bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the impact of a national clinical guideline for the management of chronic pain on opioid prescribing rates: A controlled interrupted time series analysis
Authors: Hébert Harry L. , Morales Daniel R. , Torrance Nicola , Smith Blair H. , Colvin Lesley A.
Published: February 2021

Background

Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland.

Methods

Trends in national and regional community opioid prescribing data for Scotland were analysed from quarter one (Q1) 2005 to Q2 2020. Interrupted time series regression examined the association of SIGN 136 publication with prescribing rates for opioid-containing drugs. Gabapentinoid prescribing was used as an outcome control.

Results

After a positive prescribing trend pre-publication, the timing of SIGN 136 publication was associated with a negative change in trend of opioid prescribing rates (−2.82 items per 1,000 population per quarter [PTPPQ]; P<0.01). By Q2 2020, the relative reduction in opioid prescribing rate was -20.67% (95% CI: -23.67, -17.77). This persisted after controlling for gabapentinoid prescribing and was mainly driven by reduction in weak opioids, whereas strong opioid prescribing rates continued to rise. Gabapentinoid prescribing showed a significant rise in level (8.00 items per 1,000 population; P=0.01) and trend (0.27 items PTPPQ; P=0.01) following SIGN 136 publication.

Conclusions

Publication of SIGN 136 was associated with a reduction in opioid prescribing rates. This suggests that changes in clinical policy through evidence-based national clinical guidelines may affect community opioid prescribing, though this may be partially replaced by gabapentinoids, and other factors may also contribute.
Clinical profile and factors associated with COVID-19 in Cameroon: a prospective cohort study
Authors: Mbarga Nicole Fouda , Emilienne Epee , Mbarga Marcel , Ouamba Patrick , Nanda Herwin , Kengni Aristide , Joseph Guekeme , Eyong Justin , Tossoukpe Sylvie , Sosso Noumedem Sauvia , Engelbert Ngono Ngono , Lazare Mbala Ntsama , Landry Bonyomo , Patrick Tchatchoua , Vogue Noel , Metomb Steve , Ale Franck , Ousman Moussa , Job Dorian , Charlotte Moussi , Tamakloe Modeste , Haberer Jessica E. , Atanga Ndesoh , Halle-Ekane Gregory , Boum Yap
Published: February 2021

Objectives

This study explores the clinical profiles and factors associated with COVID-19 in Cameroon.

Research design and methods

In this prospective cohort study, we followed patients admitted for suspicion of COVID-19 at Djoungolo Hospital between 01st April and 31st July 2020. Patients were categorised by age groups and disease severity: mild (symptomatic without clinical signs of pneumonia pneumonia), moderate (with clinical signs of pneumonia without respiratory distress) and severe cases (clinical signs of pneumonia and respiratory distress not requiring invasive ventilation). Demographic information and clinical features were summarised. Multivariable analysis was performed to predict risk.

Results

A total of 323 patients were admitted during the study period; 262 were confirmed cases of COVID-19 by Polymerase Chain Reaction (PCR). Among the confirmed cases, the male group aged 40 to 49 years (13.9%) was predominant. Disease severity ranged from mild (77%; N=204) to moderate (15%; N=40) to severe (7%; N=18); the case fatality rate was 1% (N=4). Dysgusia (46%; N=111) and hyposmia/anosmia (39%; N=89) were common features of COVID-19. Nearly one-third of patients had comorbidities (29%; N=53), of which hypertension was the most common (20%; N=48). Participation in a mass gathering (OR=5.47; P=0.03) was a risk factor for COVID-19. Age groups 60 to 69 (OR=7.41; P=0.0001), 50 to 59 (OR=4.09; P=0.03), 40 to 49 (OR=4.54; P=0.01), male gender (OR=2.53; P=0.04), diabetes (OR= 4.05; P= 0.01), HIV infection (OR=5.57; P=0.03), lung disease (OR= 6.29; P=0.01), dyspnoea (OR=3.70; P=0.008) and fatigue (OR=3.35; P=0.02) significantly predicted COVID-19 severity.

Conclusion

Unlike many high-income settings, most COVID-19 cases in this study were benign with low fatality. Such findings may guide public health decision-making.
An MRI-based Deep Learning Model to Predict Parkinson’s Disease Stages
Authors: Mozhdehfarahbakhsh Azadeh , Chitsazian Saman , Chakrabarti Prasun , Chakrabarti Tulika , Kateb Babak , Nami Mohammad
Published: February 2021

Parkinson’s disease (PD) is amongst the relatively prevalent neurodegenerative disorders with its course of progression classified as prodromal, stage1, 2, 3 and sever conditions. With all the shortcomings in clinical setting, it is often challenging to identify the stage of PD severity and predict its progression course. Therefore, there appear to be an ever-growing need need to use supervised and unsupervised artificial intelligence and machine learning methods on clinical and paraclinical datasets to accurately diagnose PD, identify its stage and predict its course. In today’s neuro-medicine practices, MRI-related data are regarded beneficial in detecting various pathologies in the brain. In addition, the field has recently witnessed a growing application of deep learning methods in image processing often with outstanding results. Here, we applied Convolutional Neural Networks (CNN) to propose a model helping to distinguish different stages of PD. The results showed that our current MRI-based CNN model may potentially be employed as a suitable method for the distinction of PD stages at a high accuracy rate (0.94).
Artificial Intelligence for Advance Requesting of Immunohistochemistry in Diagnostically Uncertain Prostate Biopsies
Authors: Chatrian Andrea , Colling Richard T , Browning Lisa , Alham Nasullah Khalid , Sirinukunwattana Korsuk , Malacrino Stefano , Haghighat Maryam , Aberdeen Alan , Monks Amelia , Moxley-Wyles Benjamin , Rakha Emad , Snead David R J , Rittscher Jens , Verrill Clare
Published: February 2021

The use of immunohistochemistry in the reporting of prostate biopsies is an important adjunct when the diagnosis is not definite on haematoxylin and eosin (H&E) morphology alone. The process is however inherently inefficient with delays while waiting for pathologist review to make the request and duplicated effort reviewing a case more than once. In this study, we aimed to capture the workflow implications of immunohistochemistry requests and demonstrate a novel artificial intelligence tool to identify cases in which immunohistochemistry (IHC) is required and generate an automated request.

We conducted audits of the workflow for prostate biopsies in order to understand the potential implications of automated immunohistochemistry requesting and collected prospective cases to train a deep neural network algorithm to detect tissue regions that presented ambiguous morphology on whole slide images. These ambiguous foci were selected on the basis of the pathologist requesting immunohistochemistry to aid diagnosis. A gradient boosted trees classifier was then used to make a slide level prediction based on the outputs of the neural network prediction. The algorithm was trained on annotations of 219 immunohistochemistry-requested and 80 control images, and tested by 3-fold cross-validation. Validation was conducted on a separate validation dataset of 212 images.

Non IHC-requested cases were diagnosed in 17.9 minutes on average, while IHC-requested cases took 33.4 minutes over multiple reporting sessions. We estimated 11 minutes could be saved on average per case by automated IHC requesting, by removing duplication of effort. The tool attained 99% accuracy and 0.99 Area Under the Curve (AUC) on the test data. In the validation, the average agreement with pathologists was 0.81, with a mean AUC of 0.80.

We demonstrate the proof-of-principle that an AI tool making automated immunohistochemistry requests could create a significantly leaner workflow and result in pathologist time savings.
Impact of the COVID-19 pandemic on the mental health of Greek adults: a cross-sectional survey
Authors: Dragotis Efthimios , Atsopardi Korina , Barbouni Anastasia , Poulas Konstantinos , Farsalinos Konstantinos
Published: February 2021

Objectives

The coronavirus disease 2019 (COVID-19) pandemic and mitigation measures based on social distancing are expected to have serious adverse effects on mental health. This cross-sectional study aimed to examine self-reported changes in the mental health status of Greek adults.

Study design

The current study is a primary research conducted on Greek adults during the first wave of the epidemic (March to April 2020).

Methods

A total of 527 individuals participated in an online survey using a validated questionnaire (State-Trait Anxiety Inventory-STAI and DASS-21).

Results

The respondents had a moderate mental health status based on the following scores: STAI-S, 45.8; STAI-T, 40.7; depression, 4.6; anxiety, 3.1; and stress, 6.1. Women, younger respondents, those from lower income households, and those living in smaller apartments experienced increased depression, anxiety, and stress. Additionally, infection control practices during the COVID-19 pandemic such as the use of masks, gloves, and antiseptic can drastically decrease the prevalence of mental health illnesses.

Conclusions

These findings can be used by the Greek State to reduce the effects of COVID-19 on the mental health of the population and protect socially vulnerable groups.
Does Subthalamic Deep Brain Stimulation Impact Asymmetry and Dyscoordination of Gait in Parkinson’s Disease?
Authors: Ravi Deepak K , Baumann Christian R , Bernasconi Elena , Gwerder Michelle , König Ignasiak Niklas , Uhl Mechtild , Stieglitz Lennart , Taylor William R , Singh Navrag B
Published: February 2021

Background

Subthalamic deep brain stimulation is an effective treatment for selected Parkinson’s disease patients. Axial deficits including postural stability and gait characteristics are often altered after surgery, but quantitative gait-related therapeutic effects are poorly described.

Objective

The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait six-months post-operatively in patients with Parkinson’s disease, and compare the outcomes with preoperative baseline and to asymptomatic controls.

Methods

Thirty-two patients with Parkinson’s disease (19 with postural instability and gait disorder type, 13 with tremor-dominant disease) and 51 asymptomatic controls participated. Parkinson patients were tested prior to the surgery in both OFF and ON medication states, and six months post-operatively in the ON stimulation condition. Clinical outcome parameters and medication were compared to preoperative conditions. Asymmetry ratios, phase coordination index, and walking speed were assessed.

Results

Patients’ clinical outcomes as assessed by standard clinical parameters at six-months improved significantly, and levodopa-equivalent daily dosages were significantly decreased. STN-DBS increased step time asymmetry (hedges’ g effect sizes [confidence intervals] between pre- and post-surgery: 0.27 [-0.13,0.73]) and phase coordination index (0.29 [-0.08,0.67]). These effects were higher in the Postural Instability and Gait Disorder subgroup than the Tremor Dominant (step time asymmetry: 0.38 [-0.06,0.90] vs. 0.09 [-0.83,1.0] and phase coordination index: 0.39 [-0.04,0.84] vs. 0.13 [-0.76,0.96]).

Conclusion

This study provides objective evidence of how subthalamic deep brain stimulation increases asymmetry and dyscoordination of gait in patients with Parkinson’s disease, and suggests motor subtypes-associated differences in the treatment response.
Controlling the first wave of the COVID–19 pandemic in Malawi: results from a panel study
Authors: Banda Jethro , Dube Albert N. , Brumfield Sarah , Crampin Amelia C. , Reniers Georges , Amoah Abena S. , Helleringer Stéphane
Published: February 2021

Many African countries have experienced a first wave of the COVID–19 pandemic between June and August of 2020. According to case counts reported daily by epidemiological surveillance systems, infection rates remained low in most countries. This defied early models of the potential impact of COVID–19 on the continent, that projected large outbreaks and massive strain on health systems. Theories proposed to explain the apparently limited spread of the novel coronavirus in most African countries have emphasized 1) early actions by health authorities (e.g., border closures) and 2) biological or environmental determinants of the transmissibility of SARS-CoV-2 (e.g., warm weather, cross-immunity). In this paper, we explored additional factors that might contribute to the low recorded burden of COVID–19 in Malawi, a low-income country in Southeastern Africa. To do so, we used 4 rounds of panel data collected among a sample of adults during the first 6 months of the pandemic in the country. Our analyses of survey data on SARS-CoV-2 testing and COVID-related symptoms indicate that the size of the outbreak that occurred in June-August 2020 might be larger than recorded by surveillance systems that rely on RT-PCR testing. Our data also document the widespread adoption of physical distancing and mask use in response to the outbreak, whereas most measured patterns of social contacts remained stable during the course of the panel study. These findings will help better project, and respond to, future waves of the pandemic in Malawi and similar settings.
A cross-sectional study of socioeconomic status and treatment interruption among Japanese workers during the COVID-19 pandemic
Authors: Fujimoto Kenji , Ishimaru Tomohiro , Tateishi Seiichiro , Nagata Tomohisa , Tsuji Mayumi , Eguchi Hisashi , Ogami Akira , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork Project
Published: February 2021

Background

The COVID-19 pandemic has caused interruptions to chronic disease and non-emergency treatment. The purpose of this study is to examine which socioeconomic status groups are most at risk of treatment interruption.

Methods

This cross-sectional internet monitor study was conducted on December 22–26, 2020, when Japan experienced its third wave of COVID-19 infection. Out of a total of 33,302 participants in the survey, 9510 (5392 males and 4118 females) who responded that they required regular treatment or hospital visits were included in the analysis. A multilevel logistic model nested in the prefecture of residence was used to estimate the odds ratio (OR) for treatment disruption. We examined separate multivariate models for socioeconomic factors, health factors, and lifestyle factors.

Results

During a period of rapid COVID-19 infection, about 11% of Japanese workers who required regular treatment experienced interruptions to their treatment. The OR of treatment interruption associated with not being married compared to being married was 1.44; manual labor work compared to desk work was 1.30; loss of employment when the COVID-19 pandemic started and continued unemployment compared to being employed over the entire pandemic period was 1.62 and 2.57, respectively; and feeling financially unstable was 2.92.

Conclusion

Treatment interruption is a new health inequality brought about by COVID-19 with possible medium- and long-term effects, including excess mortality, morbidity, and productivity loss due to increased presenteeism. Efforts are needed to reduce treatment interruptions among workers who require regular treatment.
Estimating the spreading and dominance of SARS-CoV-2 VOC 202012/01 (lineage B.1.1.7) across Europe
Authors: Gozzi Nicolò , Chinazzi Matteo , Davis Jessica T. , Mu Kunpeng , y Piontti Ana Pastore , Ajelli Marco , Perra Nicola , Vespignani Alessandro
Published: February 2021

We develop a two strain, age-structured, compartmental model to assess the spreading potential of the B.1.1.7 variant across several European metropolitan areas and countries. The model accounts for B.1.1.7 introductions from the UK and different locations, as well as local mitigation policies in the time period 2020/09 − 2021/02. In the case of an increase of transmissibility of 50%, the B.1.1.7 variant has the potential to become dominant in all investigated areas by the end of March 2021.
Bone mechanoregulation allows subject-specific load estimation based on time-lapsed micro-CT and HR-pQCTin vivo
Authors: Walle Matthias , Marques Francisco C. , Ohs Nicholas , Blauth Michael , Müller Ralph , Collins Caitlyn J.
Published: February 2021

Patients at high risk of fracture due to metabolic diseases frequently undergo long-term antiresorptive therapy. However, in some patients treatment is unsuccessful in preventing fractures or causes severe adverse health outcomes. Understanding load driven bone remodelling, i.e. mechanoregulation, is critical to understand which patients are at risk for progressive bone degeneration and may enable better patient selection or adaptive therapeutic intervention strategies. Bone microarchitecture assessment using high-resolution peripheral quantitative computed tomography (HR-pQCT) combined with computed mechanical loads has successfully been used to investigate bone mechanoregulation at the trabecular level. To obtain the required mechanical loads that induce local variances in mechanical strain and cause bone remodelling, estimation of physiological loading is essential. Yet, current models homogenise strain patterns throughout the bone to estimate load distributionin vivo, which may be a flawed assumption for investigating alterations in bone mechanoregulation. By further utilising available spatiotemporal information of time-lapsed bone imaging studies, we developed a mechanoregulation-based load estimation algorithm (MR). MR calculates organ scale loads by scaling and superimposing a set of predefined independent unit loads to optimise measured bone formation in high, quiescence in medium and resorption in low strain regions. We benchmarked our algorithm against a previously published load history algorithm (LH) using synthetic data, micro-CT images of murine vertebrae under defined experimentalin vivoloadings and HR-pQCT images from seven patients. Our algorithm consistently outperformed LH in all three datasets.In silicogenerated time evolutions of distal radius geometries (n = 5) indicated significantly higher sensitivity, specificity, and accuracy for MR than LH (p < 0.01). This increased performance led to substantially better discrimination between physiological and extra-physiological loading in mice (n = 8). Moreover, a significantly (p < 0.01) higher association between remodelling events and computed local mechanical signals were found using MR (CCR = 0.42) than LH (CCR = 0.38) to estimate human distal radius loading. Future applications of MR may enable clinicians to link subtle changes in bone strength to changes in day-to-day loading, identifying weak spots in the bone micro-structure for local intervention and personalised treatment approaches.
Heterogeneity and excitability ofBRAFV600E-induced tumors is determined by PI3K/mTOR-signaling state andTrp53-loss
Authors: Cases-Cunillera Silvia , van Loo Karen M. J. , Pitsch Julika , Quatraccioni Anne , Sivalingam Sugirthan , Salomoni Paolo , Dietrich Dirk , Schoch Susanne , Becker Albert J.
Published: February 2021

Background

Developmental brain tumors harboringBRAFV600Esomatic mutation are diverse. Here, we describe molecular factors that determineBRAFV600E-induced tumor biology and function.

Methods

Intraventricularin uteroelectroporation in combination with the piggyBac transposon system is employed as a tool to generate developmental brain neoplasms.In vivotumor growth is monitored by using the infrared fluorescent protein (iRFP). Lineage inference is carried out by using the Brainbow transgene. Neural activity from tumor slices is assessed by multielectrode array. RNA sequencing is exploited to analyze the induced neoplasms at the transcriptomic level.

Results

BRAFV600Ein murine neural progenitors only in concert with active PI3K/mTOR-signaling through constitutively phosphorylated Akt-kinase (pAkt) elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG). Purely glial tumors partially resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge fromBRAFV600Ealone. Additional somaticTrp53-loss is sufficient to induce anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, onlyBRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG-models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter.

Conclusion

mTOR-signaling andTrp53-loss critically determine the biological diversity and electrical activity ofBRAFV600E-induced tumors.

Key points

IUE of BRAFV600Eand activation of mTOR leads to ganglioglioma (GG)-like tumors, while BRAFV600Ealone give rise to PLNTY-like neoplasms.

Anaplastic GGs depend on the Trp53 deletion in combination to BRAFV600Eand PI3K-mTOR signaling cascade.

Importance of the Study

Glioneuronal tumors are challenging with respect to biological behavior and seizure emergence. WhileBRAFV600Ein murine neural precursors induces oligoid tumors, it requires an overactivation of PI3K/mTOR-signaling for the development of hyperexcitable gangliogliomas and additionalTrp53-loss for anaplastic transformation.
E. colichemotaxis is information-limited
Authors: Mattingly H.H. , Kamino K. , Machta B.B. , Emonet T.
Published: February 2021

Organisms must acquire and use environmental information to guide their behaviors. However, it is unclear whether and how information quantitatively limits behavioral performance. Here, we relate information to behavioral performance inEscherichia colichemotaxis. First, we derive a theoretical limit for the maximum achievable gradient-climbing speed given a cell’s information acquisition rate. Next, we measure cells’ gradient-climbing speeds and the rate of information acquisition by the chemotaxis pathway. We find thatE. colimake behavioral decisions with much less than the 1 bit required to determine whether they are swimming up-gradient. However, they use this information efficiently, performing near the theoretical limit. Thus, information can limit organisms’ performance, and sensory-motor pathways may have evolved to efficiently use information from the environment.
Effect of Initial pH and Organic Matter Concentration on Production of Volatile Organic Acids Through Acidogenesis of Sugarcane Vinasse
Authors: Martins Juliana , de Araújo Hugo Valença , Mockaitis Gustavo , da Silva Ariovaldo José
Published: February 2021

Sugarcane vinasse is an industrial liquid waste generated in great amounts in Brazilian ethanol industries. Nowadays its main use occurs at sugarcane crops, where vinasse is applied as a nutrient source for fertirrigation. However, continued use of vinasse in soil can cause several environmental impacts. So, aiming to provide a more environmentally friendly destination to the effluent, the goal of this work was to investigate the acidogenesis using a synthetic vinasse as substrate, focusing on the effects of initial pH and Chemical Oxygen Demand (COD) on short chain organic acids (SCOAs) concentrations. Synthetic vinasse was prepared at laboratory taking some real sugarcane vinasse composition given in previous works as references. So, major contribution presented here is the investigation on obtaining high added-value SCOAs from a simulated effluent. Cattle manure sludge was utilized as inoculum to promote the conversion of carbohydrate (sucrose, Suc) in synthetic vinasse into SCOAs in batch reactors during a total incubation time of 72 h. Acidogenesis profiles have shown that concentration of lactic acid (HLa) was prevailing among all metabolites, indicating that process followed through an essentially lactic route. Furthermore, considerable concentrations of propionic, acetic and isobutyric acids were also verified at some specific operation times, while solventogenesis was not detected at all. The greatest peak of lactate content was 4.96 g HLa L−1, observed under initial pH 6.0 and 25 g COD L−1, at 16 h. Maximum of lactate productivity was 332.10 g HLa L−1h−1at 8 h, associated to a yield of 189.14 g HLa (g Suc)−1, under initial pH 7.5 and 20 g COD L−1.
The G2-phase enriched lncRNASNHG26is necessary for proper cell cycle progression and proliferation
Authors: Samdal Helle , Hegre Siv A. , Chawla Konika , Liabakk Nina-Beate , Aas Per A. , Sporsheim Bjørnar , Sætrom Pål
Published: February 2021

Long noncoding RNAs (lncRNAs) are involved in the regulation of cell cycle, although only a few have been functionally characterized. By combining RNA sequencing and ChIP sequencing of cell cycle synchronized HaCaT cells we have previously identified lncRNAs highly enriched for cell cycle functions. Based on a cyclic expression profile and an overall high correlation to histone 3 lysine 4 trimethylation (H3K4me3) and RNA polymerase II (Pol II) signals, the lncRNASNHG26was identified as a top candidate. In the present study we report that downregulation ofSNHG26affects mitochondrial stress, proliferation, cell cycle phase distribution, and gene expression incis- and intrans, and that this effect is reversed by upregulation ofSNHG26. We also find that the effect on cell cycle phase distribution is cell type specific and stable over time. Results indicate an oncogenic role ofSNHG26, possibly by affecting cell cycle progression through the regulation of downstream MYC-responsive genes.
RELATIONSHIP BETWEEN PARENTAL AGE AND SEVERITY OF OROFACIAL CLEFTS
Authors: Adamson Olawale , Oladugba Abimibola V. , Alade Azeez , Awotoye Waheed O. , Busch Tamara , Li Mary , Olotu Joy , Sule Veronica C. , Fashina Azeez , Olutayo James , Ogunlewe Mobolanle O. , Adeyemo Wasiu L. , Butali Azeez
Published: February 2021

OBJECTIVES

This study aims to investigate the relationship between paternal age, maternal age, and both on the severity of orofacial clefts.

DESIGN

This was a retrospective study of cases which were subjects clinically diagnosed with non-syndromic cleft lip and/or palate (CL/P). Data was obtained from the AFRICRAN project database on Nigerian non-syndromic orofacial cleft cases.

SETTING

The samples for cases in this study were obtained at the Cleft clinic of Oral and Maxillofacial surgery at the Lagos University Teaching Hospital, Lagos.

OUTCOME

Primary outcome measure is severity of orofacial clefts and secondary outcome measure is to evaluate the effect of parental age in determining the incidence of left or right sided orofacial clefts.

RESULTS

There is no statistical significant association between type of CL ± P and parental age in young fathers (p=0.93). When old fathers are considered, percentage of complete (more severe) CL ± P cases increases especially in old mothers and this was statistically significant (p=0.036). In old fathers, the risk of CL ± P is increased (OR: 2.66, CI: 1.04-6.80) and also there is increased risk of developing right sided CL ± P (OR: 1.61, CI: 1.0-2.59). There is reduced risk of isolated cleft palate in young fathers (OR: 0.36, CI: 0.07-1.71) but the risk increases when considering complete types (more severe) of isolated cleft palates (OR: 1.63, CI: 0.71-3.7)

CONCLUSION

The study shows a higher risk of CL ± P is associated with increase father’s age.
Acidogenic Fermentation of Sugarcane Vinasse and Glucose Using Two Different Anaerobic Digestion Inocula
Authors: Martins Juliana , de Araújo Hugo Valença , Mockaitis Gustavo , da Silva Ariovaldo José
Published: February 2021

Vinasse is an agroindustrial wastewater obtained at large amounts in countries such as Brazil, which is one of the world greatest sugar and ethanol producers from sugarcane. Despite its most common use is as nutrient for fertirrigation in sugarcane crops nowadays, alternative processing has been intensely sought in last decades for vinasse aiming primarily the production of energy carriers and high-added value chemicals. One of these alternatives is the anaerobic digestion promoted by bacteria, which results in several products of economic importance. In view of these information, this work presents an investigation of acidogenic fermentation byC. acetobutylicumATCC 824 andC. beijerinckiiATCC 25752 was conducted in batch reactors by using synthetic vinasse and aqueous glucose solution as substrates. Evaluation of effects of microorganism and carbon source was focused mainly on the production of short chain organic acids (SCOAs), although other metabolites, such as ethanol, were also detected. Carbohydrates were effectively consumed by bacteria, so remaining concentrations of sucrose and glucose (Suc and Glu) in both substrates were considerably low at the end of tests. Lactic acid (HLa) was the prevailing metabolite in all experiments, determining the trends observed for total SCOAs content as a function of incubation time, while other acids were generated in much lesser amounts. Moreover, ethanol (EtOH) attained notably higher concentrations in batch reactors containing glucose as substrate, which showed more relevant production of this chemical. Maximum of 14.1 g HLa L−1was quantified for lactic acid at incubation time 96 h in reactor using synthetic vinasse andC. beijerinckii(VB), linked to a productivityP= 146.46 mg HLa L−1h−1and a yieldY= 1108.03 mg HLa (g Sue)−1. For ethanol, maximum was 1.6 g EtOH L−1, occurring in reactor containing glucose andC. acetobutylicum(GA) also at incubation time 90 h, resulting inP= 13.60 mg EtOH L−1h−1andY= 73.04 mg EtOH (g Glu)−1. Finally, kinetic models were adjusted to experimental data of carbohydrate content, lactate concentration and optical density (indicative of microorganism growth), showing good prediction capability as suggested by values of fit quality parameters such as Residual Sum of Squares (RSS) andR2.
A combined EM and proteomic analysis places HIV-1 Vpu at the crossroads of retromer and ESCRT complexes: PTPN23 is a Vpu-cofactor
Authors: Stoneham Charlotte A. , Langer Simon , De Jesus Paul D. , Wozniak Jacob M. , Lapek John , Deerinck Thomas , Thor Andrea , Pache Lars , Chanda Sumit K. , Gonzalez David J. , Ellisman Mark , Guatelli John
Published: February 2021

The HIV-1 accessory protein Vpu modulates membrane protein trafficking and degradation to provide evasion of immune surveillance. Targets of Vpu include CD4, HLAs, and BST-2. Several cellular pathways co-opted by Vpu have been identified, but the picture of Vpu’s itinerary and activities within membrane systems remains incomplete. Here, we used fusion proteins of Vpu and the enzyme ascorbate peroxidase (APEX2) to compare the ultrastructural locations and the proximal proteomes of wild type Vpu and Vpu-mutants. The proximity-omes of the proteins correlated with their ultrastructural locations and placed wild type Vpu near both retromer and ESCRT-0 complexes. Hierarchical clustering of protein abundances across the mutants was essential to interpreting the data and identified Vpu degradation-targets including CD4, HLA-C, and SEC12 as well as Vpu-cofactors including HGS, STAM, clathrin, and PTPN23, an ALIX-like protein. The Vpu-directed degradation of BST-2 required PTPN23 but not the retromer subunits. These data suggest that Vpu directs targets from sorting endosomes to degradation at multi-vesicular bodies via ESCRT-0 and PTPN23.

Author Summary

Vpu triggers the degradation or mis-localization of proteins important to the host’s immune response. Vpu acts as an adaptor, linking cellular protein targets to the ubiquitination and membrane trafficking machinery. Vpu has been localized to various cellular membrane systems. By fusing wild type Vpu and Vpu-mutants to the enzyme ascorbate peroxidase, we defined the cellular proteome in proximity to Vpu and correlated this with the protein’s location. We found that wild type Vpu is proximal to ESCRT proteins, retromer complexes, and sorting and late endosomal proteins. Functionally, we found that the Vpu-mediated degradation of the innate defense protein BST-2 required PTPN23, an ALIX-like protein, consistent with our observation of Vpu’s presence at the limiting membranes of multi-vesicular bodies.
The multidimensional nutritional niche of fungus-cultivar provisioning in free-ranging colonies of a neotropical leafcutter ant
Authors: Crumière Antonin J.J. , James Aidan , Lannes Pol , Mallett Sophie , Michelsen Anders , Rinnan Riikka , Shik Jonathan Z.
Published: February 2021

The foraging trails ofAttaleafcutter colonies are among the most iconic scenes in Neotropical ecosystems, with thousands of ants carrying freshly cut plant fragments back to their nests where they are used to provision a fungal food crop. We tested a hypothesis that the fungal cultivar’s multidimensional requirements for macronutrients (protein and carbohydrates) and minerals (Al, Ca, Cu, Fe, K, Mg, Mn, Na, P and Zn) govern the foraging breadth ofAtta colombicaleafcutter ants in a Panamanian rainforest. Analyses of freshly cut plant fragments carried by leafcutter foragers showed that the combination of fruits, flowers, and leaves provide for a broad realized nutritional niche that can maximize cultivar’s performance. And, while the leaves that comprised the most harvested resource also delivered an intake target containing protein in excess of the amounts that can maximize cultivar growth,in vitroexperiments showed that the minerals P, Al, and Fe can enhance the cultivar’s tolerance to protein-biased substrates, and potentially expand the ants’ foraging niche. Yet, the cultivar also exhibits narrow margins between mineral limitation and toxicity that may render plant fragments with seemingly optimal blends of macronutrients unsuitable for provisioning. Our approach highlights that optimal foraging is inherently multidimensional and links the foraging behavior of a generalist insect herbivore to the fundamental nutritional niche of its microbial symbiont.

Significance Statement

Colonies ofAtta colombicaleafcutter ants can contain millions of specialized workers exhibiting large-scale generalist herbivory. Yet, this generalist foraging niche also depends on the poorly understood physiological needs of the ants’ domesticated fungal cultivar. We show the cultivar’s fundamental nutritional niche is broad for carbohydrates but narrower for protein and a suite of minerals, but that the cultivar’s sensitivity to excess protein is also mediated by Al, Fe, and P. More generally, this study decouples the multidimensional foraging strategies that enable a generalist herbivore to navigate a complex nutritional landscape and mix many imbalanced foods to achieve balanced cultivar provisioning.
Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Authors: Wang Chao , Fan Li , Zhan Lihong , Kodama Lay , Liu Bangyan , Chin Marcus , Li Yaqiao , Le David , Zhou Yungui , Condello Carlo , Grinberg Lea , Seeley William W. , Miller Bruce , Mok Sue-Ann , Gestwicki Jason , Gan Li
Published: February 2021

Activation of microglia, the brain’s innate immune cells, is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in PS19 mice, consistent with the observation that NF-κB activation accelerates processing of internalized tau fibrils in primary microglia. Remarkably, inhibition of microglial NF-κB specifically also rescued tau-mediated learning and memory deficits, and restored overall transcriptomic changes while increasing tau inclusions. On a single cell level, we discovered that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a central role for microglial NF-κB signaling in mediating tau toxicity in tauopathy.
Planum Temporale grey matter volume asymmetries in new-born monkeys (Papio anubis)
Authors: Becker Yannick , Phelipon Romane , Sein Julien , Velly Lionel , Renaud Luc , Meguerditchian Adrien
Published: February 2021

The Planum Temporale (PT)is one of the key hubs of the language network in the human brain. The gross asymmetry of this perisylvian region toward the left brain was considered as the most emblematic marker of hemispheric specialization of language processes in the brain. Interestingly, this neuroanatomical signature was documented also in newborn infants and preterms, suggesting the early brain’s readiness for language acquisition. Nevertheless, this latter interpretation was questioned by a recent report in nonhuman primates of a potential similar signature in newborn baboonsPapio anubisbased onPTsurface measures. Whether this “tip of the iceberg”PTasymmetry is actually reflecting asymmetry of its underlying grey matter volume remain unclear but critical to investigate potential continuities of cortical specialization with human infants. Here we report a population-level leftward asymmetry of the Planum Temporale grey matter volume inin vivo34 newborn baboonsPapio anubis, which showed intra-individual positive correlation withPTsurface’s asymmetry measures but also a more pronounced degree of leftward asymmetry at the population-level. This finding demonstrates thatPTleftward structural asymmetry in this Old World monkey species is a robust phenomenon in early primate development, which clearly speaks for a continuity with early human brain specialization. Results also strengthen the hypothesis that early PT asymmetry might be not a human-specific marker for the pre-wired language-ready brain in infants.
Lipid type doping of the sponge (L3) mesophase
Authors: Brasnett Christopher , Squires Adam , Smith Andrew , Seddon Annela
Published: February 2021

The polymorphism of lipid aggregates has long attracted detailed study due to the myriad factors that determine the final mesophase observed. This study is driven by the need to understand mesophase behaviour for a number of applications, such as drug delivery and membrane protein crystallography. In the case of the latter, the role of the so-called ‘sponge’ (L3) mesophase has been often noted, but not extensively studied by itself. The L3mesophase can be formed in monoolein/water systems on the addition of butanediol to water, which partitions the headgroup region of the membrane, and decreases its elastic moduli. Like cubic mesophases, it is bicontinuous, but unlike them, has no long-range translational symmetry. In our present study, we show that the formation of the L3phase can delicately depend on the addition of dopant lipids to the mesophase. While electrostatically neutral molecules similar in shape to monoolein (DOPE, cholesterol) have little effect on the general mesophase behaviour, others (DOPC, DDM) significantly reduce the region in which it can form. Additionally, we show that by combining cholesterol with the anionic lipid DOPG, it is possible to form the largest stable L3mesophases observed to date, with correlation lengths over 220 Å.
Catabolism of lysosome-related organelles in color-changing spiders supports intracellular turnover of pigments
Authors: Figon Florent , Hurbain Ilse , Heiligenstein Xavier , Trépout Sylvain , Medjoubi Kadda , Somogyi Andrea , Delevoye Cédric , Raposo Graça , Casas Jérôme
Published: February 2021

Pigment organelles of vertebrates belong to the lysosome-related organelle (LRO) family, of which melanin-producing melanosomes are the prototypes. While their anabolism has been extensively unraveled through the study of melanosomes in skin melanocytes, their catabolism remains poorly known. Here, we tap into the unique ability of crab spiders to reversibly change body coloration to examine the catabolism of their pigment organelles. By combining ultrastructural and metal analyses on high-pressure frozen integuments, we first assess whether pigment organelles of crab spiders belong to the LRO family and, second, how their catabolism is intracellularly processed. Using scanning-transmission electron microscopy, electron tomography and nanoscale Synchrotron-based scanning X-ray fluorescence, we show that pigment organelles possess ultrastructural and chemical hallmarks of LROs, including intraluminal vesicles and metal deposits, similar to melanosomes. Monitoring ultrastructural changes during bleaching suggests that the catabolism of pigment organelles involves the degradation and removal of their intraluminal content, possibly through lysosomal mechanisms. In contrast to skin melanosomes, anabolism and catabolism of pigments proceed within the same cell without requiring either cell death or secretion/phagocytosis. Our work hence provides support for the hypothesis that the endolysosomal system is fully functionalized for within-cell turnover of pigments, leading to functional maintenance under adverse conditions and phenotypic plasticity. First formulated for eye melanosomes in the context of human vision, the hypothesis of intracellular turnover of pigments gets unprecedented strong support from pigment organelles of spiders.
Chemotherapy coupled to macrophage inhibition leads to enhanced T and B cell infiltration and durable triple negative breast cancer regression
Authors: Singh Swarnima , Lee Nigel , Pedroza Diego A. , Bado Igor , Zhang Licheng , Aguirre Sergio , Hamor Clark , Shen Yichao , Xu Yitian , Hu Jingyuan , Gao Yang , Zhao Na , Chen Shu-Hsia , Wan Ying-Wooi , Liu Zhandong , Chang Jeffrey T. , Hollern Daniel , Perou Charles M. , Zhang Xiang H.F. , Rosen Jeffrey M.
Published: February 2021

Immunosuppressive elements within the tumor microenvironment such as Tumor Associated Macrophages (TAMs) can present a barrier to successful anti-tumor responses by cytolytic T cells. We employed preclinical syngeneic p53 null mouse models of triple negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was used to successfully treat several highly aggressive TNBC murine mammary tumors and lung metastasis. Using this regimen and single cell RNA sequencing we characterized tumor infiltrating lymphocytes (TILs) including helper T cells and antigen-presenting B cells that were highly enriched in good responders to combination therapy. Using high dimensional imaging techniques, we identified the close spatial localization of B220+ CD86+ activated B cells and CD4+ T cells in tertiary lymphoid structures that were present up to 6 weeks post-treatment in one model that also exhibited long-term tumor regression post-treatment. We also characterized the transcriptional and metabolic heterogeneity of TAMS in these two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model is highly expressed and conserved in human claudin-low breast cancers, and high expression of the T12 signature correlated with reduced overall survival. This T12 tumor TAM signature may help identify human claudin-low breast cancer patients that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rationale combinations of immunotherapy.

Significance

A treatment regimen that harnessed the immunostimulatory effects of cyclophosphamide coupled with the inhibition of CSF1R was used to successfully treat several highly aggressive claudin-low TNBC murine mammary tumors and lung metastasis.
Rewritable Two-Dimensional DNA-Based Data Storage with Machine Learning Reconstruction
Authors: Pan Chao , Tabatabaei S. Kasra , Tabatabaei Yazdi SM Hossein , Hernandez Alvaro G. , Schroeder Charles M. , Milenkovic Olgica
Published: February 2021

DNA-based data storage platforms traditionally encode information only in the nucleotide sequence of the molecule. Here we report on a two-dimensional molecular data storage system that records information in both the sequence and the backbone structure of DNA and performs nontrivial joint data encoding, decoding and processing. Our 2DDNA method efficiently stores high-density images in synthetic DNA and embeds pertinent metadata as nicks in the DNA backbone. To avoid costly worst-case redundancy for correcting sequencing/rewriting errors and to mitigate issues associated with mismatched decoding parameters, we develop machine learning techniques for automatic discoloration detection and image inpainting. The 2DDNA platform is experimentally tested by reconstructing a library of images with undetectable or small visual degradation after readout processing, and by erasing and rewriting copyright metadata encoded in nicks. Our results demonstrate that DNA can serve both as a write-once and rewritable memory for heterogenous data and that data can be erased in a permanent, privacy-preserving manner. Moreover, the storage system can be made robust to degrading channel qualities while avoiding global error-correction redundancy.
Dynamic large-scale connectivity of intrinsic cortical oscillations supports adaptive listening in challenging conditions
Authors: Alavash Mohsen , Tune Sarah , Obleser Jonas
Published: February 2021

In multi-talker situations individuals adapt behaviorally to the listening challenge mostly with ease, but how do brain neural networks shape this adaptation? We here establish a long-sought link between large-scale neural communications in electrophysiology and behavioral success in the control of attention in difficult listening situations. In an age-varying sample of N = 154 individuals, we find that connectivity between intrinsic neural oscillations extracted from source-reconstructed electroencephalography is regulated according to the listener’s goal during a challenging dual­ talker task. These dynamics occur as spatially organized modulations in power-envelope correlations of alpha and low-beta neural oscillations during ~2 seconds intervals most critical for listening behavior relative to resting-state baseline. First, left frontoparietal low-beta connectivity (16-24 Hz) increased during anticipation and processing of spatial-attention cue before speech presentation. Second, posterior alpha connectivity (7-11 Hz) decreased during comprehension of competing speech, particularly around target-word presentation. Connectivity dynamics of these networks were predictive of individual differences in the speed and accuracy of target-word identification, respectively, but proved unconfounded by changes in neural oscillatory activity strength. Successful adaptation to a listening challenge thus latches onto two distinct yet complementary neural systems: a beta-tuned frontoparietal network enabling the flexible adaptation to attentive listening state and an alpha-tuned posterior network supporting attention to speech.

Significance Statement

Attending to relevant information during listening is key to human communication. How does this adaptive behavior rely upon neural communications? We here follow up on the long-standing conjecture that, large-scale brain network dynamics constrain our successful adaptation to cognitive challenges. We provide evidence in support of two intrinsic, frequency-specific neural networks that underlie distinct behavioral aspects of successful listening: a beta-tuned frontoparietal network enabling the flexible adaptation to attentive listening state, and an alpha-tuned posterior cortical network supporting attention to speech. These findings shed light on how large-scale neural communication dynamics underlie attentive listening and open new opportunities for brain network-based intervention in hearing loss and its neurocognitive consequences.