly recommend the usage of such tools on all hair samples analyzed for cocaine consumption.
A histone H4 gene prevents drought-induced bolting in Chinese cabbage by attenuating the expression of flowering genes
Authors: Xin Xiaoyun , Su Tongbing , Li Peirong , Wang Weihong , Zhao Xiuyun , Yu Yangjun , Zhang Deshuang , Yu Shuancang , Zhang Fenglan
Published: September 2020

Flowering is an important trait in Chinese cabbage, because premature flowering reduces yield and quality of the harvested products. Water deficit, caused by drought or other environmental conditions, induces early flowering. Drought resistance involves global reprogramming of transcription, hormone signaling, and chromatin modification. We show that a histone H4 protein, BrHIS4.A04, physically interacts with a homeodomain protein BrVIN3.1, which was selected during the domestication of late-bolting Chinese cabbage. Over-expression of BrHIS4.A04 resulted in premature flowering under normal growth conditions, but prevented further premature bolting in response to drought. We show that the expression of key abscisic acid (ABA) signaling genes, and also photoperiodic flowering genes was attenuated in BrHIS4.A04-overexpressing (BrHIS4.A04OE) plants under drought conditions. Furthermore, the relative change in H4-acetylation at these gene loci was reduced in BrHIS4.A04OE plants. We suggest that BrHIS4.A04 prevents premature bolting by attenuating the expression of photoperiodic flowering genes under drought conditions, through the ABA signaling pathway. Since BrHIS4.A04OE plants displayed no phenotype related to vegetative or reproductive development under laboratory-induced drought conditions, our findings contribute to the potential fine-tuning of flowering time in crops through genetic engineering without any growth penalty, although more data are necessary under field drought conditions.
Swift-XRT follow-up of gravitational wave triggers during the third aLIGO/Virgo observing run
Authors: Page K L , Evans P A , Tohuvavohu A , Kennea J A , Klingler N J , Cenko S B , Oates S R , Ambrosi E , Barthelmy S D , Beardmore A P , Bernardini M G , Breeveld A A , Brown P J , Burrows D N , Campana S , Caputo R , Cusumano G , D’Aì A , D’Avanzo P , D’Elia V , De Pasquale M , Emery S W K , Giommi P , Gronwall C , Hartmann D H , Krimm H A , Kuin N P M , Malesani D B , Marshall F E , Melandri A , Nousek J A , O’Brien P T , Osborne J P , Pagani C , Page M J , Palmer D M , Perri M , Racusin J L , Sakamoto T , Sbarufatti B , Schlieder J E , Siegel M H , Tagliaferri G , Troja E
Published: September 2020

The Neil Gehrels Swift Observatory followed up 18 gravitational wave (GW) triggers from the LIGO/Virgo collaboration during the O3 observing run in 2019/2020, performing approximately 6500 pointings in total. Of these events, four were finally classified (if real) as binary black hole (BH) triggers, six as binary neutron star (NS) events, two each of NSBH and Mass Gap triggers, one an unmodelled (Burst) trigger, and the remaining three were subsequently retracted. Thus far, four of these O3 triggers have been formally confirmed as real gravitational wave events. While no likely electromagnetic counterparts to any of these GW events have been identified in the X-ray data (to an average upper limit of 3.60 × 10−12 erg cm−2 s−1 over 0.3–10 keV), or at other wavelengths, we present a summary of all the Swift-XRT observations performed during O3, together with typical upper limits for each trigger observed. The majority of X-ray sources detected during O3 were previously uncatalogued; while some of these will be new (transient) sources, others are simply too faint to have been detected by earlier survey missions such as ROSAT. The all-sky survey currently being performed by eROSITA will be a very useful comparison for future observing runs, reducing the number of apparent candidate X-ray counterparts by up to 95 per cent.
A novel xeno-organoid approach: exploring the crosstalk between human iPSC-derived PGC-like and rat testicular cells
Authors: Mall E M , Rotte N , Yoon J , Sandhowe-Klaverkamp R , Röpke A , Wistuba J , Hübner K , Schöler H R , Schlatt S
Published: September 2020

Specification of germ cell-like cells from induced pluripotent stem cells has become a clinically relevant tool for research. Research on initial embryonic processes is often limited by the access to foetal tissue, and in humans, the molecular events resulting in primordial germ cell (PGC) specification and sex determination remain to be elucidated. A deeper understanding of the underlying processes is crucial to describe pathomechanisms leading to impaired reproductive function. Several protocols have been established for the specification of human pluripotent stem cell towards early PGC-like cells (PGCLC), currently representing the best model to mimic early human germline developmental processes in vitro. Further sex determination towards the male lineage depends on somatic gonadal cells providing the necessary molecular cues. By establishing a culture system characterized by the re-organization of somatic cells from postnatal rat testes into cord-like structures and optimizing efficient PGCLC specification protocols, we facilitated the co-culture of human germ cell-like cells within a surrogate testicular microenvironment. Specified conditions allowed the survival of rat somatic testicular and human PGCLCs for 14 days. Human cells maintained the characteristic expression of octamer-binding transcription factor 4, SRY-box transcription factor 17, and transcription factor AP-2 gamma and were recovered from the xeno-organoids by cell sorting. This novel xeno-organoid approach will allow the in vitro exploration of early sex determination of human PGCLCs.
Stable gene expression for normalisation and single-sample scoring
Authors: Bhuva Dharmesh D , Cursons Joseph , Davis Melissa J
Published: September 2020

Gene expression signatures have been critical in defining the molecular phenotypes of cells, tissues, and patient samples. Their most notable and widespread clinical application is stratification of breast cancer patients into molecular (PAM50) subtypes. The cost and relatively large amounts of fresh starting material required for whole-transcriptome sequencing has limited clinical application of thousands of existing gene signatures captured in repositories such as the Molecular Signature Database. We identified genes with stable expression across a range of abundances, and with a preserved relative ordering across thousands of samples, allowing signature scoring and supporting general data normalisation for transcriptomic data. Our new method, stingscore, quantifies and summarises relative expression levels of signature genes from individual samples through the inclusion of these ‘stably-expressed genes’. We show that our list of stable genes has better stability across cancer and normal tissue data than previously proposed gene sets. Additionally, we show that signature scores computed from targeted transcript measurements using stingscore can predict docetaxel response in breast cancer patients. This new approach to gene expression signature analysis will facilitate the development of panel-type tests for gene expression signatures, thus supporting clinical translation of the powerful insights gained from cancer transcriptomic studies.
DualSeqDB: the host–pathogen dual RNA sequencing database for infection processes
Authors: Macho Rendón Javier , Lang Benjamin , Ramos Llorens Marc , Gaetano Tartaglia Gian , Torrent Burgas Marc
Published: September 2020

Despite antibiotic resistance being a matter of growing concern worldwide, the bacterial mechanisms of pathogenesis remain underexplored, restraining our ability to develop new antimicrobials. The rise of high-throughput sequencing technology has made available a massive amount of transcriptomic data that could help elucidate the mechanisms underlying bacterial infection. Here, we introduce the DualSeqDB database, a resource that helps the identification of gene transcriptional changes in both pathogenic bacteria and their natural hosts upon infection. DualSeqDB comprises nearly 300 000 entries from eight different studies, with information on bacterial and host differential gene expression under in vivo and in vitro conditions. Expression data values were calculated entirely from raw data and analyzed through a standardized pipeline to ensure consistency between different studies. It includes information on seven different strains of pathogenic bacteria and a variety of cell types and tissues in Homo sapiens, Mus musculus and Macaca fascicularis at different time points. We envisage that DualSeqDB can help the research community in the systematic characterization of genes involved in host infection and help the development and tailoring of new molecules against infectious diseases. DualSeqDB is freely available at http://www.tartaglialab.com/dualseq.
THE INFLUENCE OF PINHOLES IN WATERPROOFING MATERIALS ON THE VALUE OF THE RADON DIFFUSION COEFFICIENT
Authors: Dobrovolný T , Jiránek M , Krejsová J
Published: September 2020

This article focuses on an experimental study of the influence of imperfections on the value of the radon diffusion coefficient of various waterproofing materials. Microscopic holes were made by a thin tip or by a microdrill bit to imitate the real damage that can be incurred during construction. To determine the change in the radon diffusion coefficient, each waterproofing material was measured five times. The first measurement was performed on undamaged samples, while the following measurements were performed on samples with one, two, four and eight pinholes. The radon diffusion coefficient was measured under nonstationary conditions, because homemade radon sources with a slow rate of radon emanation were used. The radon diffusion coefficients identified in the study were compared according to the thickness of the material and the number and the size of the pinholes. The exact shape and size of the imperfections were documented by an electron microscope.
2019 Pathway Award® winner
Authors: Rawlins Caitlin , Dans Maricon
Published: September 2020

Pathway to Excellence® standards promote virtual reality innovation at the Charles George VA Medical Center
Efficacy of Pembrolizumab Monotherapy in Patients With or Without Brain Metastases From Advanced Non–Small Cell Lung Cancer With a PD-L1 Expression ≥50%
Authors: Metro Giulio , Banna Giuseppe Luigi , Signorelli Diego , Gili Alessio , Galetta Domenico , Galli Giulia , Economopoulou Panagiota , Roila Fausto , Friedlaender Alex , Camerini Andrea , Christopoulou Athina , Cantale Ornella , De Toma Alessandro , Pizzutilo Pamela , Jimenez Beatriz , Collazo-Lorduy Ana , Calles Antonio , Baxevanos Panagiotis , Linardou Helena , Kosmidis Paris , Giannarelli Diana , Mountzios Giannis , Addeo Alfredo
Published: September 2020

The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non–small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.7% and 10.2% in patients with and without brain metastases, respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (P<0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (P<0.001) and OS (P<0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non–small cell lung cancers with programmed death-ligand 1≥50%. Presence of brain metastases per se does not appear to be prognostic, and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.
The prevalence of hypoactive sexual desire disorder in Australian and Iranian women at midlife
Authors: Fooladi Ensieh , Islam Rakibul M. , Bell Robin J. , Robinson Penelope J. , Masoumi Maryam , Davis Susan R.
Published: September 2020

Objective:

This study was undertaken to examine whether the prevalence of low sexual desire, sexually related personal distress, and epidemiological hypoactive sexual desire disorder (eHSDD) differed between midlife Australian and Iranian married women.

Methods:

Cross-sectional, community-based studies of women aged 40 to 65 years conducted in Australia (2013-2014, n = 2,020) and Iran (2016-2017, n = 1,520) included 60% and 89% married women, respectively. Participants completed the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. eHSDD was defined as low desire with sexually related personal distress.

Results:

Restricting the analysis to married women, 76.5% of the 1,210 Australian women, mean age (SD) 52.4 (6.8) years, and 87.8% of the 1,348 Iranian women, mean age 48.5 (6.7) years who were recently sexually active. Low desire was more prevalent in Australian women than Iranian women (68.8%, 95% CI 66.1-71.3 vs 51.3%, 95% CI 48.6-53.9, P < 0.001) as were sexually related personal distress (47.6%, 95% CI 44.8-50.4 vs 17.2%, 95% CI 15.3-19.3, P < 0.001) and eHSDD (39.7%, 95% CI 36.9-42.5 vs 13.9%, 95% CI 12.2-15.9, P < 0.001). Being sexually inactive, versus sexually active, was associated with low desire, sexually related personal distress and eHSDD in Australian women (P < 0.001), but only with low desire in Iranian women (P < 0.001).

Conclusions:

The prevalence of eHSDD in married Australian women at midlife was threefold that of Iranian women, primarily due to the higher prevalence of sexually related personal distress. The results were only adjusted for age and sexual activity, and analyses did not account for other observed differences between the study populations. Hence, future studies are warranted to explore if the differences between the two populations are due to variations in demographics such as level of education or employment and/or due to expectations, experiences, or beliefs.
Ocular leprosy: from bench to bedside
Authors: Bala Murugan Sivaraman , Mahendradas Padmamalini , Dutta Majumder Parthopratim , Kamath Yogish
Published: September 2020

Purpose of review

Ocular manifestations of leprosy do occur despite advances in the areas of leprosy research. Understanding the nuances in the domain shall guide the clinician for effective patient-centered care.

Recent findings

Despite the existence of microbiologic cure for leprosy, ocular manifestations of this disease do occur. Advances in genetic and genomic studies have better characterized the interaction that the bacteria has with the host. The ocular features vary with the spectrum of the disease. Its careful correlation can help to predict the bacillary load of the patient. Investigations are particularly relevant in multibacillary cases. The WHO suggests a treatment duration longer than the 2 years in ocular involvement.

The isolation of lepra bacilli from the iris biopsy in negative skin smear patients and multidrug therapy completion highlights the potential role of bactericidal agents in the planned intraocular treatment. Lepra reactions need careful titration of oral steroids and appropriate antibacterial agents. Advances in phacoemulsification with in the bag implantation of intraocular lenses is a game changer in the management of the most common cause of blindness of leprosy. Advances in vaccine research in leprosy are promising.
Impella 5.5 Versus Centrimag: A Head-to-Head Comparison of Device Hemocompatibility
Authors: Roka-Moiia Yana , Li Mengtang , Ivich Adriana , Muslmani Sami , Kern Karl B. , Slepian Marvin J.
Published: September 2020

Despite growing use of mechanical circulatory support, limitations remain related to hemocompatibility. Here, we performed a head-to-head comparison of the hemocompatibility of a centrifugal cardiac assist system—the Centrimag, with that of the latest generation of an intravascular microaxial system—the Impella 5.5. Specifically, hemolysis, platelet activation, microparticle (MP) generation, and von Willebrand factor (vWF) degradation were evaluated for both devices. Freshly obtained porcine blood was recirculated within device propelled mock loops for 4 hours, and alteration of the hemocompatibility parameters was monitored over time. We found that the Impella 5.5 and Centrimag exhibited low levels of hemolysis, as indicated by minor increase in plasma free hemoglobin. Both devices did not induce platelet degranulation, as no alteration of β-thromboglobulin and P-selectin in plasma occurred, rather minor downregulation of platelet surface P-selectin was detected. Furthermore, blood exposure to shear stress via both Centrimag and Impella 5.5 resulted in a minor decrease of platelet count with associated ejection of procoagulant MPs, and a decrease of vWF functional activity (but not plasma level of vWF-antigen). Greater MP generation was observed with the Centrimag relative to the Impella 5.5. Thus, the Impella 5.5 despite having a lower profile and higher impeller rotational speed demonstrated good and equivalent hemocompatibility, in comparison with the predicate Centrimag, with the advantage of lower generation of MPs.
Understanding Relations Between Intolerance of Uncertainty, Social Anxiety, and Body Dissatisfaction in Women
Authors: Bijsterbosch Jojanneke M. , van den Brink Femke , Vollmann Manja , Boelen Paul A. , Sternheim Lot C.
Published: September 2020

Body dissatisfaction (BD) is highly prevalent among young females and is associated with negative mental health outcomes. Social anxiety (SA) has been identified as an important determinant of BD; however, potential factors underlying SA-related BD remain unstudied. Research indicates that intolerance of uncertainty (IU), the tendency to respond negatively to uncertainty, may be critical for developing and maintaining SA. The current study investigated whether IU is associated with SA and whether SA, in turn, is related to BD. In a cross-sectional study, 139 women completed an online survey measuring IU, SA, and BD. Correlation analyses showed that IU, SA, and BD were strongly positively associated. A mediation analysis revealed that higher levels of IU were indirectly related to more BD through higher levels of SA. A direct effect of IU on BD was also found. These findings suggest that individuals with SA-related BD may benefit from interventions targeting IU.
The small molecule inhibitor PR-619 protects retinal ganglion cells against glutamate excitotoxicity
Authors: Hu Xinxin , Zhuang Dongli , Zhang Rong , Sun Xinghuai , Lu Qinkang , Dai Yi
Published: September 2020

Glutamate excitotoxicity may contribute to the death of retinal ganglion cell (RGC) in glaucoma and other retinal diseases such as ischemia. Deubiquitinating enzyme (DUB) inhibitors are emerging as attractive targets for pharmacological intervention in neurodegenerative diseases. However, the role of PR-619, the broad spectrum DUB inhibitor, on RGCs under different stressful environment remains largely unknown. This study was designed to investigate the role of PR-619 in regulating mitophagy of RGCs under glutamate excitotoxicity. Primary cultured RGCs were incubated with PR-619 or vehicle control in the excitotoxicity model of 100 µM glutamate treatment. Mitochondrial membrane potential was assessed by JC-1 assay. Cytotoxicity of RGCs was measured by LDH activity. Proteins levels of parkin, optineurin, LAMP1, Bax, Bcl-2 and the LC3-II/I ratio were analyzed by western blot. The distribution and morphology of mitochondria in RGCs was stained by MitoTracker and antibody against mitochondria membrane protein, and examined by confocal microscopy. We show here that in the presence of glutamate-induced excitotoxicity, PR-619 stabilized the mitochondrial membrane potential of RGCs, decreased cytotoxicity and apoptosis, attenuated the expression of Bax. Meanwhile, PR-619 promoted the protein levels of Bcl-2, parkin, optineurin, LAMP1 and the LC3-II/I ratio. While knockdown of parkin by siRNA diminished the neuroprotective effect of PR-619 on RGCs. These findings demonstrate that PR-619 exerted a neuroprotective effect and promoted parkin-mediated mitophagy on cultured RGCs against glutamate excitotoxicity. DUB inhibitors may be useful in protecting RGCs through modulating the parkin-mediated mitophagy pathway against excitotoxicity.
Brain-derived neurotrophic factor Val66Met polymorphism affects cortical thickness of rostral anterior cingulate in patients with major depressive disorder
Authors: Shen Zonglin , Lu Yi , Jiang Hongyan , Ye Jing , Zhou Cong , He Mengxin , Li Na , Xu Xiufeng , Cheng Yuqi
Published: September 2020

Objective

The neuro-anatomical substrates of major depressive disorder (MDD) remain poorly understood. Brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met/rs6265) is associated with neuro-plasticity and development. In the present study, we explore the influence of BDNF gene polymorphism on cortical thickness in nonelderly, first episode, drug-naive patients with MDD.

Methods

Two hundred and sixteen participants (105 MDD patients and 111 healthy controls) were divided into subgroups based on the BDNF genotype. High-resolution MRI was obtained in all participants. A relationship of BDNF Val66Met gene polymorphism and cortical thickness was investigated.

Results

The significant main effect of diagnosis was identified in the left rostal anterior cingulate (rACC), right inferior temporal and right lateral orbitofrontal (lOFC). The main effect of the genotype was observed in the left posterior cingulate cortex. The diagnosis-by-genotype interaction effect was found located in the left rACC. MDD patients who were Met-carriers exhibited thinner cortical thickness in the left rACC than healthy controls Met-carriers. Neither the symptom severity nor the illness duration was correlated significantly with cortical thickness.

Conclusion

Our findings suggested that the BDNF gene polymorphism was associated with cortical thickness alterations of the left rACC in MDD patients, and genotype that carries Met may serve as a vulnerability factor in MDD regarding the cortical thickness loss in the left rACC. This finding can be considered as a supportive evidence for the neurotrophic factor hypothesis of depression.
Mediterranean Diet, Stress Resilience, and Aging in Nonhuman Primates
Authors: Shively Carol A. , Appt Susan E. , Chen Haiying , Day Stephen M. , Frye Brett M. , Shaltout Hossam A. , Silverstein-Metzler Marnie G. , Snyder-Mackler Noah , Uberseder Beth , Vitolins Mara Z. , Register Thomas C.
Published: September 2020

Persistent psychological stress increases the risk of many chronic diseases of aging. Little progress has been made to effectively reduce stress responses or mitigate stress effects suggesting a need for better understanding of factors that influence stress responses. Limited evidence suggests that diet may be a factor in modifying the effects of stress. However, long-term studies of diet effects on stress reactive systems are not available, and controlled randomized clinical trials are difficult and costly. Here we report the outcomes of a controlled, randomized preclinical trial of the effects of long-term consumption (31 months, ∼ equivalent to 9 human years) of Western versus Mediterranean - like diets on behavioral and physiological responses to acute (brief social separation) and chronic (social subordination) psychosocial stress in 38 adult, socially-housed, female cynomolgus macaques. Compared to animals fed a Western diet, those fed the Mediterranean diet exhibited enhanced stress resilience as indicated by lower sympathetic activity, brisker and more overt heart rate responses to acute stress, more rapid recovery, and lower cortisol responses to acute psychological stress and adrenocorticotropin (ACTH) challenge. Furthermore, age-related increases in sympathetic activity and cortisol responses to stress were delayed by the Mediterranean diet. Population level diet modification in humans has been shown to be feasible. Our findings suggest that population-wide adoption of a Mediterranean-like diet pattern may provide a cost-effective intervention on psychological stress and promote healthy aging with the potential for widespread efficacy.

Highlights

There is no population level treatment to reduce stress and associated disease.

Mediterranean diet reduced sympathetic activity.

Mediterranean diet reduced cortisol response to acute stress and to ACTH challenge.

Mediterranean diet delayed age-related increases in sympathetic activity and cortisol responses to stress.

These results suggest a dietary strategy to increase stress resilience.
Biomarker potential of real-world voice signals to predict abnormal blood glucose levels
Authors: Jeon Jouhyun , Palanica Adam , Sarabadani Sarah , Lieberman Michael , Fossat Yan
Published: September 2020

Background

Voice signal analysis is an emerging non-invasive technique to examine health conditions, and is implemented in various real-life applications and devices. The purpose of this study was to evaluate the association of voice signals with blood glucose levels in healthy individuals. The study aimed to investigate the longitudinal stabilities of voice signals and identify voice biomarkers to predict abnormal blood glucose levels.

Methods

We created voice profiles composed of 17,552,688 voice signals from 44 participants and their 1,454 voice recordings. From each voice recording, 12,082 voice-features were extracted. Longitudinal stabilities of voice-features were quantified using linear mixed-effect modelling. Voice-features that showed significant difference between different blood glucose levels, strong intra-stability and the ability to make distinct choice in decision trees were selected as voice biomarker. Voice biomarkers were fed into a multi-class random forest classifier to predict high, normal, and low blood glucose levels.

Findings

In total, 196 voice biomarkers were characterized. Results showed a predictive model with an overall accuracy of 78.66%, overall AUC of 0.83 (95% confidence interval is 0.80 – 0.85), and 0.41 of Matthews Correlation Coefficient (MCC) to discriminate three different blood glucose levels in an independent test set.

Interpretation

Our voice biomarkers could serve as a noninvasive and conventional surrogate of blood glucose monitoring in daily life as well as a screening tool to estimate potential risk of poor glycemic control.

Funding

This research was internally funded and received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson’s disease
Authors: Li Peipei , Killinger Bryan A. , Beddows Ian , Ensink Elizabeth , Yilmaz Ali , Lubben Noah , Lamp Jared , Schilthuis Meghan , Vega Irving E. , Britschgi Markus , Pospisilik J. Andrew , Brundin Patrik , Brundin Lena , Graham Stewart , Labrie Viviane
Published: September 2020

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. We find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Proteomic and transcript analysis corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis reveals an increase in microbially-derived, toxic secondary bile acids. Synucleinopathy in mice induces similar microbiome alterations to those of PD patients. The mouse model of synucleinopathy has elevated DCA and LCA. An analysis of blood markers shows evidence of biliary abnormalities early in PD, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.
No evidence that plasmablasts transdifferentiate into developing neutrophils in severe COVID-19 disease
Authors: Alquicira-Hernandez José , Powell Joseph E , Phan Tri Giang
Published: September 2020

A recent study by Wilk et al. of the transcriptome of peripheral blood mononuclear cells (PBMCs) in seven patients hospitalized with COVID-19 described a population of “developing neutrophils” that were “phenotypically related by dimensionality reduction” to plasmablasts, and that these two cell populations represent a “linear continuum of cellular phenotype”1. The authors suggest that, in the setting of acute respiratory distress syndrome (ARDS) secondary to severe COVID-19, a “differentiation bridge from plasmablasts to developing neutrophils” connected these distantly related cell types. This conclusion is controversial as it appears to violate several basic principles in cell biology relating to cell lineage identity and fidelity. Correctly classifying cells and their developmental history is an important issue in cell biology and we suggest that this conclusion is not supported by the data as we show here that: (1) regressing out covariates such as unique molecular identifiers (UMIs) can lead to overfitting; and (2) that UMAP embeddings may reflect the expression of similar genes but not necessarily direct cell lineage relationships.
Synthetic auxotrophy remains stable after continuous evolution and in co-culture with mammalian cells
Authors: Kunjapur Aditya M. , Napolitano Michael G. , Hysolli Eriona , Noguera Karen , Appleton Evan M. , Schubert Max G. , Jones Michaela A. , Iyer Siddharth , Mandell Daniel J. , Church George M.
Published: September 2020

Understanding the evolutionary stability and possible context-dependence of biological containment techniques is critical as engineered microbes are increasingly under consideration for applications beyond biomanufacturing. While batch cultures of synthetic auxotrophicEscherichia colipreviously exhibited undetectable escape throughout 14 days of monitoring, the long-term effectiveness of synthetic auxotrophy is unknown. Here, we report automated continuous evolution of a synthetic auxotroph using custom chemostats that supply a decreasing concentration of essential biphenylalanine (BipA). After 100 days of evolution in three separate trials, populations exhibit no observable escape and are capable of normal growth rates at 10-fold lower BipA concentration than the ancestral synthetic auxotroph. Allelic reconstruction of three proteins implicated in small molecule transport reveals their contribution to increased fitness at low BipA concentrations. Mutations do not appear in orthogonal translation machinery nor in synthetic auxotrophic markers. Based on its evolutionary stability, we introduce the progenitor synthetic auxotroph directly to mammalian cell culture. We observe containment of bacteria without detrimental effects on HEK293T cells. Overall, our findings reveal that synthetic auxotrophy is effective on timescales and in contexts that enable diverse applications.

One Sentence Summary

To ascertain whether life inevitably finds a way, we continuously evolve anEscherichia colistrain that was not able to escape from engineered biocontainment before, and we find that it does not escape even after 100 days of evolution, nor does it escape when added to mammalian cell culture.
Hydroxychloroquine increased psychiatric-like behaviors and disrupted the expression of related genes in the mouse brain
Authors: Xu H , Zhang XY , Wang WW , Wang JS
Published: September 2020

Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for SARS-COV-2, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days and enhanced depressive behavior at 24 h. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta and corticotropin-releasing hormone (Crh) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Most of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.