bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha-synucleinopathy reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
Authors: Parsons Richard B , Kocinaj Altin , Ruiz Pulido Gustavo , Prendergast Sarah A , Parsons Anna E , Facey Paul D , Hirth Frank
Published: April 2022

Parkinson’s disease is characterized by the deposition of α-synuclein, which leads to synaptic dysfunction, the loss of neuronal connections and ultimately progressive neurodegeneration. Despite extensive research into Parkinson’s disease pathogenesis, the mechanisms underlying α-synuclein-mediated synaptopathy have remained elusive. Several lines of evidence suggest that altered nicotinamide adenine dinucleotide (NAD+) metabolism might be causally related to synucleinopathies, including Parkinson’s disease. NAD+ metabolism is central to the maintenance of synaptic structure and function. Its synthesis is mediated by nicotinamide mononucleotide adenylyltransferases (NMNATs), but their role in Parkinson’s disease is not known. Here we report significantly decreased levels of NMNAT3 protein in the caudate nucleus of patients who have died with Parkinson’s disease, which inversely correlated with the amount of monomeric α-synuclein. The detected alterations were specific and significant as the expression levels of NMNAT1, NMNAT2 and sterile alpha and TIR motif containing 1 (SARM1) were not significantly different in Parkinson’s disease patients compared to controls. To test the functional significance of these findings, we ectopically expressed wild-type α-synuclein in retinoic acid-differentiated dopaminergic SH-SY5Y cells that resulted in decreased levels of NMNAT3 protein plus a neurite pathology, which could be rescued by FK866, an inhibitor of nicotinamide phosphoribosyltransferase that acts as a key enzyme in the regulation of NAD+ synthesis. Our results establish, for the first time, NMNAT3 alterations in Parkinson’s disease and demonstrate in human cells that this phenotype together with neurite pathology is causally related to α-synucleinopathy. These findings identify alterations in the NAD+ biosynthetic pathway as a pathogenic mechanism underlying α-synuclein-mediated synaptopathy.
The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy
Authors: Li Dalin , Xu Alexander , Mengesha Emebet , Elyanow Rebecca , Gittelman Rachel M , Chapman Heidi , Prostko John C , Frias Edwin C , Stewart James L , Pozdnyakova Valeriya , Debbas Philip , Mujukian Angela , Horizon Arash A , Merin Noah , Joung Sandy , Botwin Gregory J , Sobhani Kimia , Figueiredo Jane C , Cheng Susan , Kaplan Ian M , McGovern Dermot P B , Merchant Akil , Melmed Gil Y , Braun Jonathan
Published: April 2022

Lay Summary

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.
Humoral Immunogenicity of 3 COVID-19 Messenger RNA Vaccine Doses in Patients With Inflammatory Bowel Disease
Authors: Schell Trevor L , Knutson Keith L , Saha Sumona , Wald Arnold , Phan Hiep S , Almasry Mazen , Chun Kelly , Grimes Ian , Lutz Megan , Hayney Mary S , Farraye Francis A , Caldera Freddy
Published: April 2022

Lay Summary

Herein, we evaluated the humoral immunogenicity of a third coronavirus disease 2019 messenger RNA vaccine dose in patients with inflammatory bowel diseases. All patients displayed a humoral immune response, and median antibody concentrations were higher after the third dose than after completion of the 2-dose series.
Tackling antimicrobial resistance in practice: dental students’ evaluation of university teaching supplemented by an online course
Authors: Cooper Lesley , Sneddon Jacqueline , Thompson Wendy , Guise Tracey , Robertson Douglas , Smith Andrew
Published: April 2022

Background

Antimicrobial resistance (AMR) presents a global threat to public health. Engaging all healthcare professionals including undergraduates in efforts to tackle AMR is vital. Sharing and spreading good practice in teaching on AMR and antimicrobial stewardship (AMS) is a key ambition in Scotland. In 2020, the University of Glasgow Dental School supplemented teaching with mandatory completion by final year undergraduates of an online education programme on the essential role of dental teams in reducing AMR.

Objectives

To evaluate final year dental students’ knowledge and experience of utilizing an online international educational, interactive resource to supplement university teaching: Tackling Antibiotic Resistance: What Should Dental Teams Do?

Methods

Cross-sectional qualitative evaluation using a self-administered questionnaire with open questions about course content, learning and personal action planning. Data were thematically analysed using NVivo12 Pro software.

Results

A total of 88 students completed a questionnaire, which indicated online training had increased their understanding of AMR and AMS from a global perspective and confirmed these topics were an integral part of their undergraduate education programme. Their action plans demonstrated enthusiasm for creating an AMS culture in clinical practice and an understanding of the need for ongoing education of themselves, their colleagues and patients.

Conclusions

Education delivery using a variety of media to support teaching and learning in Glasgow Dental School was effective in ensuring that students understand their role in tackling AMR. Students were positive about the addition of an online education programme to supplement university teaching. This approach may be beneficial for other undergraduate dentistry programmes.
Department-focused electronic health record thrive training
Authors: Livingston Katie , Bovi Joseph
Published: April 2022

A novel approach of department-focused electronic health record (EHR) training was implemented to improve efficiency and time management of EHR use. Based off baseline log data, 5 in-person training sessions were designed, focusing on the common inefficiencies of 6 chosen participants. Log data of 4 key metrics and 2 efficiency scores were analyzed 4 months post-training. A survey was conducted to assess self-reported EHR competence. Individually, several participants had improved efficiency scores. There was a reduced average time spent in the inbox per day, in notes per dictation, and in notes per day. This translated to an average of 8.9 min saved per day (range 0–29.1 min/day) and 37.1 hours saved per year (range 0–116.2 hours/year). From the post-training surveys, all participants felt more efficient in their use of the EHR. This study demonstrates an example of department-focused EHR training and log-based analysis improving time management and efficiency.
Immunomodulatory Treatment of Lyell’s Syndrome: A Simultaneous Plasmapheresis and Intravenous Immunoglobulins Therapy
Authors: Strużyna Jerzy , Surowiecka Agnieszka , Korzeniowski Tomasz , Piszczek Joanna , Korulczyk Patrycja , Drozd Lukasz , Stachura Aldona , Torres Kamil , Krajewski Andrzej
Published: April 2022

Lyell’s syndrome, or toxic epidermal necrolysis (TEN) is a rare but life-threatening condition. It manifests with blistering of skin and mucous due to subepidermal bullae and keratinocyte necrosis. In most cases, it is an immune response to drugs or their metabolites. The mortality in TEN is high despite optimal infection and wound control. There are no unequivocal treatment guidelines in TEN. Immunosuppressive treatment may increase the wound infection risk and mortality. The aim of the study was to evaluate a 10-year experience with immunomodulatory therapy in TEN. We perform a combination of plasmapheresis and intravenous immunoglobulins to control the disease. There were 35 patients in the group and we performed a post hoc evaluation. Twenty-eight patients received the full protocol and there were seven patients who did not complete the treatment (single therapy group). The mortality in the test group was 14.29%, and the difference reached statistical significance in comparison with the single therapy group (P < .05). Our protocol reduced the mortality risk five times. Our study proved that simultaneous plasmaphereses with intravenous immunoglobulins administration were safe and improved patients’ outcome in TEN.
The impact of fascia iliaca nerve blockade on early postoperative pain and recovery after hip arthroscopy for femoroacetabular impingement syndrome
Authors: August Grant , Johnson Andrea H , Turcotte Justin J , Petre Benjamin M
Published: April 2022

Fascia iliaca nerve blockade (FIB) has been previously described as an effective technique for reducing postoperative pain and opioid consumption after hip arthroscopy for femoroacetabular impingement syndrome (FAIS). We hypothesize that an FIB will significantly reduce opioid consumption, pain scores and recovery time in our population. A retrospective observational study of 326 consecutive patients undergoing hip arthroscopy for FAIS at a single institution was performed. Patients were classified based on whether or not they received an FIB. Patient demographics, surgical details, medication details and 6-month postoperative outcomes were collected. The primary endpoint was the amount of narcotics required intraoperatively and in the postanesthesia care unit (PACU). Of the 326 patients included in the study, 37 received an FIB. No differences in sex, age or other surgical details were observed between groups. Patients receiving an FIB were more likely to receive celecoxib (P < 0.001), pregabalin (P = 0.001) and methocarbamol (P = 0.002). The FIB group received lower doses of narcotics intraoperatively (P = 0.001), postoperatively (P < 0.001) and in total (P < 0.001). The FIB group also self-reported lower first pain scores upon arrival to PACU (P = 0.001) and experienced shorter PACU recovery times (P < 0.001). After controlling for differences between groups, patients who received an FIB required significantly lower amounts of narcotics, had shorter PACU times and lower first PACU pain score than those who did not (P < 0.001). No differences in complication rates were noted between groups. The use of FIB resulted in lower pain scores, reduced recovery time and decreased early postoperative narcotic requirements for patients undergoing hip arthroscopy for femoroacetabular impingement. Further study is required to validate these findings and determine the optimal approach to regional analgesia in this patient population.
Methodological Problems in Quantitative Research on Environmental Effects in Phonology
Authors: Hartmann Frederik
Published: April 2022

This paper engages with the quantitative methodology underlying studies proposing a link between environment and phonology by replicating three prominent studies on ejectives and altitude, vowels and humidity, and sonority and ambient temperature. It argues that there are several issues regarding the methodological footing of such correlational studies. Further, the paper finds that the problems of statistically analyzing environmental datasets in phonology run deeper than the focus on individual phonetic features suggests: there are several overarching patterns of correlations to be found in these datasets that, if not understood and accounted for, render mistaking spurious correlations for real effects inevitable. This paper further makes concrete suggestions for what is needed to move beyond pairwise correlational studies between environmental and phonological variables in future investigations.
New evidences in IRDC G333.73 + 0.37: colliding filamentary clouds, hub-filament system, and embedded cores
Authors: Dewangan L K
Published: April 2022

To unravel the star formation process, we present a multi-scale and multi-wavelength study of the filamentary infrared dark cloud (IRDC) G333.73 + 0.37, which hosts previously known two H ii regions located at its center. Each H ii region is associated with a mid-infrared source, and is excited by a massive OB star. Two filamentary structures and a hub-filament system (HFS) associated with one H ii region are investigated in absorption using the Spitzer 8.0 μm image. The 13CO(J = 2–1) and C18O(J = 2–1) line data reveal two velocity components (around −35.5 and −33.5 km s−1) toward the IRDC, favouring the presence of two filamentary clouds at different velocities. Non-thermal (or turbulent) motions are depicted in the IRDC using the C18O line data. The spatial distribution of young stellar objects (YSOs) identified using the VVV near-infrared data traces star formation activities in the IRDC. Low-mass cores are identified toward both the H ii regions using the ALMA 1.38 mm continuum map. The VLT/NACO adaptive-optics L′-band images show the presence of at least three point-like sources and the absence of small-scale features in the inner 4000 AU around YSOs NIR31 and MIR 16 located toward the H ii regions. The H ii regions and groups of YSO are observed toward the central part of the IRDC, where the two filamentary clouds intersect. A scenario of cloud–cloud collision or converging flows in the IRDC seems to be applicable, which may explain star formation activities including HFS and massive stars.
A study of the F-giant star θ Scorpii A: a post-merger rapid rotator?
Authors: Lewis Fiona , Bailey Jeremy , Cotton Daniel V , Howarth Ian D , Kedziora-Chudczer Lucyna , van Leeuwen Floor
Published: April 2022

We report high-precision observations of the linear polarization of the F1III star θ Scorpii. The polarization has a wavelength dependence of the form expected for a rapid rotator, but with an amplitude several times larger than seen in otherwise similar main-sequence stars. This confirms the expectation that lower-gravity stars should have stronger rotational-polarization signatures as a consequence of the density dependence of the ratio of scattering to absorption opacities. By modelling the polarization, together with additional observational constraints (incorporating a revised analysis of Hipparcos astrometry, which clarifies the system’s binary status), we determine a set of precise stellar parameters, including a rotation rate $\omega \, (= \Omega /\Omega _{\rm c})\ge 0.94$, polar gravity $\log (g_{\rm p})= 2.091 ^{+0.042}_{-0.039}$ (dex cgs), mass $3.10 ^{+0.37}_{-0.32}$ M⊙, and luminosity $\log (L/\rm{L}_{\odot }) =3.149^{+0.041}_{-0.028}$. These values are incompatible with evolutionary models of single rotating stars, with the star rotating too rapidly for its evolutionary stage, and being undermassive for its luminosity. We conclude that θ Sco A is most probably the product of a binary merger.
De novo major cardiovascular events in kidney transplant recipients: a comparative matched cohort study
Authors: Kim Ji Eun , Park Jina , Park Sehoon , Yu Mi-yeon , Baek Seon Ha , Park Sang Hyun , Han Kyungdo , Kim Yong Chul , Kim Dong Ki , Oh Kook-Hwan , Joo Kwon Wook , Kim Yon Su , Lee Hajeong
Published: April 2022

Background

Although cardiovascular disease is known to be one of the leading causes of death after kidney transplantation (KT), evidence on the risk difference of de novo major adverse cardiovascular events (MACEs) in kidney transplant recipients (KTRs) compared with that in dialysis patients or the general population (GP) remains rare.

Methods

We identified KTRs using the nationwide health insurance database in South Korea and then 1:1 matched them with the dialysis and GP controls without a pre-existing MACE. The primary endpoint was defined as de novo MACEs consisting of myocardial infarction, coronary revascularization and ischemic stroke. The secondary endpoints were all-cause mortality and death-censored graft failure (DCGF) in KTRs.

Results

We included 4156 individuals in each of the three groups and followed them up for 4.7 years. De novo MACEs occurred in 3.7, 21.7 and 2.5 individuals per 1000 person-years in the KTRs, dialysis controls and GP controls, respectively. KTRs showed a lower MACE risk {adjusted hazard ratio (aHR) 0.16 [95% confidence interval (CI) 0.12–0.20], P < .001} than dialysis controls, whereas a similar MACE risk to GP controls [aHR 0.81 (95% CI 0.52–1.27), P = .365]. In addition, KTRs showed a similar MACE risk compared with the GP group, regardless of age, sex and the presence of comorbidities, including hypertension, diabetes and dyslipidemia. Among KTRs, de novo MACEs were associated with an increased risk of all-cause mortality, but not with DCGF.

Conclusions

De novo MACEs in KTRs were much lower than that in dialysis patients and had a similar risk to the GP, but once it occurred it caused elevated mortality risk in KTRs.
Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma
Authors: Rosenberg Tom , Yeo Kee Kiat , Mauguen Audrey , Alexandrescu Sanda , Prabhu Sanjay P , Tsai Jessica W , Malinowski Seth , Joshirao Mrinal , Parikh Karishma , Farouk Sait Sameer , Rosenblum Marc K , Benhamida Jamal K , Michaiel George , Tran Hung N , Dahiya Sonika , Kachurak Kara , Friedman Gregory K , Krystal Julie I , Huang Michael A , Margol Ashley S , Wright Karen D , Aguilera Dolly , MacDonald Tobey J , Chi Susan N , Karajannis Matthias A
Published: April 2022

Background

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained.

Methods

We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/– MEK inhibitors as part of their initial therapy.

Results

Nineteen patients were identified, with a median age of 11.7 years (range, 2.3–21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3–6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies.

Conclusions

Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.
Adult brain tumors in Sub-Saharan Africa: A scoping review
Authors: Kanmounye Ulrick Sidney , Karekezi Claire , Nyalundja Arsene Daniel , Awad Ahmed K , Laeke Tsegazeab , Balogun James A
Published: April 2022

Background

Sub-Saharan African (SSA) neuro-oncologists report high workloads and challenges in delivering evidence-based care; however, these reports contrast with modeled estimates of adult neuro-oncology disease burden in the region. This scoping review aimed to better understand the reasons for this discrepancy by mapping out the SSA adult brain tumor landscape based on published literature.

Methods

Systematic searches were conducted in OVID Medline, Global Index Medicus, African Journals Online, Google Scholar, and faculty of medicine libraries from database inception to May 31, 2021. The results were summarized quantitatively and narratively. English and French peer-reviewed articles were included (title, abstract, and full text).

Results

Of the 819 records identified, 119 articles by 24 SSA countries (42.9%) were included in the final review. Odeku published the first article in 1967, and nine of the ten most prolific years were in the 21st century. The greatest contributing region was Western Africa (n = 58, 48.7%) led by Nigeria (n = 37, 31.1%). Central Africa had fewer articles published later than the other SSA regions (P = .61). Most studies were nonrandomized (n = 75, 63.0%) and meningiomas (n = 50, 42.0%) were the most common brain tumors reported. Less than 30 studies reported on adjuvant treatment or patient outcomes.

Conclusions

Most publications were hospital-based, and there was significant heterogeneity in the quality of evidence and reporting. This study highlights the need for rapid and sustainable investments and brain tumor research capacity in SSA.
Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis
Authors: Sulis Giorgia , Tavaziva Gamuchirai , Gore Genevieve , Benedetti Andrea , Solomons Regan , van Toorn Ronald , Thee Stephanie , Day Jeremy , Verkuijl Sabine , Brands Annemieke , Viney Kerri , Masini Tiziana , Ahmad Khan Faiz , Chiang Silvia S
Published: April 2022

Background

Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown.

Methods

To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months’ duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes.

Results

Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%–13.4%) vs 23.9% (95% CI, 17.5%–31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%–99.1%) vs 75.4% (95% CI, 68.7%–81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%–75.3%) vs 36.3% (95% CI, 30.1%–43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen.

Conclusions

Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.
Approaching 65 Years: Is It Time to Consider Retirement of Vancomycin for Treating Methicillin-Resistant Staphylococcus aureus Endovascular Infections?
Authors: Rose Warren , Volk Cecilia , Dilworth Thomas J , Sakoulas George
Published: April 2022

Vancomycin was introduced nearly 65 years ago and remains the standard antibiotic for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Staphylococcus aureus remains highly susceptibility to vancomycin (>97%). Despite this, MRSA treatment failure with vancomycin is high in complicated bacteremia. Additionally, vancomycin can cause nephrotoxicity, leading to new therapeutic drug monitoring guidance. This demonstrates how difficult it is to dose vancomycin in a way that is both efficacious and safe, especially during long courses of therapy. Often underappreciated are the cost, resources, and complexity of vancomycin care at a time when alternative antibiotics are becoming cost comparable. This perspective highlights a bigger picture of how the treatment repertoires of many other diseases have changed and advanced since vancomycin’s introduction in the 1950s, yet the vancomycin MRSA treatment standard remains. While vancomycin can still have a role, 65 years may be a practical retirement age for vancomycin in highly complex endovascular infections.
A Desirability of Outcome Ranking Analysis of a Randomized Clinical Trial Comparing Seven Versus Fourteen Days of Antibiotics for Uncomplicated Gram-Negative Bloodstream Infection
Authors: Howard-Anderson Jessica , Dai Weixiao , Yahav Dafna , Hamasaki Toshimitsu , Turjeman Adi , Koppel Fidi , Franceschini Erica , Hill Carol , Sund Zoë , Chambers Henry F , Fowler Vance G , Boucher Helen W , Evans Scott R , Paul Mical , Holland Thomas L , Doernberg Sarah B
Published: April 2022

Background

Although a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome.

Methods

We applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy.

Results

For the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy.

Conclusions

Both short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB.
Geographic Variation of Infectious Disease Diagnoses Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis
Authors: Wright William F , Yenokyan Gayane , Simner Patricia J , Carroll Karen C , Auwaerter Paul G
Published: April 2022

Background

Fever of unknown origin (FUO) investigations yield a substantial number of patients with infectious diseases. This systematic review and meta-analysis aimed to quantify more common FUO infectious diseases etiologies and to underscore geographic variation.

Methods

Four databases (PubMed, Embase, Scopus, and Web of Science) were searched for prospective studies reporting FUO rates among adult patients from 1 January 1997 to 31 March 2021. The pooled proportion for infectious diseases etiology was estimated using the random-effects meta-analysis model.

Results

Nineteen prospective studies were included with 2667 total cases. No studies were available for Africa or the Americas. Overall, 37.0% (95.0% confidence interval [CI], 30.0%–44.0%) of FUO patients had an infectious disease etiology. Infections were more likely from Southeastern Asia (pooled proportion, 0.49 [95% CI, .43–.55]) than from Europe (pooled proportion, 0.31 [95% CI, .22–.41]). Among specifically reported infectious diseases (n = 832), Mycobacterium tuberculosis complex predominated across all geographic regions (n = 285 [34.3%]), followed by brucellosis (n = 81 [9.7%]), endocarditis (n = 62 [7.5%]), abscesses (n = 61 [7.3%]), herpesvirus (eg, cytomegalovirus and Epstein-Barr virus) infections (n = 60 [7.2%]), pneumonia (n = 54 [6.5%]), urinary tract infections (n = 54 [6.5%]), and enteric fever (n = 40 [4.8%]).

Conclusions

FUO patients from Southeastern Asia were more likely to have an infectious diseases etiology when compared to other regions. The predominant factor for this finding appears to be differences in disease prevalence among various geographical locations or other factors such as access to timely care and diagnosis. Noting epidemiological disease factors in FUO investigations could improve diagnostic yields and clinical outcomes.
First muon acceleration and muon linear accelerator for measuring the muon anomalous magnetic moment and electric dipole moment
Authors: Otani Masashi
Published: April 2022

Muon acceleration using a radio-frequency accelerator was recently demonstrated for the first time. Measurement of the muon anomalous magnetic moment and electric dipole moment at the Japan Proton Accelerator Research Complex is the first experiment using accelerated muon beams, and construction will begin soon. The radio-frequency accelerator used in the experiment and the first muon acceleration are described. subject Index
COVID-19 and changes in global agri-food trade
Authors: Engemann Helena , Jafari Yaghoob
Published: April 2022

COVID-19 has raised questions about the resilience of agri-food trade to global shocks to the system. This paper analyses the changes in agri-food trade (values, extensive and intensive margin, and diversification) during the pandemic at global and regional levels. It also considers parallels in the changes in agri-food trade and changes of various COVID-19-related factors (infections, deaths, mobility, policy stringency, and industrial production output). The results show that changes in trade remained limited to short-term disruptions that mostly occurred at the extensive margin of trade and, primarily, at the height of policy stringency, mobility reductions, and the overall reduction of economic output. The trade of staples was most resilient, while that of other agri-food products declined considerably. Inter-regional trade of Asia, Africa, and Latin America and the Caribbean proved generally more resilient than these regions’ intra-regional trade.
Melatonin protects against nonylphenol caused pancreatic β-cells damage through MDM2-P53-P21 axis
Authors: Tao Shasha , Yang Youjing , Fan Yayun , Chu Kaimiao , Sun Jiaojiao , Wu Qianqian , Wang Aiqing , Wan Jianmei , Tian Hailin
Published: April 2022

Nonylphenol (NP) is an endocrine disrupting chemical, which widely exists in environment and can result in multiple system dysfunction. Pancreas as one of the most important organs is sensitive to NP, while the detail toxic effect is still less studied. Previously, we unveiled nonylphenol causes pancreatic damage in rats, herein, we further explore the potential mechanism and seek protection strategy in vitro. Insulinoma (INS-1) cells exposed to NP were observed to suffer oxidative stress and mitochondrial dysfunction, as reflected by the abnormal levels of reactive oxygen species, malonic dialdehyde, superoxide dismutase, Ca2+, and mitochondrial membrane potential. Melatonin (MT) was found to alleviate NP-induced mitochondrial dysfunction and oxidative stress, further inhibit apoptosis and restore pancreas function. Mechanically, MT induced the MDM2-P53-P21 signaling, which upregulated the Nrf2 signaling pathway. In summary, our study clarified NP-induced INS-1 cells mitochondrial dysfunction and oxidative stress, which could be ameliorated by MT through MDM2-P53-P21 axis.
EcoFun-MAP: An Ecological Function Oriented Metagenomic Analysis Pipeline
Authors: Shi Zhou Jason , Xiao Naijia , Ning Daliang , Tian Renmao , Zhang Ping , Curtis Daniel , Nostrand Joy D. Van , Wu Liyou , Hazen Terry C. , Rocha Andrea M. , He Zhili , Arkin Adam P. , Firestone Mary K. , Zhou Jizhong
Published: April 2022

Annotating ecological functions of environmental metagenomes is challenging due to a lack of specialized reference databases and computational barriers. Here we present the Ecological Function oriented Metagenomic Analysis Pipeline (EcoFun-MAP) for efficient analysis of shotgun metagenomes in the context of ecological functions. We manually curated a reference database of EcoFun-MAP which is used for GeoChip design. This database included ∼1,500 functional gene families that were catalogued by important ecological functions, such as carbon, nitrogen, phosphorus, and sulfur cycling, metal homeostasis, stress responses, organic contaminant degradation, antibiotic resistance, microbial defense, electron transfer, virulence and plant growth promotion. EcoFun-MAP has five optional workflows from ultra-fast to ultra-conservative, fitting different research needs from functional gene exploration to stringent comparison. The pipeline is deployed on High Performance Computing (HPC) infrastructure with a highly accessible web-based interface. We showed that EcoFun-MAP is accurate and can process multi-million short reads in a minute. We applied EcoFun-MAP to analyze metagenomes from groundwater samples and revealed interesting insights of microbial functional traits in response to contaminations. EcoFun-MAP is available as a public web server at http://iegst1.rccc.ou.edu:8080/ecofunmap/.
Integrating bulk and single cell RNA-seq refines transcriptomic profiles of individualC. elegansneurons.
Authors: Barrett Alec , Varol Erdem , Weinreb Alexis , Taylor Seth R. , McWhirter Rebecca , Cros Cyril , Vidal Berta , Basavaraju Manasa , Poff Abigail , Tipps John A. , Majeed Maryam , Wang Chen , Bayer Emily A. , Reilly Molly , Yemini Eviatar , Sun HaoSheng , Hobert Oliver , Miller David M. , Hammarlund Marc
Published: April 2022

Neuron-specific morphology and function are fundamentally tied to differences in gene expression across the nervous system. We previously generated a single cell RNA-seq (scRNA-Seq) dataset for every anatomical neuron class in the C. elegans hermaphrodite. Here we present a complementary set of bulk RNA-seq samples for 52 of the 118 canonical neuron classes inC. elegans. We show that the bulk RNA-seq dataset captures both lowly expressed and noncoding RNAs that are not detected in the scRNA-Seq profile, but also includes false positives due to contamination by other cell types. We present an analytical strategy that integrates the two datasets, preserving both the specificity of scRNA-Seq data and the sensitivity of bulk RNA-Seq. We show that this integrated dataset enhances the sensitivity and accuracy of transcript detection and differential gene analysis. In addition, we show that the bulk RNA-Seq data set detects differentially expressed non-coding RNAs across neuron types, including multiple families of non-polyadenylated transcripts. We propose that our approach provides a new strategy for interrogating gene expression by bridging the gap between bulk and single cell methodologies for transcriptomic studies. We suggest that these datasets advance the goal of delineating the mechanisms that define morphology and connectivity in the nervous system.
Neuroscout, a unified platform for generalizable and reproducible fMRI research
Authors: de la Vega Alejandro , Rocca Roberta , Blair Ross W. , Markiewicz Christopher J. , Mentch Jeff , Kent James D. , Herholz Peer , Ghosh Satrajit S. , Poldrack Russell A. , Yarkoni Tal
Published: April 2022

Functional magnetic resonance imaging (fMRI) has revolutionized cognitive neuroscience, but methodological barriers limit the generalizability of findings from the lab to the real world. Here, we present Neuroscout, an end-to-end platform for analysis of naturalistic fMRI data designed to facilitate the adoption of robust and generalizable research practices. Neuroscout leverages state-of-the-art machine learning models to automatically annotate stimuli from dozens of naturalistic fMRI studies, allowing researchers to easily test neuroscientific hypotheses across multiple ecologically-valid datasets. In addition, Neuroscout builds on a robust ecosystem of open tools and standards to provide an easy-to-use analysis builder and a fully automated execution engine that reduce the burden of reproducible research. Through a series of meta-analytic case studies, we validate the automatic feature extraction approach and demonstrate its potential to support more robust fMRI research. Owing to its ease of use and a high degree of automation, Neuroscout makes it possible to overcome modeling challenges commonly arising in naturalistic analysis and to easily scale analyses within and across datasets, democratizing generalizable fMRI research.
Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A generational study
Authors: Barros Susana , Ribeiro Marta , Coimbra Ana M. , Pinheiro Marlene , Morais Hugo , Alves Nélson , Montes Rosa , Rodil Rosario , Quintana José Benito , Santos Miguel. M. , Neuparth Teresa
Published: April 2022

Metformin (MET) is an anti-diabetic pharmaceutical with a large-scale consumption, which is increasingly detected in surface waters. However, current knowledge on the generational effects of MET exposure in the metabolism of non-target organisms is limited. The present study aimed at investigating the effects of MET in the model freshwater teleost Danio rerio, following a generational exposure (from egg up to 9 months exposure) to environmentally relevant concentrations ranging from 361 ng/L to 13 000 ng/L. Biochemical markers were used to determine cholesterol and triglycerides levels, as well as mitochondrial complex I activity in males and females zebrafish liver. mRNA transcript changes were also assessed in the liver of both sexes by means of an exploratory RNA-seq analysis and expression levels of key genes involved in the energy metabolism and lipid homeostasis, i.e. acaca, acadm, cox5aa, idh3a, hmgcra, prkaa1, were determined using qRT-PCR analysis. The findings here reported revealed that MET was able to significantly disrupt critical biochemical and molecular processes involved in zebrafish metabolism, such as cholesterol and fatty acid biosynthesis, the mitochondrial electron transport chain and the tricarboxylic acid cycle, concomitantly to changes on the hepatosomatic index. Non-monotonic dose response curves were frequently detected in the gene expression profile, with higher effects observed for 361 ng/L and 2 166 ng/L concentrations. Collectively, the obtained results suggest that environmentally relevant concentrations of MET are able to severely disrupt D. rerio metabolism, with potential impacts at the ecological level, supporting the need to update the environmental quality standard (EQS) and predicted no-effect concentration (PNEC) for MET.

Graphical abstract

Highlights

Danio rerio was exposed to metformin for a full generation;

MET affected COX I activity, as well as Chol and TGL content in zebrafish liver;

MET altered mRNA levels of genes involved in energy metabolism and lipid content;

Non-monotonic dose-response curves were frequently detected;

Due to the results obtained, MET PNEC should be reviewed.
Chromenone derivatives as novel pharmacological chaperones for retinitis pigmentosa-linked rod opsin mutants
Authors: Ortega Joseph T. , McKee Andrew G. , Roushar Francis J. , Penn Wesley D. , Schlebach Jonathan P. , Jastrzebska Beata
Published: April 2022

The correct expression of folded, functional rhodopsin (Rho) is critical for visual perception. However, this seven-transmembrane helical G protein-coupled receptor (GPCR) is prone to mutations with pathological consequences of retinal degeneration in retinitis pigmentosa (RP) due to Rho misfolding. Pharmacological chaperones that stabilize the inherited Rho variants by assisting their folding and membrane targeting could slow the progression of RP. In this study, we employed virtual screening of synthetic compounds with natural product scaffold in conjunction within vitroandin vivoevaluations to discover a novel chromenone-containing small molecule with favorable pharmacological properties that stabilizes rod opsin. This compound reversibly binds to unliganded bovine rod opsin with an EC50value comparable to the 9-cis-retinal chromophore analog and partially rescued membrane trafficking of multiple RP-related rod opsin variantsin vitro. Importantly, this novel ligand of rod opsin was effectivein vivoin murine models, protecting photoreceptors from deterioration caused either by bright light or genetic insult. Together, our current study suggests potential broad therapeutic implications of the new chromenone-containing non-retinoid small molecule against retinal diseases associated with photoreceptor degeneration.
A Systematic Evaluation of the Computational Tools for Ligand-receptor-based Cell-Cell Interaction Inference
Authors: Wang Saidi , Zheng Hansi , Choi James S. , Lee Jae K. , Li Xiaoman , Hu Haiyan
Published: April 2022

Cell-cell interactions (CCIs) are essential for multicellular organisms to coordinate biological processes and functions. Many molecules and signaling processes can mediate CCIs. One classical type of CCI mediator is the interaction between secreted ligands and cell surface receptors, i.e., ligand-receptor (LR) interaction. With the recent development of single-cell technologies, a large amount of single-cell RNA Sequencing (scRNA-Seq) data has become widely available. This data availability motivated the single-cell-resolution study of CCIs, particularly LR-based CCIs. Dozens of computational methods and tools have been developed to predict CCIs by identifying LR-based CCIs. Many of these tools have been theoretically reviewed. However, there is little study on current LR-based CCI prediction tools regarding their performance and running results on public scRNA-Seq datasets. In this work, to fill this gap, we tested and compared nine of the most recent computational tools for LR-based CCI prediction. We used fifteen mouse scRNA-Seq samples that correspond to nearly 100K single cells under different experimental conditions for testing and comparison. Besides briefing the methodology used in these nine tools, we summarized the similarities and differences of these tools in terms of both LR prediction and CCI inference between cell types. We provided insight into using these tools to make meaningful discoveries in understanding cell communications.
The non-random assembly of functional motifs in plant-pollinator networks
Authors: Lanuza Jose B. , Allen-Perkins Alfonso , Bartomeus Ignasi
Published: April 2022

Ecological processes leave distinct structural imprints on the species interactions that shape the topology of mutualistic networks. Detecting those relationships is not trivial since they go beyond pairwise interactions, but may get blurred when considering full network descriptors. Recent work has shown that the network meso-scale can capture this important information. The meso-scale describes network subgraphs representing patterns of interactions between a small number of species (i.e., motifs) that constitute the building blocks of the whole network. Despite the possible implications of network motifs to better capture species interactions, they remain overlooked in natural plant-pollinator networks. By exploring 60 empirical plant-pollinator networks from 18 different studies with wide geographical coverage we show that some motifs are consistently under- or over-represented worldwide, suggesting that the building blocks of plant-pollinator networks are not random. Furthermore, we find that distinct motif positions describing species ecological roles (e.g., generalisation and number of indirect interactions) are occupied by different plant and floral visitor groups on both trophic levels. Bees appear less frequently in specialised motif positions with high number of indirect interactions, while the rest of floral visitor groups are infrequent in generalised motif positions with low number of indirect interactions. All plant groups tend to be over-represented on specialised motif positions, except tall plant species with separated sexes (e.g., woody dioecious or monoecious species), which are more frequent on motif positions with low number of indirect interactions. Interestingly, the realized combinations of different species groups within a motif can not be retrieved from their joint probability distributions, indicating that group combinations are not random either. Our result highlights the non-random structure of the meso-scale on plant-pollinators networks and the association of different plant and floral visitor groups with certain motifs that involve different ecological roles at a macro-ecological scale.
Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila
Authors: Sebastian Benjamin , Fey Rosalyn M. , Morar Patrick , Lasher Brittany , Chow Eileen S. , Geibultowicz Jadwiga M. , Hendrix David A.
Published: April 2022

Many critical life processes are regulated by input from 24-hour external light/dark cycles, such as metabolism, cellular homeostasis, and detoxification. The circadian clock, which helps coordinate the response to these diurnal light/dark cycles, remains rhythmic across lifespan; however, rhythmic transcript expression is altered during normal aging. To better understand how aging impacts diurnal expression, we present an improved Fourier-based method for detecting and visualizing rhythmicity that is based on the relative power of the 24-hour period compared to other periods (RP24). We apply RP24 to transcript-level expression profiles from the heads of young (5-day) and old (55-day) Drosophila melanogaster, and reveal novel age-dependent rhythmicity changes that may be masked at the gene level. We show that core clock transcripts phase advance during aging, while most rhythmic transcripts phase delay. Transcripts rhythmic only in young flies tend to peak before lights on, while transcripts only rhythmic in old peak after lights on. We show that several pathways including glutathione metabolism, gain or lose coordinated rhythmic expression with age providing insight into possible mechanisms of age-onset neurodegeneration. Remarkably, we find that many pathways show very robust coordinated rhythms across lifespan, highlighting their putative roles in promoting neural health. We investigate statistically enriched transcription factor binding site motifs that may be involved in these rhythmicity changes.
Prioritizing Candidate eQTL Causal Genes in Arabidopsis using Random Forests
Authors: Hartanto Margi , Sami Asif Ahmed , de Ridder Dick , Nijveen Harm
Published: April 2022

Expression quantitative trait locus (eQTL) mapping has been widely used to study the genetic regulation of gene expression in Arabidopsis thaliana. As a result, a large amount of eQTL data has been generated for this model plant; however, only a few causal eQTL genes have been identified, and experimental validation is costly and laborious. A prioritization method could help speed up the identification of causal eQTL genes. This study extends the machine-learning-based QTG-Finder2 method for prioritizing candidate causal genes in phenotype QTLs to be used for eQTLs by adding gene structure, protein interaction, and gene expression. Independent validation shows that the new algorithm can prioritize sixteen out of twenty-five potential eQTL causal genes within the 20% rank percentile. Several new features are important in prioritizing causal eQTL genes, including the number of protein-protein interactions, unique domains, and introns. Overall, this study provides a foundation for developing computational methods to prioritize candidate eQTL causal genes. The prediction of all genes is available in the AraQTL workbench (https://www.bioinformatics.nl/AraQTL/) to support the identification of gene expression regulators in Arabidopsis.