bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 N gene dropout and N gene Ct value shift as indicator for the presence of B.1.1.7 lineage in a widely used commercial multiplex PCR assay
Authors: Wollschlaeger P , Gerlitz N , Todt D , Pfaender S , Bollinger T , Sing A , Dangel A , Ackermann N , Korn K , Ensser A , Steinmann E , Buhl M , Steinmann J 
Published: March 2021

AbstractObjectivesIncreased importance in detection and surveillance of SARS-CoV-2 has been demonstrated due to the emergence of variants of concern (VOCs). In this study we evaluated if a commercially available real-time SARS-CoV-2 PCR assay can identify B.1.1.7 lineage samples by a specific N gene dropout or Ct value shift compared to the S or RdRP gene.MethodsPatients samples with confirmed B.1.1.7 variant by whole-genome sequencing and variant-specific PCR (n=48) and non-B.1.1.7 samples (n=53) were tested by the Allplex™ SARS-CoV-2/FluA/FluB/RSV™ PCR assay for presence of S, RdRP and N gene of SARS CoV-2. The N gene coding sequence of SARS-CoV-2 with and without D3L mutation (specific for B.1.1.7) were cloned into pCR®-TOPO vectors and Allplex™ SARS-CoV-2/FluA/FluB/RSV™ PCR assay was performed.ResultsAll studied B.1.1.7 patient samples showed significantly higher Ct values (Δ 6-10, N-gene dropout on Ct values >29) in the N gene compared to the respective values of S and RdRP gene. Receiver operating characteristic (ROC) curve analysis resulted in 100% sensitivity and specificity for ΔCt N/RdRP and ΔCt N/S. As a result of the reversed genetic experiments we found also the shift in Ct values for the 3L variant N-gene.ConclusionsN gene dropout or Ct value shift is specific for B.1.1.7 positive samples using the Allplex™ SARS-CoV-2/FluA/FluB/RSV PCR assay. This approach can be used as a rapid tool for B.1.1.7 detection in single assay high throughput diagnostics.
The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders
Authors: Toledano Annette C. 
Published: March 2021

ABSTRACTWe tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.We postulate that naltrexone’s toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines’ production in the trigeminal ganglion averting “overactive nerves” (layman’s term) and migraine. Although this trial used low-dose naltrexone (defined as 1 – 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses.
A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus
Authors: Ajjan Ramzi , Hensor Elizabeth MA , Shams Kave , Del Galdo Francesco , Abbas Afroze , Woods Janet , Fairclough Rebecca J , Webber Lorraine , Pegg Lindsay , Freeman Adrian , Morgan Ann , Stewart Paul M , Taylor Angela E , Arlt Wiebke , Tahrani Abd , Russell David , Tiganescu Ana 
Published: March 2021

AbstractChronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: www.isrctn.com/ISRCTN74621291.FundingMRC Confidence in Concept and NIHR Senior Investigator Award.]Single Sentence SummaryAZD4017 was safe; data suggested improved skin healing / integrity, and modestly reduced epidermal barrier function in patients with type 2 diabetes.Disclosure SummaryI certify that neither I nor my co-authors have a conflict of interest as described above that is relevant to the subject matter or materials included in this Work.
Toward Community Surveillance: Detecting Intact SARS-CoV-2 Using Exogeneous Oligonucleotide Labels
Authors: Carey Thomas R. , Kozminsky Molly , Hall Jennifer , Vargas-Zapata Valerie , Geiger Kristina , Coscoy Laurent , Sohn Lydia L. 
Published: March 2021

AbstractThe persistence of the COVID-19 pandemic demands a dramatic increase in testing efficiency. Testing pooled samples for SARS-CoV-2 could meet this need; however, the sensitivity of RT-qPCR, the gold standard, significantly decreases with an increasing number of samples pooled. Here, we introduce DIVER, a method that quantifies intact virus and is robust to sample dilution. DIVER first tags viral particles with exogeneous oligonucleotides, then captures the tagged particles on ACE2-functionalized beads, and finally quantifies the oligonucleotide tags using qPCR. Using spike-presenting liposomes and Spike-pseudotyped lentivirus as SARS-CoV-2 models, we show that DIVER can detect 1×105 liposomes and 100 pfu lentivirus and can successfully identify positive samples in pooling experiments. Overall, DIVER is well-positioned for efficient sample pooling and expanded community surveillance.
Association between the physical work environment and work functioning impairment while working from home under the COVID-19 pandemic in Japanese workers
Authors: Okawara Makoto , Ishimaru Tomohiro , Tateishi Seiichiro , Hino Ayako , Tsuji Mayumi , Ikegami Kazunori , Nagata Masako , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork project
Published: March 2021

AbstractObjectiveThis study examined the relationship between the physical work environment and work functioning impairment while working from home in the context of rapid changes associated with the COVID-19 pandemic.MethodsThis cross-sectional study of internet monitors was conducted between December 22 and 26, 2020. Of a total of 33,302 participants, 5,760 who worked from home at least 1 day a month, excluding those who met the exclusion criteria, were included in the analysis. A binary subjective assessment of the physical work environment while working from home was used as an exposure factor. We examined 9 items related to the physical work environment, including level of illuminance and use of suitable desks and chairs, traditionally recommended for health and safety management when working at a desk. The number of non-conformities to 7 items was also used as an exposure factor. The presence of severe work functioning impairment was measured using the Work Functioning impairment Scale (WFun), a self-reported outcome measure of the degree of work functioning impairment. Odds ratios of severe work functioning impairment were estimated using mixed-effects logistic regression analysis with the prefecture of residence as a random effect.ResultsMultivariate analysis showed that the odds ratio of severe work functioning impairment was significantly higher among those who indicated “No” to all recommended items except for “I work at a desk/chair for office use.” The highest odds ratio of work functioning impairment was associated with a “No” response to “There is enough light to do my work” (aOR: 2.02, 95%CI: 1.73–2.35, p<0.01). Our results also suggest the presence of a dose-response relationship between the number of non-conformities to recommendations for work environments while working from home and work functioning impairment.ConclusionsOur findings suggest that it is important for both companies and individual workers to create a work environment that prevents negative health outcomes and improves productivity while working from home.
Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2
Authors: El-Hay Tal , Karavani Ehud , Peretz Asaf , Ninio Matan , Ravid Sivan , Chorev Michal , Rosen-Zvi Michal , Patalon Tal , Shimoni Yishai , Jain Anil 
Published: March 2021

AbstractBackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk – while adjusting for underlying risk driven by comorbidities – is not yet established.MethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.Results131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.During the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16– 4.62), bacterial pneumonia (3.25, 2.76–3.83), sepsis (1.71, 1.53–1.91), renal (1.69, 1.57–1.83), hematologic/immune (1.32, 1.20–1.45), neurological (1.23, 1.09–1.38).ConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.
Tenofovir-DF versus Hydroxychloroquine in the Treatment of Hospitalized Patients with COVID-19: An Observational Study (TEDHICOV)
Authors: Cornejo-Giraldo Mario , Rosado Nelson , Salinas Jesús , Aspilcueta Nelson , Bernales Eduardo , Lipa Jimmy , Coacalla Johanna , Flores Yoisi , Leon Pamela , Chamby Claudia 
Published: March 2021

SummaryBackgroundAlthough several therapeutic agents have been suggested for the treatment of the disease caused by the Coronavirus of the year 2019 (COVID-19), no antiviral has yet demonstrated consistent efficacy.MethodsThe results of an observational study comparing Tenofovir-DF (TDF) with Hydroxychloroquine (HCQ) in the treatment of hospitalized patients with COVID-19 with evidence of pulmonary compromise and the vast majority with supplemental oxygen requirement are presented. Patients received HCQ consecutively at the dose of 400 mg. 12 hourly for 01 day and then 200 mg. every 8 to 12 hours PO for 5 to10 days; or TDF 300 mg. per day PO for 7 to 10 days. The primary outcomes of the study were the differences between the two groups regarding: hospital stay, the need for intensive care or mechanical ventilation (ICU / MV) and mortality.Results104 patients were included: 36 in the HCQ group and 68 in the TDF group. The unadjusted primary outcomes were: LOS (length of stay) 16.6 ± 12.1 for HCQ versus 12.2 ± 7.0 days for TDF (p = o.o102); need for admission to ICU / mechanical ventilation (MV): 61.1% for HCQ versus 11.8% for TDF (p = o.ooo); and mortality: 50.0% for HCQ and 8.8% for TDF (p = o.ooo). The patients in the HCQ group had significant differences at admission compared to those in the TDF group regarding: male sex, cardiovascular risk factor, greater respiratory involvement and higher glucose and creatinine levels, lower albumin levels and higher. Inflammatory markers. When the outcomes were adjusted for these baseline differences, in the multiple regression model for LOS, it was found that TDF decreased the hospital stay by 6.10 days (C.I.: −11.97 to −2.40, p = o.o42); In the logistic regression model for the need for ICU / MV, it was found that the use of TDF had an O.R. of 0.15 (C.I.: 0.03-0.76, p = o.o22); and for the Cox proportional hazards model for mortality, the H.R. was 0.16 for TDF (C.I.: 0.03-0.96, p = o.o41). In the estimation model of the treatment effects by regression adjustment, it was found that TDF decreased the stay by −6.38 days (C.I.: −12.34 to −0.42, p = o.o36); the need for ICU / MV at −41.74% (C.I.: −63.72 to −19.7, p = o.ooo); and mortality by −35.22% (C.I.: −56.47 to −13.96, p = o.oo1).ConclusionTDF may be an effective antiviral in the treatment of COVID-19. Some of its advantages include: its wide availability, cost and oral presentation. Randomized clinical trials are imperatively required to confirm this possibility.
Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs
Authors: Byttebier Geert , Belmans Luc , Alexander Myriam , Saxberg Bo E.H. , De Spiegeleer Bart , De Spiegeleer Anton , Devrecker Nick , Van Praet Jens T. , Vanhove Karolien , Reybrouck Reinhilde , Wynendaele Evelien , Fedson David S. 
Published: March 2021

AbstractThe COVID-19 pandemic has disrupted life throughout the world. Newly developed vaccines promise relief to people who live in high-income countries, although vaccines and expensive new treatments are unlikely to arrive in time to help people who live in low-and middle-income countries. The pathogenesis of COVID-19 is characterized by endothelial dysfunction. Several widely available drugs like statins, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have immunometabolic activities that (among other things) maintain or restore endothelial cell function. For this reason, we undertook an observational study in four Belgian hospitals to determine whether in-hospital treatment with these drugs could improve survival in 959 COVID-19 patients. We found that treatment with statins and ACEIs/ARBs reduced 28-day mortality in hospitalized COVID-19 patients. Moreover, combination treatment with these drugs resulted in a 3-fold reduction in the odds of hospital mortality (OR=0.33; 95% CI 0.17-0.69). These findings were in general agreement with other published studies. Additional observational studies and clinical trials are needed to convincingly show that in-hospital treatment with statins, ACEIs/ARBs, and especially their combination saves lives.
Effect of control measures on the pattern of COVID-19 Epidemics in Japan
Authors: Konishi Tomokazu 
Published: March 2021

AbstractBackgroundCOVID-19 has spread worldwide since its emergence in 2019. In contrast to many other countries with epidemics, Japan differed in that it avoided lockdowns and instead asked people for self-control. A travel campaign was conducted with a sizable budget, but the number of PCR tests was severely limited. These choices may have influenced the course of the epidemic.MethodsThe increase or decrease in the classes of SARS-CoV-2 variants was estimated by analyzing the published sequences with an objective multivariate analysis. This approach observes the samples in multiple directions, digesting complex differences into simpler forms. The results were compared over time with the number of confirmed cases, PCR tests, and overseas visitors. The kinetics of infection were analyzed using the logarithmic growth rate.ResultsThe declared states of emergency failed to alter the movement of the growth rate. Three epidemic peaks were caused by domestically mutated variants. In other countries, there are few cases in which multiple variants have peaked. However, due to the relaxation of immigration restrictions, several infective variants have been imported from abroad and are currently competing for expansion, creating the fourth peak. By April 2021, these foreign variants exceeded 80%. The chaotic situation in Japan will continue for some time, in part because no effort has been made to identify asymptomatic carriers, and details of the vaccination program are undecided.
Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain – convergent evidence from neuroimaging meta-analysis
Authors: Ferraro Stefania , Klugah-Brown Benjamin , Tench Christopher R , Yao Shuxia , Nigri Anna , Demichelis Greta , Bruzzone Maria Grazia , Becker Benjamin 
Published: March 2021

AbstractNeurobiological pain models propose that the transition from acute to chronic pain is accompanied by neuropathological adaptations that mediate progressive pain processing dysfunctions. In contrast, meta-analytic studies on neurofunctional dysregulations in chronic pain have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders (i.e., fibromyalgia, irritable bowel syndrome, chronic low back pain, neuropathic pain; n = 295 patients, n = 211 controls; 86 foci). Across the meta-analytic approaches, convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex, with study characteristics indicating generalized pain processing abnormalities. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.
Mapping dopaminergic projections in the human brain with resting-state fMRI
Authors: Oldehinkel Marianne , Llera Alberto , Faber Myrthe , Huertas Ismael , Buitelaar Jan K. , Bloem Bastiaan R. , Marquand Andre F. , Helmich Rick C. , Haak Koen V. , Beckmann Christian F. 
Published: March 2021

AbstractThe striatum receives dense dopaminergic projections making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson’s disease and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as the striatum is highly interconnected and current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that “connectopic mapping” –a novel approach for characterizing fine-grained and overlapping modes of functional connectivity– can be used to map dopaminergic projections and as such, enables the investigation of dopamine-related functioning both in health and disease.We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N=839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a very high spatial correlation (r=0.884) with dopamine transporter availability –a marker of dopaminergic projections– derived from DaT-SPECT scans of 209 healthy control subjects of the Parkinson’s Progression Markers Initiative. Next, we obtained the subject-specific second-order modes from 20 controls, and 39 Parkinson’s disease patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed marker of dopamine function indeed tracks Parkinson’s disease diagnosis, symptom severity and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers of the Human Connectome Project, we establish strong associations between the second-order striatal connectivity mode and self-reported weekly use of alcohol and nicotine.Our findings provide compelling evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in symptom severity and L-DOPA sensitivity in Parkinson’s disease patients, and exhibits strong associations with levels of nicotine and alcohol use in a population-based cohort. We hereby provide a new biomarker for dopamine-related dysfunction in the human brain with potential clinical utility that could foster insights into the neurobiological underpinnings of various dopamine-associated conditions.