bluuebunny/crossref_metadata_2025_split huggingface dataset:
Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy
Authors: VerPlank Jordan J S , Gawron Joseph , Silvestri Nicholas J , Feltri M Laura , Wrabetz Lawrence , Goldberg Alfred L 
Published: July 2021

Abstract
Agents that raise cyclic guanosine monophosphate (cGMP) by activating protein kinase G increase 26S proteasome activities, protein ubiquitination and degradation of misfolded proteins. Therefore, they may be useful in treating neurodegenerative and other diseases caused by an accumulation of misfolded proteins.
Mutations in myelin protein zero (MPZ) cause the peripheral neuropathy Charcot-Marie-Tooth type 1B (CMT1B). In peripheral nerves of a mouse model of CMT1B, where the mutant MPZS63del is expressed, proteasome activities are reduced, mutant MPZS63del and polyubiquitinated proteins accumulate and the unfolded protein response (p-eif2α) is induced. In HEK293 cells, raising cGMP stimulated ubiquitination and degradation of MPZS63del, but not of wild-type MPZ. Treating S63del mice with the phosphodiesterase 5 inhibitor, sildenafil—to raise cGMP—increased proteasome activity in sciatic nerves and reduced the levels of polyubiquitinated proteins, the proteasome reporter ubG76V-GFP and p-elF2α. Furthermore, sildenafil treatment reduced the number of amyelinated axons, and increased myelin thickness and nerve conduction velocity in sciatic nerves.
Thus, agents that raise cGMP, including those widely used in medicine, may be useful therapies for CMT1B and other proteotoxic diseases.
Regional hierarchies of discontent: an accessibility approach
Authors: Larsson Johan P , Öner Özge , Sielker Franziska 
Published: July 2021

AbstractWe argue that so-called geographies of discontent work within regional hierarchies in a spatial continuum, whereas the previous literature has mainly invoked dichotomous divides, such as core-periphery or the North-South. A place’s relation to surrounding communities and regions remains an understudied topic. We analyse the municipal distribution of electoral support for Sweden Democrats (Sverigedemokraterna, SD) in the 2014 and 2018 Swedish national general elections. We show that higher accessibility to other large municipalities within the same region, as well as being surrounded by relatively larger neighbouring regions, is associated with further support for SD. The within-region associations are only reliably identified among the urban group.
Real-World Experience With Proactive Therapeutic Drug Monitoring During Infliximab Reintroduction
Authors: Normatov Inessa , Fluxa Daniela , Wang Jingzhou D , Ollech Jacob E , Gulotta George E , Patel Shivani , Quintero Maria A , De la Torre Bety , Solis Norma , Damas Oriana M , Deshpande Amar R , Kerman David H , Abreu Maria T , Rubin David T 
Published: July 2021

Abstract

Background
Interruptions in infliximab therapy are associated with the development of antibodies to infliximab (ATI), infusion reactions (IRs), and loss of response. Despite these challenges, recent observational studies suggest that reinitiating infliximab after a drug holiday can be safe and effective. We assessed the utility of our protocol for restarting infliximab using early serum infliximab and ATI measurements.

Methods
A retrospective cohort study of patients restarted on infliximab after at least a 6-month drug holiday. The cohort was divided into 2 groups: a “therapeutic drug monitoring (TDM) group,” those who had serum infliximab and ATI measured 1–3 weeks after first reinduction dose, and a “non-TDM group.” Outcomes included results of TDM, occurrence of immediate IR (IIR) and delayed hypersensitivity reactions, and medication persistence at 14 weeks and 1 year.

Results
About 76 patients were included: 49 in the TDM group and 27 in the non-TDM group. Of 76, 67 (88%) patients tolerated the first reinduction dose without IR. Formation of ATI was seen in 17 of 49 (35%) patients and was associated with longer drug holidays. Most did not experience IR during the entire therapy course—in 26 of 32 (81%) without ATI and 20 of 27 (74%) in the non-TDM group. Infliximab persistence at 14 weeks and 1 year was 76% and 57% for the cohort, respectively.

Conclusion
Infliximab can be safely and effectively restarted after a drug holiday. We suggest performing TDM with a drug-tolerant assay 1–3 weeks after the first reinduction infusion as a means to identify patients at risk for severe IIR at the second dose.
Multimarker profiling identifies protective and harmful immune processes in heart failure: findings from BIOSTAT-CHF
Authors: Markousis-Mavrogenis George , Tromp Jasper , Ouwerkerk Wouter , Ferreira João Pedro , Anker Stefan D , Cleland John G , Dickstein Kenneth , Filippatos Gerasimos , Lang Chim C , Metra Marco , Samani Nilesh J ,   The BIOSTAT-CHF Consortium, de Boer Rudolf A , van Veldhuisen Dirk J , Voors Adriaan A , van der Meer Peter 
Published: July 2021

Abstract

Aims
The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF.

Methods and results
We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of ‘T-cell costimulation’ and ‘response to interferon-gamma/positive regulation of interferon-gamma production’ showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets.

Conclusions
We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.
Orthodontic space closure in sliding mechanics: a systematic review and meta-analysis
Authors: Sebastian Biju , Bhuvaraghan Aarthi , Thiruvenkatachari Badri 
Published: July 2021

SummaryBackground/ObjectivesThe aim of this systematic review was to compare the different force delivery systems for orthodontic space closure by sliding mechanics.Search methodsMultiple sources including Cochrane Central, Ovid Medline, Embase etc. were used to identify all relevant studies.Selection criteriaRandomized controlled trials (RCT) of parallel-group and split-mouth designs were included.ParticipantsOrthodontic patients of any age treated with fixed orthodontic appliances and requiring space closure.Data collection and analysisSearch result screening, data extraction and quality assessment were performed independently and in duplicate by 2 reviewers. The included studies were grouped into parallel-arm and split-mouth studies and subgroup analysis was then performed for the type of retraction subsets; en-masse and individual canine retraction. A traditional meta-analysis, and network meta-analysis (NMA) for direct and indirect comparisons for the rate of space closure were performed.ResultsThirteen studies, six parallel-arm and seven split-mouth were included. The traditional meta-analysis comparing Nickel-titanium (NiTi) closed coil springs and elastomeric power chain for the rate of tooth movement showed statistically significant difference favouring NiTi springs (MD: 0.24; 95% CI, 0.03–0.45; I2 0%, P = 0.02) and the comparison between NiTi springs and active ligatures also showed statistically significant result favouring NiTi springs (MD: 0.53; 95% CI, 0.44–0.63; I2 0%, P ˂ 0.00001) for the rate of tooth movement. NMA for the rate of space closure showed fairly confident evidence for NiTi coil springs when compared with elastomeric chain and active ligatures. The NiTi coil spring ranked best between all methods of space closure.ConclusionsThere is moderate quality evidence in favour of NiTi coil springs for the rate of space closure when compared with active ligature and low quality of evidence favouring NiTi springs when compared with elastomeric chain. The ranking from NMA showed NiTi coil springs to be the best method for space closure with 99% chance. An urgent need for standardization of study designs and the need for development of an agreed core outcome sets and core outcome instrument measurement sets is evident.RegistrationPROSPERO CRD42020157811
Frescobaldi at the Ospedale di Santo Spirito: a portfolio career in 17th-century Rome
Authors: Barker Naomi J 
Published: July 2021

Abstract
During the 1620s Girolamo Frescobaldi held the post of organist at St Peter’s in Rome concurrently with that of organist at the Ospedale di Santo Spirito. Both jobs had substantial duties. In this article, the three main requirements of the organist at Santo Spirito—to play for Mass and Vespers, the Saturday litanies and in the hospital ward at meal times—provide the means both for reconstructing part of the daily schedule at Santo Spirito and for tracing Frescobaldi’s activities. The identity of Nicolò Cochi, who frequently signed for Frescobaldi’s salary at St Peter’s, is investigated; previously unpublished documents from the Ospedale archive and financial records are compared; and some conclusions reached as to how a musician such as Frescobaldi could successfully hold dual, if not multiple employments. At the same time, new information about liturgical practice at the Ospedale di Santo Spirito is presented.
Electrocardiographic characteristics and ablation of ventricular arrhythmias originating from the basal inferoseptal area
Authors: Larsen Timothy R , Shepard Richard K , Koneru Jayanthi N , Cabrera José-Angel , Ellenbogen Kenneth A , Padala Santosh K 
Published: July 2021

Abstract

Aims
Ventricular arrhythmias (VAs) from the basal inferoseptal (BIS) area are rare and can pose unique challenges during catheter ablation (CA) due to the anatomic complexity. The study sought to describe the electrocardiographic and clinical characteristics of VAs originating from the BIS area.

Methods and results
Patients with VAs and successful ablation at the BIS area from 2016 to 2020 were included. The 12-lead electrocardiogram (ECG), intracardiac findings, and outcomes were analysed. Of 482 patients with VAs referred for CA, 17 (3.5%) had successful ablation at BIS area. There were 12 males, mean age was 66.7 ± 9 years, 82% had ejection fraction &lt;50%. Mean baseline premature ventricular complex burden was 28.6 ± 9%. All patients had a leftward superior axis. Left bundle branch block (LBBB) with early transition in V2 was noted in eight patients and right bundle branch block (RBBB) in nine patients. Detailed mapping of the right ventricle (RV) was performed in 15 patients (88%), coronary sinus (CS)/middle cardiac vein (MCV) in 13 (76%), right atrium (RA) adjacent to the inferoseptal process (ISP) of left ventricle (LV) in 5 (29%), ISP-LV in 13 (76%), and epicardium in 2 (12%). Successful ablation site was in LV in 10 (59%), RV in 2 (12%), CS/MCV in 1 (6%), RA in 1 (6%), and epicardium in 2 (12%). Fifteen patients (88%) required mapping in at least two chambers (range 2–5) and seven patients (41%) required ablation in at least two chambers (range 2–3).

Conclusions
Ventricular arrhythmias originating in the BIS are uncommon. The most common ECG patterns were leftward superior axis, LBBB with transition in V2 or RBBB. The VA foci can be endocardial or epicardial and meticulous mapping/ablation from multiple chambers is often required to eliminate these foci successfully.
Draft genome assembly of the Aral barbell Luciobarbus brachycephalus using PacBio sequencing
Authors: Geng Longwu , Zou Ming , Jiang Haifeng , Meng Minghui , Xu Wei 
Published: July 2021

Abstract
The endangered Aral barbell Luciobarbus brachycephalus is endemic to the water systems of the Caspian Sea and Aral Sea. Given the scarcity of genetic data for the species, we present a draft assembly based on PacBio long read sequencing technology. Approximate 299.4 Gb of long reads representing 166X of the estimated genome size were generated, and the final assembly was composed of 653 contigs totaling approximately 1,698.3 Mb, with a contig N50 length of 4.5 Mb. A total of 807.6 Mb represented approximately 47.6% of the assembly and were identified as repeats. Fifty-four thousand and six hundred possible protein genes were predicted, among which 50,727, representing approximately 92.9%, could be annotated by at least one database. Evolutionary analysis showed that L. brachycephalus and Labeo rohita diverged by approximately 42.6 Mya, and the obvious expansion of gene families residing in the L. brachycephalus genome may be attributed to the specific whole genome duplication of the species. The first genome assembly of L. brachycephalus can not only provide a foundation for genetic conservation and molecular breeding of this species but also contribute to comparative analyses of genome biology and evolution within Cyprinidae.
Surviving Older Patients Show Preserved Cellular and Humoral Immunological Memory Several Months After SARS-CoV-2 Infection
Authors: García-Torre Alejandra , Bueno-García Eva , López-Martínez Rocío , Rioseras Beatriz , Moro-García Marco Antonio , Alonso-Alvarez Sara , Lluna-González Alba , Sousa-Fernández Alejandra , Fernández-Gudin Marta , Campos-Riopedre Laura , Castro-del Cueto Corina , Pérez-Fernández Ana Belén , Alonso-Rodríguez Ana , Menéndez-Peña Carla , Menéndez-Peña Lara , García-Arnaldo Noelia , Feito-Díaz Estefanía , Fernández-Lorences Adriana , Fraile-Manzano Agustín , Fernández-Iglesias Carolina , Rivera José Arturo , Pérez-Fonseca Carmen , Urdiales-Ruano Estibaliz , Debán-Fernández María , Mendes-Moreira Hugo , Herrero-Puente Pablo , Alonso-Arias Rebeca 
Published: July 2021

Abstract
Understanding how older people respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical if we are to confront the coronavirus disease 2019 (COVID-19) pandemic and establish effective vaccination strategies. Immunosenescence reduces the ability to respond to neoantigens and may compromise the life of infected individuals. Here, we analyzed the immunological memory to SARS-CoV-2 in 102 recovered patients aged over 60 years several months after the infection had been resolved. Specific memory T lymphocytes against the virus were measured by interferon-γ (IFN-γ) and granzyme B release by ELISpot; memory B-lymphocyte responses were quantified by detection of anti-S IgG1 producer cells by ELISpot and anti-S and anti-N antibodies were determined by enzyme-linked immunosorbent assay (ELISA). Memory T lymphocytes were found in peripheral blood of most of the studied donors, more than 7 months after the infection in some of them. Fewer patients maintained memory B lymphocytes, but antibodies, mainly anti-S, were highly durable and positively correlated with T responses. More robust humoral responses were found in patients who had more severe symptoms and had been admitted to hospital. We concluded that specific immunity against SARS-CoV-2 is effectively preserved regardless of age, despite the great heterogeneity of their immune responses, and that memory T lymphocytes and anti-S IgG might be more durable than memory B cells and anti-N IgG.
Stated job preferences of three health worker cadres in Ethiopia: a discrete choice experiment
Authors: Lamba Shyam , Arora Nikita , Keraga Dorka Woldesenbet , Kiflie Abiyou , Jembere Birkety Mengistu , Berhanu Della , Dubale Mehret , Marchant Tanya , Schellenberg Joanna , Umar Nasir , Estafinos Abiy Seifu , Quaife Matthew 
Published: July 2021

Abstract
Attracting, training and retaining high-quality health workers are critical for a health system to function well, and it is important to know what health workers value in their roles. Many studies eliciting the labour market preferences of health workers have interviewed doctors or medical students, and there has been little research on the job preferences of lower-skilled cadres such as community health workers, mid-skilled clinical care staff such as nurses and midwives, or non-patient facing staff who manage health facilities. This study estimated the job preferences of public health sector community health extension workers (HEWs), care providers including nurses and midwives, and non-patient-facing administrative and managerial staff in Ethiopia. We used a discrete choice experiment to estimate which aspects of a job are most influential to health worker choices. A multinomial logistic regression model estimated the importance of six attributes to respondents: salary, training, workload, facility quality, management and opportunities to improve patient outcomes. We found that non-financial factors were important to respondents from all three cadres: e.g., supportive management [odds ratio (OR) = 2.96, P-value = 0.001] was the only attribute that influenced the job choices of non-patient-facing administrative and managerial staff. Training opportunities (OR = 3.45, P-value &lt; 0.001), supportive management (OR = 3.26, P-value &lt; 0.001) and good facility quality (OR = 2.42, P-value &lt; 0.001) were valued the most amongst HEWs. Similarly, supportive management (OR = 3.22, P-value &lt; 0.001), good facility quality (OR = 2.69, P-value &lt; 0.001) and training opportunities (OR = 2.67, P-value &lt; 0.001) influenced the job choices of care providers the most. Earning an average salary also influenced the jobs choices of HEWs (OR = 1.43, P-value = 0.02) and care providers (OR = 2.00, P-value &lt; 0.001), which shows that a combination of financial and non-financial incentives should be considered to motivate health workers in Ethiopia.
Effects of a new health financing scheme on out-of-pocket health expenditure: findings from a longitudinal household study in Yangon, Myanmar
Authors: Thein Si Thu , Thet May Me , Aung Ye Kyaw 
Published: July 2021

Abstract
Since 2017, Population Services International Myanmar (PSI/Myanmar) has been running Strategic Purchasing (SP) clinics in Hlegu and Shwepyithar townships in Yangon, Myanmar. In the project, Population Services International Myanmar simulated the role of a purchaser and contracted SP clinics through a capitation payment scheme. The project aimed to reduce the health-related financial burden of poor populations in the catchment area, by having them registered under respective SP clinics for access to a package of essential health services for a minimal fixed co-payment, as a replacement for usual fee-for-service payments. Four longitudinal surveys of households registered under SP clinics were conducted in 2017, 2018 and 2019. Among 2506 registered households, 867 households sought some health care in all surveys, resulting in 3468 observations. Multivariable linear mixed-effect regression model was used to analyse the changes in out-of-pocket expenditure for health care in relation to household capacity to pay (OOPCTP). The utilization of SP clinics increased over time, and the rates were much higher in Hlegu (20.5% in baseline to 61.9% in round three) compared with those in Shwepyithar (0.2 to 7.9%). Compared with the baseline assessment, household OOPCTP decreased significantly during and after the implementation (0.76 times in round one, 0.80 in round two and 0.82 in round three; P &lt; 0.001). Households in Shwepyithar with less utilization of SP clinics had 1.8 times higher OOPCTP compared with those in Hlegu (1.82, 95% CI 1.58, 2.09; P &lt; 0.001). Household direct expenditures on care-seeking and family planning were up to 50% lower among those who used SP clinics. Our study highlighted that capitation-based health financing schemes could successfully lower out-of-pocket health expenditures among the poor. Optimal utilization of services was paramount in the successful implementation of such programmes. Therefore, for the effective scale-up of new health financing schemes, service utilization rates should be carefully monitored as one of the critical indicators.
The Promise of Patient-Derived Colon Organoids to Model Ulcerative Colitis
Authors: Ojo Babajide A , VanDussen Kelli L , Rosen Michael J 
Published: July 2021

AbstractPhysiologic, molecular, and genetic findings all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of ulcerative colitis (UC). The lack of epithelial-directed therapies is a conspicuous weakness of our UC therapeutic armamentarium. However, a critical barrier to new drug discovery is the lack of preclinical human models of UC. Patient tissue–derived colon epithelial organoids (colonoids) are primary epithelial stem cell–derived in vitro structures capable of self-organization and self-renewal that hold great promise as a human preclinical model for UC drug development. Several single and multi-tissue systems for colonoid culture have been developed, including 3-dimensional colonoids grown in a gelatinous extracellular matrix, 2-dimensional polarized monolayers, and colonoids on a chip that model luminal and blood flow and nutrient delivery. A small number of pioneering studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding the persistence of inflammatory transcriptional programs in culture over time. Additional research is needed to fully characterize the extent to which and under what conditions colonoids accurately model disease-associated epithelial molecular and functional aberrations. With further advancement and standardization of colonoid culture methodology, colonoids will likely become an important tool for realizing precision medicine in UC.
Knowledge, attitudes and practices of healthcare professionals regarding drug–food interactions: a scoping review
Authors: Osuala Emmanuella Chinonso , Ojewole Elizabeth Bolanle 
Published: July 2021

Abstract

Objectives
Drug–food interactions (DFIs) are a problem in clinical practice as they can alter the bioavailability of drugs and nutrients and may lead to various adverse effects. Healthcare professionals (HCPs) play a significant role in counselling patients and preventing these interactions. Knowledge, attitudes and practices (KAPs) regarding DFIs are, therefore, vital to ensure that they carry out their role efficiently. This review maps evidence on KAPs of HCPs regarding DFIs and highlights gaps for further research.

Methods
A systematic literature search for the period from 1990 to 2018 was done using Google Scholar, PubMed and ScienceDirect. Keywords such as ‘knowledge, attitudes, practices, healthcare professionals, drug-food interactions’ in combination with the Boolean operator (AND) were used. Articles published only in English that described KAPs of HCPs relating to DFIs were included.

Key findings
Twelve studies were included in this review. Inadequate knowledge was observed among the HCPs as they were unable to identify important DFIs. The HCPs had a positive attitude towards acquiring knowledge, reporting and counselling patients on DFIs. Most of the medical residents felt that they were inadequately trained on DFIs and over half believed that DFIs were only slightly important in clinical practice.

Conclusion
Deficits exist in the KAPs of HCPs regarding DFIs. An educational intervention targeting HCPs is recommended. Further research assessing the KAPs of the HCPs is required as the small number of studies conducted was a limitation.