bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of Universal Hepatitis C Screening in Pregnant Women
Authors: Saab Sammy , Kullar Ravina , Khalil Haydar , Gounder Prabhu
Published: April 2020

Background:

Hepatitis C virus (HCV) epidemiology has shifted from the baby-boomer generation to young women of childbearing age. The health benefits and cost-effectiveness (CE) of screening pregnant women remain controversial.

Aim:

To systematically review published studies evaluating the CE of screening pregnant women for HCV in the era of direct-acting antivirals (DAAs).

Materials and Methods:

We conducted a systematic literature search of CE studies evaluating the costs and benefits of screening pregnant women for HCV. Pertinent information including antiviral agent, drug costs, incremental cost-effective ratio (ICER), and infant care was collected. The authors’ definition of the threshold price at which screening was deemed CE was also recorded. The quality of studies was assessed using the Consolidated Health Economic Evaluation Reports Standards (CHEERS) checklist.

Results:

We identified 5 studies that evaluated the ICER of screening pregnant women for HCV. Of these, 2 utilized all oral DAAs, with universal screening CE. The ICER of these 2 studies was $3000 and $41,000 per quality of life-years gained. The remaining studies were interferon-based regimens. Most studies did not include screening of infants.

Conclusions:

Universally screening pregnant women for HCV was CE in studies that utilized oral DAAs. Most pharmacoeconomic studies failed to incorporate the impact of vertical transmission on infants.
The Effect of Hopelessness and Perceived Group Compatibility on Treatment Outcome for Patients With Personality Dysfunction
Authors: Aafjes-van Doorn Katie , Kealy David , Ehrenthal Johannes C. , Ogrodniczuk John S. , Joyce Anthony S. , Weber Rainer
Published: April 2020

Improvement in life satisfaction is hard to achieve for any patient with personality psychopathology, and possibly even moreso for those who feel hopeless at the start of treatment. The present research investigated the potential influence of hopelessness in the treatment of patients with personality dysfunction, using data from patients who completed an intensive group therapy program designed to reduce symptom distress and support optimal psychosocial functioning (N= 80). In the present study, we sought to examine whether hopelessness would moderate (i.e., strengthen or weaken) relations between compatibility ratings and life satisfaction outcome. Hopelessness had a significant moderating effect on the relationship between compatibility and outcome, suggesting that, for patients who entered treatment feeling more hopeless, higher appraisals of fit within the group facilitated better gains in life satisfaction. If replicated, the findings underlie the importance of focusing on increasing hope and perceived group affiliation in the treatment of personality dysfunction.
Trends in Condomless Sex Among MSM Who Participated in CDC-Funded HIV Risk-Reduction Interventions in the United States, 2012-2017
Authors: Zhang Kudon Hui , Mulatu Mesfin S. , Song Wei , Heitgerd Janet , Rao Shubha
Published: April 2020

Consistent and correct use of condoms can reduce the risk for sexually transmitted diseases, including HIV/AIDS. Studies have reported that condomless sex among men who have sex with men (MSM) has steadily increased in recent years. We analyzed data reported by 51 health departments regarding 82 556 HIV-positive and HIV-negative MSM 13 years or older and participated in Centers for Disease Control and Prevention–funded behavioral risk-reduction intervention programs during 2012-2017. The percentages of condomless sex increased from 56.3% to 72.0% (estimated annual percent change [EAPC] = 7.1%) among HIV-positive MSM and from 46.0% to 70.5% (EAPC = 4.1%) among HIV-negative MSM. Continued increases in condomless sex might disrupt progress in ending the HIV/AIDS epidemic. Transmission risk associated with condomless sex can be reduced by ensuring that HIV-positive persons know their status early and are linked to care to achieve viral suppression and those at risk for acquiring HIV/AIDS can readily access preexposure prophylaxis.
Comparison of Census Tract–Level Chronic Disease Prevalence Estimates From 500 Cities and Local Health Claims Data
Authors: Monaghan Alyssa , Jones Lynda , Brink LuAnn , Hacker Karen
Published: April 2020

Objectives:

To compare city and census tract–level diabetes and hypertension prevalence using 500 Cities Project modeled estimates from the Centers for Disease Control and Prevention (CDC) and insurance claims data.

Methods:

Insurance claims by census tract were collected from 3 local health plans for the city of Pittsburgh, Pennsylvania, for 2015-2016; conditions were defined using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes. Crude prevalence estimates with 95% confidence intervals were downloaded from the CDC 500 Cities Web site to obtain modeled estimates by census tract. Confidence intervals were calculated for claims and compared with modeled estimates; nonoverlapping intervals were considered significant. Pearson correlation coefficients were generated for census tract–level comparison.

Results:

City-level model-based and claims estimates were 9% versus 10% for diabetes and 31% versus 21% for hypertension. At the census tract level, model-based and insurance claims estimates were more concordant for diabetes (r = 0.366) than for hypertension (r = 0.220). Modeled estimates were significantly higher than claims estimates for 89% of census tracts for hypertension and 35% for diabetes.

Conclusions:

Modeled estimates from the 500 Cites Project were significantly higher than insurance claims estimates for hypertension but were more consistent for diabetes. Utilization of multiple data sources to understand local-level chronic disease burden requires consideration of the strengths and limitations of each.
Tuberculous meningitis: where to from here?
Authors: Donovan Joseph , Thwaites Guy E. , Huynh Julie
Published: April 2020

Purpose of review

Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults.

Recent findings

Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials.

Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.
Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA - Secondary Publication
Authors: Simpson Scott , Kay Fernando U. , Abbara Suhny , Bhalla Sanjeev , Chung Jonathan H. , Chung Michael , Henry Travis S. , Kanne Jeffrey P. , Kligerman Seth , Ko Jane P. , Litt Harold
Published: April 2020

Routine screening CT for the identification of COVID-19 pneumonia is currently not recommended by most radiology societies. However, the number of CTs performed in persons under investigation (PUI) for COVID-19 has increased. We also anticipate that some patients will have incidentally detected findings that could be attributable to COVID-19 pneumonia, requiring radiologists to decide whether or not to mention COVID-19 specifically as a differential diagnostic possibility. We aim to provide guidance to radiologists in reporting CT findings potentially attributable to COVID-19 pneumonia, including standardized language to reduce reporting variability when addressing the possibility of COVID-19. When typical or indeterminate features of COVID-19 pneumonia are present in endemic areas as an incidental finding, we recommend contacting the referring providers to discuss the likelihood of viral infection. These incidental findings do not necessarily need to be reported as COVID-19 pneumonia. In this setting, using the term “viral pneumonia” can be a reasonable and inclusive alternative. However, if one opts to use the term “COVID-19” in the incidental setting, consider the provided standardized reporting language. In addition, practice patterns may vary, and this document is meant to serve as a guide. Consultation with clinical colleagues at each institution is suggested to establish a consensus reporting approach. The goal of this expert consensus is to help radiologists recognize findings of COVID-19 pneumonia and aid their communication with other healthcare providers, assisting management of patients during this pandemic.
Time to tracheostomy impacts overall outcomes in patients with cervical spinal cord injury
Authors: Anand Tanya , Hanna Kamil , Kulvatunyou Narong , Zeeshan Muhammad , Ditillo Michael , Castanon Lourdes , Tang Andrew , Gries Lynn , Joseph Bellal
Published: April 2020

BACKGROUND

The morbidity associated with cervical spine injury increases in the setting of concomitant cervical spinal cord injury (CSCI). A significant proportion of these patients require placement of a tracheostomy. However, it remains unclear if timing to tracheostomy following traumatic CSCI can impact outcomes. The aim of our study was to characterize outcomes associated with tracheostomy timing following traumatic CSCI.

METHODS

We performed a 5-year (2010–2014) analysis of the American College of Surgeons Trauma Quality Improvement Program database and included all adult (age, ≥18 years) trauma patients who had traumatic CSCI and received tracheostomy. Patients were subdivided into two groups: early tracheostomy (ET) (≤4 days from initial intubation) and late tracheostomy (LT) (>4 days). Outcome measures included respiratory complications, ventilator-free days, intensive care unit–free days and hospital length of stay, and mortality. Multivariate logistic regression analysis was performed.

RESULTS

A total of 5,980 patients were included in the study, of which 1,010 (17%) patients received ET, while 4,970 (83%) patients received LT. Mean age was 46 years, and 73% were men. In terms of CSCI location, 48% of the patients had high CSCI (C1–C4), while 52% had low CSCI (C5–C7). Patients in the ET group had lower rates of respiratory complications (30% vs. 46%, p = 0.01), higher ventilator-free days (13 days vs. 9 days; p = 0.02), intensive care unit–free days (11 days vs. 8 days; p = 0.01), and a shorter hospital length of stay (22 days vs. 29 days; p = 0.01) compared with those in the LT group. On regression analysis, ET was associated with lower rates of respiratory complications in patients with high CSCI (odds ratio, 0.55 [0.41–0.81]) and low CSCI (odds ratio, 0.93 [0.72–0.95]). However, no association was found between time to tracheostomy and in-hospital mortality.

CONCLUSION

Early tracheostomy regardless of CSCI level may lead to improved outcomes. Quality improvement efforts should focus on defining the optimal time to tracheostomy and considering ET as a component of SCI management bundle.

LEVEL OF EVIDENCE

Therapeutic, level IV.
MATHEMATICAL MODELING FOR TRANSMISSIBILITY OF COVID-19 VIA MOTORCYCLES
Authors: Okelo Benard
Published: April 2020

Abstract

In this paper, we present a mathematical model of trigonometric type for transmissibility and deaths as a result of COVID-19. In the model, we analyze the spread of COVID-19 by considering a new parameter, the motor-cycle as a means of public transport, which has not been considered in several other models for COVID-19. We use the mathematical model to predict the spread and deaths and we suggest strategies that can be put in place to prevent the spread caused by motorcycle as a means of public transport.
Higher mortality in men from COVID19 infection-understanding the factors that drive the differences between the biological sexes
Authors: Iyer Swaminathan P. , Ensor Joe , Anand Kartik , Hwu Patrick , Subbiah Vivek , Flowers Christopher , Channappanavar Rudragouda
Published: April 2020

The emergent global pandemic caused by the rapid spread of Severe Acute Respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has led to increased mortality and negatively impacted day to day activities of humankind within a short period of time. As the data is rapidly emerging from earlier outbreak locations around the world, there are efforts to assimilate this with the knowledge from prior epidemics and find rapid solutions for this. One of the observations and a recurring theme is the disproportionate differences in the incidence of infection and the consequent mortality between males and females. We, therefore, analyzed retrospective datasets from the previous epidemics and the ongoing pandemic in order to address these differences in clinical outcomes. The data shows that even though the infection rates are similar, the odds ratio of male mortality remains high, indicating a divergence in the crosstalk between the three pathogenic human Coronavirus (hCoVs)-the SARS-CoV, MERS-CoV and the SARS-CoV-2 and immune effectors in the two sexes. One proximate cause is the sex-specific modulation of the X-linked genes that can influence susceptibility to infection. Future studies are needed to confirm these findings, which can form the basis for developing rational strategies for ending the current and preventing future pandemics.
Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly
Authors: Pérez-Jurado Luis A. , Cáceres Alejandro , Esko Tonu , López de Heredia Miguel , Quintela Inés , Cruz Raquel , Lapunzina Pablo , Carracedo Ángel ,   SCOURGE Cohort Group, González Juan R.
Published: April 2020

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
Improving the Induction of PPI Contributors on Trial Oversight Committees
Authors: Pickering Emily C , Hanley Bec , Bell Philip , Gath Jacqui , Hanlon Patrick , Oldroyd Robert , Stephens Richard , Tweed Conor D
Published: April 2020

Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, delivery, oversight and dissemination. This research explored the induction and training of PPI Contributors joining trial oversight committees. It was used to create an induction pack for new PPI Contributors at the Medical Research Council Clinical Trials Unit at University College London’s (MRC CTU at UCL). We have made this resource available to all researchers and in this we report describe the methodology behind its production.
Clinical and Imaging Findings in COVID-19 Patients Complicated by Pulmonary Embolism
Authors: Li Ting , Kicska Gregory , Kinahan Paul E , Zhu Chengcheng , Oztek Murat Alp , Wu Wei
Published: April 2020

Objective

To describe clinical, and imaging findings including the evolution pattern in COVID-19 pneumonia complicated by pulmonary embolism (PE).

Methods

Eleven of 1453 patients with a probable diagnosis of COVID-19 pneumonia were retrospectively selected for the presence of PE. Clinical and laboratory data were recorded. All cross-sectional CT imaging was qualitatively scored for the first 28 days after onset of symptoms.

Results

Of 24 patients underwent CTA-PE, 11 were confirmed with PE. All 11 patients developed acute respiratory distress syndrome (ARDS). The pulmonary emboli were most common in segmental and subsegmental pulmonary arteries. We observed an evolution pattern of predominant findings with ground-glass opacities (GGO) to GGO with crazy paving in 3 patients, then to consolidation with linear densities, or to reticulation in 9 patients. Lung cysts or traction bronchiectasis could be seen from day 5 to 9 after symptoms and reticulation, subpleural curvilinear lines were more common from day 20. The pulmonary opacities were predominantly peripheral in distribution with relative sparing of nondependent lungs. The severity of lung involvement was high with an average score of 9.7 in the first phase, 18 in the second phase plateauing in the next two phases, with a slight decrease to 16.9 in the late phase.

Conclusion

The incidence of PE among suspected patients in COVID-19 was high. The pulmonary emboli were most common in segmental and subsegmental pulmonary arteries. Our study suggests PE may occur with increased frequency in the ARDS subgroup. The evolution of radiographic abnormalities showed a general pattern, but are also unique with more extensive lung injury and specific imaging features, which may due to the exist of ARDS in these patients.
Liver transplantation without graft ischemia in humans
Authors: Guo Zhiyong , Zhao Qiang , Huang Shanzhou , Huang Changjun , Zhang Jian , Wang Dongping , Yang Lu , Chen Maogen , Wu Linwei , Zhang Zhiheng , Zhu Zebin , Wang Linhe , Zhu Caihui , Zhang Yixi , Tang Yunhua , Sun Chengjun , Xiong Wei , Shen Yuekun , Chen Xiaoxiang , Xu Jinghong , Wang Tielong , Ma Yi , Hu Anbin , Chen Yinghua , Zhu Xiaofeng , Rong Jian , Cai Changjie , Gong Fengqiu , Guan Xiangdong , Huang Wenqi , Ko Dicken Shiu-Chung , Li Xianchang , Huang Jiefu , Ju Weiqiang , He Xiaoshun
Published: April 2020

BACKGROUND

Ischemia-reperfusion injury is considered an inevitable event that compromises posttransplant outcomes. Numerous treatments have been proposed to reduce its impact. However, most of them have had limited success, as none of them can completely avoid graft ischemia.

METHODS

Ischemia-free liver transplantation (IFLT) comprises surgical techniques to enable continuous oxygenated blood supply to brain-dead donor livers during procurement, preservation and implantation using normothermic machine perfusion technology. In this nonrandomized study, 38 donor livers were transplanted using IFLT and were compared to 130 livers procured and transplanted using a conventional procedure (CLT).

RESULTS

One patient (2.6%) suffered early allograft dysfunction in the IFLT group, compared with 43.8% of patients in the CLT group (absolute risk difference, 41.2 percentage points; 95% confidence interval, −31.3, −51.1). The median (range) peak aspartate aminotransferase levels within the first week (336, 149-4112 vs. 1445, 149-25083 U/L, P<0.001), and the median (range) total bilirubin levels on day 7 (2.11, 0.68-12.47 vs. 5.11, 0.56-51.97 mg/dL, P<0.001) posttransplantation were much lower in the IFLT than in the CLT group. The IFLT recipients had less need for renal replacement therapy (2.6% vs. 16.9%, P=0.02), shorter median (range) intensive care unit stay (34, 12-235 vs. 43.5, 7-936 hours, P=0.003), and higher one-year recipient survival (97.4% vs. 84.6%, P=0.02) and graft survival (94.7% vs. 83.8%, P=0.04) rates than the CLT recipients. The extended criteria donor livers in IFLT yielded faster posttransplant recovery than the standard criteria donor livers in CLT.

CONCLUSIONS

IFLT provides a new approach to minimize ischemia-reperfusion injury and improve post-transplant outcomes.

Clinical trial registry

This trial is registered with http://www.chictr.org.cn, number ChiCTR-OPN-17012090.
Comments on “EpiRank: Modeling Bidirectional Disease Spread in Asymmetric Commuting Networks” for Analyzing Emerging Coronavirus Epidemic Patterns
Authors: Benny Chin Wei Chien , Huang Chung-Yuan
Published: April 2020

Huang et al.1 used their EpiRank algorithm, which emphasizes forward-and-backward commuter flow between homes and workplaces, to analyze the distribution patterns of two infectious diseases in Taiwan: the 2009-H1N1 influenza virus and the widespread emergence of the 2000-2008 type 71 enterovirus (EV). As this article was being prepared, the spreading mechanism of the novel coronavirus disease now designated as COVID-19 had yet to be identified, but according to the American Centers for Disease Control, its spreading mechanism and patterns are likely more similar to influenza than to other coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-1) or Middle East Respiratory Syndrome (MERS-CoV). To consider potential COVID-19 spatial patterns, we applied EpiRank to the 2003 SARS outbreak in north Taiwan for comparison with H1N1 and EV. SARS was found to be less contagious than H1N1 or EV, but with a significantly higher fatality rate. The characteristics of these diseases determined their specific spatial spreading patterns, as reflected in the different effects of forward and backward commuting movement. Our motivation is to highlight these differences and to illustrate EpiRank spatial patterns for the 2003 SARS outbreak for comparison with EpiRank-determined distributions for the H1N1 and EV outbreaks. Our results indicate that the daytime parameter (i.e., forward movement effect) range was slightly higher (0.5-0.55) for the SARS outbreak than for either the influenza (0.4-0.5) or EV (0.3-0.5) outbreaks, suggesting that the forward-and-backward movements of individuals between residential and core urban areas with concentrated populations were equally important regarding the spread of SARS. While COVID-19 might resemble either SARS or H1N1 in terms of spatial spreading, its daytime parameter is likely somewhere in-between, with backward movement being dominant (similar to H1N1) or with forward and backward movement being equally important (similar to SARS). Building on Huang et al.’s paper, we present an estimated risk distribution pattern for the Taipei Metropolitan Area for a daytime parameter of 0.55.
Anti-biofilm efficacy of a medieval treatment for bacterial infection requires the combination of multiple ingredients
Authors: Furner-Pardoe Jessica , Anonye Blessing O , Cain Ricky , Moat John , Ortori Catherine A. , Lee Christina , Barrett David A. , Corre Christophe , Harrison Freya
Published: April 2020

Novel antimicrobials are urgently needed to combat the increasing occurrence of drug-resistant bacteria and to overcome the inherent difficulties in treating biofilm-associated infections. Research into natural antimicrobials could provide candidates to fill the antibiotic discovery gap, and the study of plants and other natural materials used in historical infection remedies may enable further discoveries of natural products with useful antimicrobial activity. We previously reconstructed a 1,000-year-old remedy containing onion, garlic, wine, and bile salts, which is known as ‘Bald’s eyesalve’, and showed it to have promising antibacterial activity. In this paper, we have found this remedy has bactericidal activity against a range of Gram-negative and Gram-positive wound pathogens in planktonic culture and, crucially, that this activity is maintained againstAcinetobacter baumannii, Stenotrophomonas maltophilia, Staphylococcus aureus, Staphylococcus epidermidisandStreptococcus pyogenesin a model of soft-tissue wound biofilm. While the presence of garlic in the mixture is sufficient to explain activity against planktonic cultures, garlic alone has no activity against biofilms. We have found the potent anti-biofilm activity of Bald’s eyesalve cannot be attributed to a single ingredient and requires the combination of all ingredients to achieve full activity. Our work highlights the need to explore not only single compounds but also mixtures of natural products for treating biofilm infections. These results also underline the importance of working with biofilm models when exploring natural products for the anti-biofilm pipeline.

Importance

Bacteria can live in two ways, as individual planktonic cells or as a multicellular biofilm. Biofilm helps protect bacteria from antibiotics and makes them much harder to treat. Both the biofilm lifestyle and the evolution of antibiotic resistance mean we urgently need new drugs to treat infections. Here, we show that a medieval remedy made from onion, garlic, wine, and bile can kill a range of problematic bacteria grown both planktonically and as biofilms. A single component of the remedy – allicin, derived from garlic – is sufficient to kill planktonic bacteria. However, garlic or allicin alone do nothing against bacteria when they form a biofilm. All four ingredients are needed to fully kill bacterial biofilm communities, hinting that these ingredients work together to kill the bacteria. This suggests that future discovery of antibiotics from natural products could be enhanced by studying combinations of ingredients, rather than single plants or compounds.
Naïve orangutans (Pongo abelii & Pongo pygmaeus) individually acquire nut-cracking using hammer tools
Authors: Bandini Elisa , Grossmann Johannes , Funk Martina , Serrano Anna Albiach , Tennie Claudio
Published: April 2020

Nut-cracking using hammer tools has been argued to be one of the most complex tool-use behaviours observed in non-human animals (henceforth: animals). Recently, even the United Nations Convention on the Conservation of Migratory Species (CMS) recognised the unique nature of chimpanzee nut-cracking by making it the first animal behaviour to be awarded UN-protected status (Picheta, 2020). So far, only chimpanzees, capuchins and macaques have been observed using tools to crack nuts in the wild (Boesch & Boesch, 1990; Gumert, Kluck, & Malaivijitnond, 2009; Ottoni & Mannu, 2001). However, the learning mechanisms behind this behaviour, and the extent of nut-cracking in other primate species are still unknown. The aim of this study was two-fold. First, we aimed to examine whether other great ape species would develop nut-cracking when provided with all the tools and motivation to do so. Second, we wanted to examine the mechanisms behind the emergence of nut-cracking in a naïve sample. Orangutans (Pongo abelii; pygmaeus) have not been observed cracking nuts in the wild, despite having the second most extensive tool-use repertoire of the great apes (after chimpanzees), having the materials for the behaviour in the wild (albeit rarely) and possessing flexible problem-solving capacities. Therefore, orangutans are a valid candidate species for the investigation of the development of nut-cracking. Four nut-cracking-naïve orangutans at Leipzig zoo (Pongo abelii;Mage=16; age range=10-19; 4F; at time of testing) were provided with nuts and hammers but were not demonstrated the nut-cracking behavioural form, in order to control for the role of copying social learning in the acquisition of this behaviour. Additionally, we report data from a previously unpublished study by one of the authors (MF) with eight orangutans housed at Zürich zoo (10Pongo abeliiand twoPongo pygmaeus;Mage=14; age range =2-30; 5F; at time of testing) that followed a similar testing paradigm. Out of the twelve orangutans across both testing institutions, at least four individuals, one from Leipzig (Pongo abelii) and three from Zürich (Pongo abelii;pygmaeus), spontaneously expressed nut-cracking with a wooden hammer. These results suggest that the behavioural form of nut-cracking using hammer tools can emerge in orangutans when required through individual learning combined, in some cases, with non-copying social learning mechanisms.
Skipping a beat: heartbeat-evoked potentials reflect predictions during interoceptive-exteroceptive integration
Authors: Banellis Leah , Cruse Damian
Published: April 2020

Several theories propose that emotions and self-awareness arise from the integration of internal and external signals and their respective precision-weighted expectations. Supporting these mechanisms, research indicates that the brain uses temporal cues from cardiac signals to predict auditory stimuli, and that these predictions and their prediction errors can be observed in the scalp heartbeat-evoked potential (HEP). We investigated the effect of precision modulations on these cross-modal predictive mechanisms, via attention and interoceptive ability. We presented auditory sequences at short (perceived synchronous) or long (perceived asynchronous) cardio-audio delays, with half of the trials including an omission. Participants attended to the cardio-audio synchronicity of the tones (internal attention) or the auditory stimuli alone (external attention). Comparing HEPs during omissions allowed for the observation of pure predictive signals, without contaminating auditory input. We observed an early effect of cardio-audio delay, reflecting a difference in heartbeat-driven expectations. We also observed a larger positivity to omissions of sounds perceived as synchronous than to omissions of sounds perceived as asynchronous when attending internally only, consistent with the role of attentional precision for enhancing predictions. These results provide support for attentionally-modulated cross-modal predictive coding, and suggest a potential tool for investigating its role in emotion and self-awareness.
Karyotype asymmetry shapes diversity within the physaloids (Physalidinae, Physalideae, Solanaceae)
Authors: Rodríguez Julieta , Deanna Rocío , Chiarini Franco
Published: April 2020

Within the cosmopolitan family Solanaceae, Physalideae is the tribe with the highest generic diversity (30 genera and more than 200 species). This tribe embraces subtribe Physalidinae, in which positions of some genera are not entirely resolved. Chromosomes may help on this goal, by providing information on the processes underlying speciation. Thus, cytogenetic analyses were carried out in the subtribe in order to establish its chromosome number and morphology. Physalidinae is characterized by x = 12 and most species shows a highly asymmetric karyotype. These karyotype traits were mapped onto a molecular phylogeny to test the congruence between karyotype evolution and clade differentiation. A diploid ancestor was reconstructed for the subtribe, and five to six polyploidy independent events were estimated, plus one aneuploidy event (X = 11 in the monotypic genusQuincula). Comparative phylogenetic methods showed that asymmetry indices and chromosome arm ratio (r) have a high phylogenetic signal, whereas the number of telocentric and submetacentric chromosomes presented a conspicuous amount of changes. Karyotype asymmetry allow us to differentiate genera within the subtribe. Overall, our study suggests that Physalidineae diversification has been accompanied by karyotype changes, which can be applied to delimit genera within the group.
Customizable high-throughput platform for profiling cofactor recruitment to DNA to characterize cis-regulatory elements and screen non-coding single-nucleotide polymorphisms
Authors: Bray David , Hook Heather , Zhao Rose , Keenan Jessica L. , Penvose Ashley , Osayame Yemi , Mohaghegh Nima , Siggers Trevor
Published: April 2020

Determining how DNA variants affect the binding of regulatory complexes to cis-regulatory elements (CREs) and non-coding single-nucleotide polymorphisms (ncSNPs) is a challenge in genomics. To address this challenge, we have developed CASCADE (ComprehensiveASsessment ofComplexAssembly atDNAElements), which is a protein-binding microarray (PBM)-based approach that allows for the high-throughput profiling of cofactor (COF) recruitment to DNA sequence variants. The method also enables one to infer the identity of the transcription factor-cofactor (TF-COF) complexes involved in COF recruitment. We use CASCADE to characterize regulatory complexes binding to CREs and SNP quantitative trait loci (SNP-QTLs) in resting and stimulated human macrophages. By profiling the recruitment of the acetyltransferase p300 and MLL methyltransferase component RBBP5, we identify key regulators of the chemokine CXCL10, and by profiling a set of five functionally diverse COFs we identify a prevalence of ETS sites mediating COF recruitment at SNP-QTLs in macrophages. Our results demonstrate that CASCADE is a customizable, high-throughput platform to link DNA variants with the biophysical complexes that mediate functions such as chromatin modification or remodeling in a cell state-specific manner.
Localization of the Lens Intermediate Filament Switch by Imaging Mass Spectrometry
Authors: Wang Zhen , Ryan Daniel J. , Schey Kevin L
Published: April 2020

Imaging mass spectrometry (IMS) enables targeted and untargeted visualization of the spatial localization of molecules in tissues with great specificity. The lens is a unique tissue that contains fiber cells corresponding to various stages of differentiation that are packed in a highly spatial order. The application of IMS to lens tissue localizes molecular features that are spatially related to the fiber cell organization. Such spatially resolved molecular information assists our understanding of lens structure and physiology; however, protein IMS studies are typically limited to abundant, soluble, low molecular weight proteins. In this study, a method was developed for imaging low solubility cytoskeletal proteins in the lens; a tissue that is filled with high concentrations of soluble crystallins. Optimized tissue washes combined with on-tissue enzymatic digestion allowed successful imaging of peptides corresponding to known lens cytoskeletal proteins. The resulting peptide signals facilitated segmentation of the bovine lens into molecularly distinct regions. A sharp intermediate filament transition from vimentin to lens-specific beaded filament proteins was detected in the lens cortex. MALDI IMS also revealed the region where posttranslational myristoylation of filensin occurs and the results indicate that truncation and myristoylation of filensin starts soon after filensin expression increased in the inner cortex. From intermediate filament switch to filensin truncation and myristoylation, multiple remarkable changes occur in the narrow region of lens cortex. MALDI images delineated the boundaries of distinct lens regions that will guide further proteomic and interactomic studies.
Non-bursting non-rhythmic neurons of the ventral pallidum form cell assemblies and respond to reward and punishment during Pavlovian conditioning
Authors: Hegedüs Panna , Heckenast Julia , Hangya Balázs
Published: April 2020

The ventral pallidum (VP) is a major hub interfacing striatopallidal and limbic circuits, conveying information about salience and valence crucial to adjusting behavior. However, how neuron populations of the VP with different firing properties represent these variables is not fully understood. Therefore, we trained mice on auditory Pavlovian conditioning and recorded the activity of VP neurons while mice were performing the task. Many VP neurons responded to punishment (51%) and reward (44%), either by firing rate increase or decrease. Additionally, 20% of cells responded to outcome-predicting auditory stimuli, showing larger responses to reward-predicting cues compared to those that signaled likely punishment. We found that a large subset of VP neurons showed burst firing based on their auto-correlograms, while a small population exhibited fast rhythmic discharge in the beta/gamma frequency range. Some bursting neurons exhibited distinct response properties of their bursts and single spikes, suggesting a multiplexed coding scheme in the VP. However, non-bursting, non-rhythmic neurons were the most sensitive to reward and punishment. Finally, we demonstrate the presence of synchronously firing neuron assemblies in the VP. Neurons participating in such assemblies were particularly responsive to reinforcing stimuli. This suggests that a synchronous, non-bursting, non-rhythmic neuron population of the VP is responsible for the lion’s share of ventral pallidal salience representation, likely important for reinforcement learning.

Significance statement

The ventral pallidum (VP) is a subcortical brain area that participates in regulating motion and emotion by processing information related to appetitive and aversive stimuli. However, how these stimuli are represented by VP neural circuits is not well understood. Therefore, we investigated how VP neuron populations defined by their firing properties respond to reward and punishment during Pavlovian conditioning. We found that a distinct, non-bursting-non-rhythmic group of neurons was responsible for most responses to reward and punishment in the VP. Neurons of this group formed co-active cell assemblies and multiplexed different types of information via different firing patterns, revealing flexible and plastic neuronal representation strategies in the VP during associative learning.
An opaque cell-specific expression program of secreted proteases and transporters allows cell-type cooperation inCandida albicans
Authors: Lohse Matthew B. , Brenes Lucas R. , Ziv Naomi , Winter Michael B. , Craik Charles S. , Johnson Alexander D.
Published: April 2020

An unusual feature of the opportunistic pathogenC. albicansis its ability to stochastically switch between two distinct, heritable cell types called white and opaque. Here, we show that only opaque cells, in response to environmental signals, massively up-regulate a specific group of secreted proteases and peptide transporters, allowing exceptionally efficient use of proteins as sources of nitrogen. We identify the specific proteases (members of the secreted aspartyl protease (SAP) family) needed for opaque cells to proliferate under these conditions, and we identify four transcriptional regulators of this specialized proteolysis and uptake program. We also show that, in mixed cultures, opaque cells enable white cells to also proliferate efficiently when proteins are the sole nitrogen source. Based on these observations, we suggest that one role of white-opaque switching is to create mixed populations where the different phenotypes derived from a single genome are shared between two distinct cell types.

The opportunistic human fungal pathogenCandida albicansswitches between two distinct, heritable cell types, named “white” and “opaque.” We show that opaque cells, in response to proteins as the sole nitrogen source, up-regulate a specialized program, including specific secreted aspartyl proteases and peptide transporters. We demonstrate that, in mixed cultures, opaque cells enable white cells to respond and proliferate more efficiently under these conditions. These observations suggest that white-opaque switching creates mixtures of cells where the population characteristics - which derive from a single genome - reflect the contributions of two distinct cell types.

Dataset Reference Numbers

The .RAW files for both sets of Mass Spectrometry experiments have been deposited at the ProteoSAFe resource (https://proteomics.ucsd.edu/ProteoSAFe/).

MSP-MS experiment reference number: MSV000085279. For reviewer access use login “MSV000085279_reviewer” and password “candidamspms”.

Proteomics experiment reference number: MSV000085283. For reviewer access use login “MSV000085283_reviewer” and password “candidaprot”.
Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity
Authors: Heindel Daniel W. , Koppolu Sujeethraj , Zhang Yue , Kasper Brian , Meche Lawrence , Vaiana Christopher , Bissel Stephanie J. , Carter Chalise E. , Kelvin Alyson A. , Zhang Bin , Zhou Bin , Chou Tsui-Wen , Lashua Lauren , Ross Ted M. , Ghedin Elodie , Mahal Lara K.
Published: April 2020

Influenza virus infections cause a wide variety of outcomes, from mild disease to 3-5 million cases of severe illness and ~290,000-645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity.

SIGNIFICANCE

Influenza virus infection causes a range of outcomes from mild illness to death. The molecular mechanisms leading to these differential host responses are currently unknown. Herein, we identify the induction of high mannose, a glycan epitope, as a key mediator of severe disease outcome. We propose a mechanism in which activation of the unfolded protein response (UPR) upon influenza virus infection turns on expression of high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and leading to subsequent inflammation. This work is the first to systematically study host glycomic changes in response to influenza virus infection, identifying high mannose as a key feature of differential host response.
Genes adapt to outsmart gene targeting strategies in mutant mouse strains by skipping exons to reinitiate transcription and translation
Authors: Hosur Vishnu , Low Benjamin E. , Li Daniel , Stafford Grace A. , Kohar Vivek , Shultz Leonard D. , Wiles Michael V.
Published: April 2020

Gene disruption in mouse embryonic stem cells or zygotes is a conventional genetics approach to identify gene functionin vivo. However, because different gene-disruption strategies use different mechanisms to disrupt genes, the strategies can result in diverse phenotypes in the resulting mouse model. To determine whether different gene-disruption strategies affect the phenotype of resulting mutant mice, we characterizedRhbdf1mouse mutant strains generated by three commonly used strategies—definitive-null, targeted knockout (KO)-first, and CRISPR/Cas9. We find thatRhbdf1responds differently to distinct KO strategies, for example, by skipping exons and reinitiating translation to potentially yield gain-of-function alleles rather than the expected null or severe hypomorphic alleles. Our analysis also revealed that at least 4% of mice generated using the KO-first strategy show conflicting phenotypes, suggesting that exon skipping is a widespread phenomenon occurring across the genome. Additionally, our study emphasizes that at least 35% of mouse and 45% of human protein-coding genes could be predisposed to targeted KO-first- and CRISPR/Cas9-mediated unexpected translation. Our findings have significant implications for the application of genome editing in both basic research and clinical practice.
German-wide interlaboratory study compares consistency, accuracy and reproducibility of whole-genome short read sequencing
Authors: Uelze Laura , Borowiak Maria , Brinks Erik , Deneke Carlus , Stingl Kerstin , Kleta Sylvia , Tausch Simon H. , Szabo Kathrin , Wöhlke Anne , Malorny Burkhard
Published: April 2020

We compared the consistency, accuracy and reproducibility of next-generation short read sequencing between ten laboratories involved in food safety (research institutes, state laboratories, universities and companies) from Germany and Austria. Participants were asked to sequence six DNA samples of three bacterial species (Campylobacter jejuni, Listeria monocytogenesandSalmonella enterica) in duplicate, according to their routine in-house sequencing protocol. Four different types of Illumina sequencing platforms (MiSeq, NextSeq, iSeq, NovaSeq) and one Ion Torrent sequencing instrument (S5) were involved in the study. Sequence quality parameters were determined for all data sets and centrally compared between laboratories. SNP / and cgMLST calling were performed to assess the reproducibility of sequence data collected for individual samples. Overall, we found Illumina short read data to be more accurate and consistent than Ion Torrent sequence data, with little variation between the different Illumina instruments. Two laboratories with Illumina instruments submitted sequence data with lower quality, probably due to the use of a library preparation kit, which shows difficulty in sequencing low GC genome regions. Differences in data quality were more evident after assembling short reads into genome assemblies, with Ion Torrent assemblies featuring a great number of allele differences to Illumina assemblies. Clonality of samples was confirmed through SNP calling, which proved to be a more suitable method for an integrated data analysis of Illumina and Ion Torrent data sets, than cgMLST calling.
Egg-surface bacteria deter oviposition by the oriental fruit flyBactrocera dorsalis
Authors: Li Huijing , Ren Lu , Xie Mingxue , Gao Yang , He Muyang , Hassan Babar , Lu Yongyue , Cheng Daifeng
Published: April 2020

Finding a suitable oviposition site is a challenging task for a gravid female fly, since the hatched maggots have limited mobility, making it difficult to find an alternative host. The oriental fruit fly,Bactrocera dorsalis, oviposits on many types of fruits. Maggots hatching in a fruit that is already occupied by conspecific worms will face food competition. Here, we showed that maggot-occupied fruits deterB. dorsalisoviposition and that this deterrence is based on the increased β-caryophyllene concentration in fruits. Using a combination of bacterial identification, volatile content quantification, and behavioural analyses, we demonstrated that the egg-surface bacteria ofB. dorsalis, includingProvidencia sp. andKlebsiella sp., are responsible for this increase in the β-caryophyllene contents of host fruits. Our research shows a type of tritrophic interaction between microorganisms, insects, and insect hosts, which will provide considerable insight into the evolution of insect behavioural responses to volatile compounds.