bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential immunogenicity of BNT162b2 or ChAdOx1 vaccines after extended-interval homologous dual vaccination in older people
Authors: Parry Helen , Bruton Rachel , Stephens Christine , Brown Kevin , Amirthalingam Gayatri , Otter Ashley , Hallis Bassam , Zuo Jianmin , Moss Paul 
Published: August 2021

AbstractBackgroundSeveral SARS-CoV-2 vaccines have shown clinical efficacy against Covid-19 infection but there remains uncertainty about the immune responses elicited by different regimens. This is a particularly important question for older people who are at increased clinical risk following infection and in whom immune senescence may limit vaccine responses. The BNT162b2 mRNA and ChAdOx1 adenovirus vaccines were the first two vaccines deployed in the UK programme using an 8–12 week ‘extended interval’.ObjectivesWe undertook analysis of the spike-specific antibody and cellular immune response in 131 participants aged 80+ years after the second dose of ‘extended interval’ dual vaccination with either BNT162b2 mRNA (n = 54) or ChAdOx1 (n = 77) adenovirus vaccine. Blood samples were taken 2–3 weeks after second vaccine and were paired with samples taken at 5-weeks after first vaccine which have been reported previously. Antibody responses were measured using the Elecsys® electrochemiluminescence immunoassay assay and cellular responses were assessed by IFN-γ ELISpot.ResultsAntibody responses against spike protein became detectable in all donors following dual vaccination with either vaccine. 4 donors had evidence of previous natural infection which is known to boost vaccine responses. Within the 53 infection-naïve donors the median antibody titre was 4030 U/ml (IQR 1892–8530) following BNT162b2 dual vaccination and 1405 (IQR 469.5–2543) in the 74 patients after the ChAdOx1 vaccine (p = < 0.0001). Spike-specific T cell responses were observed in 30% and 49% of mRNA and ChAdOx1 recipients respectively and median responses were 1.4-times higher in ChAdOx1 vaccinees at 14 vs 20 spots/million respectively (p = 0.022).ConclusionDual vaccination with BNT162b2 or ChAdOx1 induces strong humoral immunity in older people following an extended interval protocol. Antibody responses are 2.9-times higher following the mRNA regimen whilst cellular responses are 1.4-times higher with the adenovirus-based vaccine. Differential patterns of immunogenicity are therefore elicited from the two vaccine platforms. It will be of interest to assess the relative stability of immune responses after these homologous vaccine regimens in order to assess the potential need for vaccine boosting. Furthermore, these findings indicate that heterologous vaccine platforms may offer the opportunity to further optimize vaccine responses.
Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo
Authors: Watchon Maxinne , Luu Luan , Robinson Katherine J. , Yuan Kristy C. , De Luca Alana , Suddull Hannah J. , Tym Madelaine C. , Guillemin Gilles J. , Cole Nicholas J. , Nicholson Garth A. , Chung Roger S. , Lee Albert , Laird Angela S. 
Published: August 2021

AbstractMachado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.Graphical abstract
Bedshift: perturbation of genomic interval sets
Authors: Gu Aaron , Cho Hyun Jae , Sheffield Nathan C. 
Published: August 2021

AbstractFunctional genomics experiments, like ChIP-Seq or ATAC-Seq, produce results that are summarized as a region set. There is no way to objectively evaluate the effectiveness of region set similarity metrics. We present Bedshift, a tool for perturbing BED files by randomly shifting, adding, and dropping regions from a reference file. The perturbed files can be used to benchmark similarity metrics, as well as for other applications. We highlight differences in behavior between metrics, such as that the Jaccard score is most sensitive to added or dropped regions, while coverage score is most sensitive to shifted regions.
Effective control of large deletions after double-strand breaks by homology-directed repair and dsODN insertion
Authors: Wen Wei , Quan Zi-Jun , Li Si-Ang , Yang Zhi-Xue , Fu Ya-Wen , Zhang Feng , Li Guo-Hua , Zhao Mei , Yin Meng-Di , Xu Jing , Zhang Jian-Ping , Cheng Tao , Zhang Xiao-Bing 
Published: August 2021

AbstractBackgroundAfter repairing double-strand breaks (DSBs) caused by CRISPR-Cas9 cleavage, genomic damage, such as large deletions, may have pathogenic consequences.ResultsWe show that large deletions are ubiquitous but are dependent on editing sites and cell types. Human primary T cells display more significant deletions than hematopoietic stem and progenitor cells (HSPCs), whereas we observe low levels in induced pluripotent stem cells (iPSCs). We find that the homology-directed repair (HDR) with single-stranded oligodeoxynucleotides (ssODNs) carrying short homology reduces the deletion damage by almost half, while adeno-associated virus (AAV) donors with long homology reduce large deletions by approximately 80%. In the absence of HDR, the insertion of a short double-stranded ODN by NHEJ reduces deletion indexes by about 60%.ConclusionsTimely bridging of broken ends by HDR and NHEJ vastly decreases the unintended consequences of dsDNA cleavage. These strategies can be harnessed in gene editing applications to attenuate unintended outcomes.
The impact of recipient age on the effects of umbilical cord mesenchymal stem cells on HBV-related acute-on-chronic liver failure and liver cirrhosis
Authors: Zhang Ka , Sun Haixia , Cao Huijuan , Jia Yifan , Shu Xin , Cao Hong , Zhang Yufeng , Yang Xiaoan 
Published: August 2021

Abstract
Background
The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age.

Methods
Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (< 45 vs. ≥ 45 years). Group A included young ACLF patients (< 45 y), and group B included older ACLF patients (≥ 45 y). Young LC patients (< 45 y) were assigned to group C, and group D included older LC patients (≥ 45 y). Patients’ clinical characteristics, demographics, biochemical factors, and model for end-stage liver disease (MELD) scores were compared for 24 weeks.

Results
Sixty-four ACLF patients and 59 LC patients were enrolled in this study. Compared with patients in groups B and C, patients in group A did not show significant superiority in terms of the levels of ALT, AST, TBIL, AFP, and PTA and MELD scores. However, the median decrease and cumulative decrease in the TBIL and ALT levels of patients in group C were larger than those of patients in group D after four weeks of UCMSC transfusions. For older patients (≥ 45 y), the cumulative decrease and the median decrease in the TBIL of ACLF patients were significantly greater than those of LC patients after UCMSC treatment. However, the median decrease in ALT levels of ACLF patients was significantly greater than that of LC patients during UCMSC treatment, and the cumulative decrease in ALT levels of ACLF patients was significantly greater than that of LC patients at all time points.

Conclusion
The therapeutic effects of UCMSCs for HBV-related acute-on-chronic liver failure and liver cirrhosis varied partly by patient age. Assessing patient age is necessary prior to UCMSC clinical use.
On this month's Round the Corner: I welcome the argument about ECT
Authors: Read John 
Published: August 2021

SUMMARYA recent review of research in electroconvulsive therapy (ECT) for depression, for which I was the first author, found that only 11 placebo-controlled studies have even been conducted, all pre-1986. Our review concluded that they were so flawed that the meta-analyses that relied on them were wrong to conclude that ECT is effective. This commentary responds to a critique of the review by Ian Anderson. Some valuable comments are acknowledged and several errors or misunderstandings rectified.
The Court of Protection: expert witness and professional reports
Authors: Curtice Martin 
Published: August 2021

SUMMARYThe Court of Protection has the legal jurisdiction to make decisions about people who lack capacity to make decisions themselves (in England and Wales). When hearing cases, evidence can be provided to the court by expert witnesses and professionals. The Court of Protection Rules 2017 inform the practice and procedure within the Court of Protection. This article reviews the judgment from a Court of Protection case that analyses the proper role of the expert witness in the court. In doing so the article provides guidance to authors of expert witness reports and reports under section 49 of the Mental Capacity Act 2005 submitted as evidence to the court.
Reassessment of Postural Stimulation Testing as a Simple Tool to Identify a Subgroup of Patients With Unilateral Primary Aldosteronism
Authors: Teresa Fuss Carmina , Brohm Katharina , Fassnacht Martin , Kroiss Matthias , Hahner Stefanie 
Published: August 2021

Abstract

Context
Adrenal vein sampling (AVS) represents the current diagnostic gold standard for differentiation between unilateral and bilateral primary aldosteronism (PA). Postural stimulation testing (PST) has been used to provide additional diagnostic information.

Objective
This work aimed to evaluate the diagnostic utility of PST in the differential diagnosis of PA.

Methods
This cohort study was conducted at a single tertiary reference center. We analyzed 106 PST performed between 2008 and 2020. Diagnosis of PA and cause of PA were determined according to the Endocrine Society Clinical Practice Guideline, taking into account results of saline infusion testing, AVS, preoperative imaging, and outcome after medical or surgical treatment. The suggested cutoffs for the diagnosis of unilateral PA were revisited and optimized for high specificity using receiver operating characteristics (ROC) analysis.

Results
A total of 106 patients had confirmed PA (unilateral PA: n = 55, bilateral PA: n = 29, AVS unsuccessful/declined by patients: n = 22). Based on decreased aldosterone plasma concentration of 28% or more after 4 hours in the upright position, the PST showed a sensitivity of 36.4% at a specificity of 100% to identify unilateral disease (area under the curve [AUC] = 0.72; 95% CI, 0.62-0.83; P = .001). In patients with valid testing (drop of cortisol of 10% or more after 4 hours, n = 53) the sensitivity of PST rose to 51.4% at a specificity of 100% (AUC = 0.77; 95% CI, 0.65-0.90; P = .001).

Conclusion
The high specificity of 100% for the detection of unilateral PA in patients with decreased aldosterone by at least 28% after 4 hours makes PST a simple, noninvasive contribution to subtype differentiation in PA.
Risk of Incident Heart Failure in Individuals With Early-Onset Type 2 Diabetes
Authors: Liu Jian-Jun , Liu Sylvia , Wang Jiexun , Lee Janus , Tang Justin I-Shing , Gurung Resham L , Ang Keven , Shao Yi Ming , Tavintharan Subramaniam , Tang Wern Ee , Sum Chee Fang , Lim Su Chi 
Published: August 2021

Abstract

Context
Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce.

Objective
We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes.

Methods
We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined.

Results
A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P &lt; 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures.

Conclusion
Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population.
Surgical, Obstetric, and Anesthetic Mortality Measurement at a Ugandan Secondary Referral Hospital
Authors: Firth Paul G. , Mushagara Rhina , Musinguzi Nicholas , Liu Charles , Boatin Adeline A. , Mugabi Walter , Kayaga Dorothy , Naturinda Phionah , Twesigye Deus , Sanyu Frank , Mugyenyi Godfrey , Ngonzi Joseph , Ttendo Stephen S. 
Published: August 2021

BACKGROUND:
The health care systems of low-income countries have severely limited capacity to treat surgical diseases and conditions. There is limited information about which hospital mortality outcomes are suitable metrics in these settings.

METHODS:
We did a 1-year observational cohort study of patient admissions to the Surgery and the Obstetrics and Gynecology departments and of newborns delivered at a Ugandan secondary referral hospital. We examined the proportion of deaths captured by standardized metrics of mortality.

RESULTS:
There were 17,015 admissions and 9612 deliveries. A total of 847 deaths were documented: 385 (45.5%) admission deaths and 462 (54.5%) perinatal deaths. Less than one-third of admission deaths occurred during or after an operation (n = 126/385, 32.7%). Trauma and maternal mortality combined with perioperative mortality produced 79.2% (n = 305/385) of admission deaths. Of 462 perinatal deaths, 412 (90.1%) were stillborn, and 50 (10.9%) were early neonatal deaths. The combined metrics of the trauma mortality rate, maternal mortality ratio, thirty-day perioperative mortality rate, and perinatal mortality rate captured 89.8% (n = 761/847) of all deaths documented at the hospital.

CONCLUSIONS:
The combination of perinatal, maternal, trauma, and perioperative mortality metrics captured most deaths documented at a Ugandan referral hospital.
First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland
Authors: Nowicki Michał , Komar Monika , Kusztal Mariusz , Mizia-Stec Katarzyna , Liberek Tomasz , Małyszko Jolanta , Muras-Szwedziak Katarzyna , Pawlaczyk Krzysztof , Podolec Piotr , Sławek Jarosław 
Published: August 2021

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wrocław, Poznań, Gdańsk, Warszawa, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.
Predictive Search for Capacitated Multi-Item Lot Sizing Problems
Authors: Wu Tao 
Published: August 2021

For capacitated multi-item lot sizing problems, we propose a predictive search method that integrates machine learning/advanced analytics, mathematical programming, and heuristic search into a single framework. Advanced analytics can predict the probability that an event will happen and has been applied to pressing industry issues, such as credit scoring, risk management, and default management. Although little research has applied such technique for lot sizing problems, we observe that advanced analytics can uncover optimal patterns of setup variables given properties associated with the problems, such as problem attributes, and solution values yielded by linear programming relaxation, column generation, and Lagrangian relaxation. We, therefore, build advanced analytics models that yield information about how likely a solution pattern is the same as the optimum, which is insightful information used to partition the solution space into incumbent, superincumbent, and nonincumbent regions where an analytics-driven heuristic search procedure is applied to build restricted subproblems. These subproblems are solved by a combined mathematical programming technique to improve solution quality iteratively. We prove that the predictive search method can converge to the global optimal solution point. The discussion is followed by computational tests, where comparisons with other methods indicate that our approach can obtain better results for the benchmark problems than other state-of-the-art methods. Summary of Contribution: In this study, we propose a predictive search method that integrates machine learning/advanced analytics, mathematical programming, and heuristic search into a single framework for capacitated multi-item lot sizing problems. The advanced analytics models are used to yield information about how likely a solution pattern is the same as the optimum, which is insightful information used to divide the solution space into incumbent, superincumbent, and nonincumbent regions where an analytics-driven heuristic search procedure is applied to build restricted subproblems. These subproblems are solved by a combined mathematical programming technique to improve solution quality iteratively. We prove that the predictive search method can converge to the global optimal solution point. Through computational tests based on benchmark problems, we observe that the proposed approach can obtain better results than other state-of-the-art methods.
Changes in Risky Benefits and in Risky Costs: A Question of the Right Order
Authors: Menegatti Mario , Peter Richard 
Published: August 2021

We organize and extend findings on the comparative static effects of risk changes on optimal behavior in a unifying expected utility model. We determine restrictions on preferences for clear-cut results. Risk increases of a benefit are compensated by lowering exposure to risk. For risk increases of a cost, the response depends on the order of the risk change. This discrepancy arises because even-order risk increases of a cost raise the riskiness of the payoff distribution, whereas odd-order risk increases of a cost reduce it. We identify the stochastic dominance orders to resolve this discrepancy and discuss specific decision problems as applications. This paper was accepted by Manel Baucells, behavioral economics and decision analysis.
Low-loss off-axis curved waveguide grating demultiplexer
Authors: Hadij-ElHouati Abdelfettah , Ortega-Moñux Alejandro , Wangüemert-Pérez J. Gonzalo , Halir Robert , Wang Shurui , Schmid Jens H. , Cheben Pavel , Molina-Fernández I. 
Published: August 2021

Current optical communication systems rely on the use of wavelength division multiplexing (WDM) to keep up with the increasing data rate requirements. The wavelength demultiplexer is the key component to implement WDM systems. In this Letter, we design and experimentally demonstrate a demultiplexer based on a curved grating waveguide geometry that separates eight channels with a spacing of 10 nm (1249 GHz) around the central wavelength of 1550 nm. The fabricated device shows very low insertion loss (

∼

1

d
B

) and a crosstalk (XT) below

−

25

d
B

. This device leverages metamaterial index engineering to implement the lateral cladding on one side of the waveguide. This makes it possible to design a waveguide grating with highly directional lateral emission by operating in a regime where diffraction into the silica upper cladding is frustrated, thus suppressing losses due to off-chip radiation.
Spectral filtering effect on the ultrafast mid-infrared Er3+-doped ZBLAN fiber laser
Authors: Ma Chunyang , Luo Mulin , Zhang Han , Tang Pinghua , Liu Jun 
Published: August 2021

We investigate the spectral filtering effect on the mid-infrared ultrafast

E
r

3
+

-doped ZBLAN fiber laser based on nonlinear polarization evolution (NPE). A broad wavelength tuning range from 2720 nm to 2800 nm is achieved using a diffraction grating as the narrowband filter. Furthermore, numerical simulations are also carried out so that, by inserting a highly nonlinear fiber combined with an appropriate spectral filter in the laser system, a 329 nm ultra-broadband spectrum with a Fourier transform limit pulse as short as 47 fs can be achieved. Our results are conducive to understanding the spectral filtering effect on the lasing performance of mid-infrared ultrafast fiber lasers.