bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact
Authors: Dave Jaydev , Raad Nour , Mittal Nishka , Zhang Lu , Fargnoli Anthony , Oh Jae Gyun , Savoia Maria Elisabetta , Hansen Jens , Fava Marika , Yin Xiaoke , Theofilatos Konstantinos , Ceholski Delaine , Kohlbrenner Erik , Jeong Dongtak , Wills Lauren , Nonnenmacher Mathieu , Haghighi Kobra , Costa Kevin D , Turnbull Irene C , Mayr Manuel , Cai Chen-Leng , Kranias Evangelia G , Akar Fadi G , Hajjar Roger J , Stillitano Francesca
Published: February 2022

Aims

A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus-9 (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del.

Methods and results

Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3 ± 1.2 Hz in hPLN-R14del vs. 25.7 ± 1.3 Hz in WT, P < 0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital polymerase chain reaction and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end-diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9 ± 2.3 Hz vs. 21.3 ± 1.5 Hz; P < 0.01).

Conclusions

This study is the first to show that disruption of hPLN-R14del allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease.
Mechanical stretching and chemical pyloroplasty to prevent delayed gastric emptying after esophageal cancer resection—a meta-analysis and review of the literature
Authors: Nienhüser Henrik , Heger Patrick , Crnovrsanin Nerma , Schaible Anja , Sisic Leila , Fuchs Hans F , Berlth Felix , Grimminger Peter P , Nickel Felix , Billeter Adrian T , Probst Pascal , Müller-Stich Beat P , Schmidt Thomas
Published: February 2022

Background

Delayed gastric emptying (DGE) occurs in up to 40% of patients after esophageal resection and prolongs recovery and hospital stay. Surgically pyloroplasty does not effectively prevent DGE. Recently published methods include injection of botulinum toxin (botox) in the pylorus and mechanical interventions as preoperative endoscopic dilatation of the pylorus. The aim of this study was to investigate the efficacy of those methods with respect to the newly published Consensus definition of DGE.

Methods

A systematic literature search using CENTRAL, Medline, and Web of Science was performed to identify studies that described pre- or intraoperative botox injection or mechanical stretching methods of the pylorus in patients undergoing esophageal resection. Frequency of DGE, anastomotic leakage rates, and length of hospital stay were analyzed. Outcome data were pooled as odd’s ratio (OR) or mean difference using a random-effects model. Risk of bias was assessed using the Robins-I tool for non-randomized trials.

Results

Out of 391 articles seven retrospective studies described patients that underwent preventive botulinum toxin injection and four studies described preventive mechanical stretching of the pylorus. DGE was not affected by injection of botox (OR 0.87, 95% confidence interval [CI] 0.37–2.03, P = 0.75), whereas mechanical stretching resulted in significant reduction of DGE (OR 0.26, 95% CI 0.14–0.5, P < 0.0001).

Conclusion

Mechanical stretching of the pylorus, but not injection of botox reduces DGE after esophageal cancer resection. A newly developed consensus definition should be used before the conduction of a large-scale randomized-controlled trial.
Days alive and out of hospital after enhanced recovery video-assisted thoracoscopic surgery lobectomy
Authors: Huang Lin , Frandsen Mikkel Nicklas , Kehlet Henrik , Petersen René Horsleben
Published: February 2022

OBJECTIVES

Days alive and out of hospital (DAOH) integrates overall information of hospitalization, readmissions, and mortality that have been applied as a new outcome measure. However, DAOH after video-assisted thoracoscopic surgery (VATS) in an established enhanced recovery after surgery (ERAS) programme has not been reported.

METHODS

Patients aged ≥18 years with non-small-cell lung cancer undergoing VATS lobectomy in an established ERAS programme were eligible. The primary and secondary outcomes were DAOH during the first postoperative 365 days and reasons for reduced DAOH.

RESULTS

A total of 316 consecutive patients with well-defined inclusion criteria and complete follow-up were assessed retrospectively. The median length of stay was 3 days (IQR 2–6). The medians (IQR) of postoperative 30, 60, 90, 180 and 365 DAOH were 27 (22–28), 57 (51–58), 86 (80–88), 176 (169–178) and 359 (349–363) days, respectively. Air leak was the dominant factor for reduced DAOH from postoperative day (POD) 0–30 (47.2%) and 0–365 (38.3%). Side effects of adjuvant chemotherapy were dominant from POD 31–60 and 61–90 (23.5% and 47.1%) and recurrence/metastases from POD 91–180 and 181–365 (25.6% and 50.0%). A low diffusing capacity for carbon monoxide (odds ratios 1.28, 95% confidence interval 1.07–1.53; P=0.007) and prior surgical history (odds ratios 1.80, 95% confidence interval 1.08–2.99; P=0.023) were predictors for low DAOH.

CONCLUSIONS

DAOH after 1 year with an established VATS lobectomy ERAS programme was only reduced with a median of 6 days. The main factors reducing DAOH were air leak, adjuvant chemotherapy and recurrence. DAOH may be an important patient-centred outcome to define future improvement strategies.
Epidemiology of cerebral microbleeds and risk of adverse outcomes in atrial fibrillation: a systematic review and meta-analysis
Authors: Corica Bernadette , Romiti Giulio Francesco , Raparelli Valeria , Cangemi Roberto , Basili Stefania , Proietti Marco
Published: February 2022

Aims

The aim of this study is to perform a systematic review and meta-analysis on the epidemiology of cerebral microbleeds (CMBs) and the risk of intracranial haemorrhage (ICH) and ischaemic stroke (IS) in patients with atrial fibrillation (AF).

Methods and results

PubMed and EMBASE databases were systematically searched from inception to 6 March 2021. All studies reporting the prevalence of CMBs and incidence of ICH and IS in AF patients with and without CMBs were included. Meta-analysis was conducted using random-effect models; odds ratios (ORs), 95% confidence intervals (CIs), and prediction intervals (PIs) were calculated for each outcome. Subgroup analyses were performed according to the number and localization of CMBs. A total of 562 studies were retrieved, with 17 studies finally included in the meta-analysis. Prevalence of CMBs in AF population was estimated at 28.3% (95% CI: 23.8–33.4%). Individuals with CMBs showed a higher risk of ICH (OR: 3.04, 95% CI: 1.83–5.06, 95% PI 1.23–7.49) and IS (OR: 1.78, 95% CI: 1.26–2.49, 95% PI 1.10–2.87). Patients with ≥5 CMBs showed a higher risk of ICH. Metaregression showed how higher of prevalence of diabetes mellitus in AF cohort is associated with higher prevalence of CMBs.

Conclusions

Cerebral microbleeds are common in patients with AF, found in almost one out of four subjects. Cerebral microbleeds were associated with both haemorrhagic and thromboembolic events in AF patients. Moreover, the risk of ICH increased consistently with the burden of CMBs. Cerebral microbleeds may represent an important overlooked risk factor for both ICH and IS in adults with AF.
Clinical impact of Bachmann’s bundle pacing defined by electrocardiographic criteria on atrial arrhythmia outcomes
Authors: Infeld Margaret , Nicoli Charles D , Meagher Sean , Tompkins Bradley J , Wayne Shawn , Irvine Benjamin , Betageri Omkar , Habel Nicole , Till Sean , Lobel Jennings , Meyer Markus , Lustgarten Daniel L
Published: February 2022

Aims

Evaluate whether Bachmann’s bundle pacing (BBp) defined by electrocardiographic (ECG) criteria is associated with less atrial fibrillation/tachycardia (AF/AT) compared with anatomically defined right atrial septal pacing (RASp) and right atrial appendage pacing (RAAp).

Methods and results

This is a retrospective study comparing BBp with non-specific RASp and RAAp on new incidence, burden, and recurrence of AF/AT. We included patients who underwent atrial lead placement between 2006 and 2019 and received > 20% atrial pacing. BBp was defined by paced P-wave morphology and fluoroscopic lead position. Compared with RASp (n = 107) and RAAp (n = 108), AF/AT burden was lower in the BBp (n = 134) group by repeated measures ANOVA (P < 0.001). Over 2-year follow-up, AF/AT burden increased in the RASp (P < 0.01) and RAAp (P < 0.01) groups but did not significantly change in the BBp group (P = 0.91). Atrial arrhythmia burden was lower in the BBp group than the RASp and RAAp groups at 12–15, 18–21, and 24–27 months (P < 0.05) after pacemaker placement. Risk of AF/AT recurrence was lower in BBp than RASp (HR 0.43; P < 0.01) and RAAp patients (HR 0.29, P < 0.01). Risk of de novo AF/AT was also lower in BBp than in RASp (OR 0.12; P < 0.01) and RAAp patients (OR 0.20, P < 0.01).

Conclusion

Bachmann’s bundle pacing defined using P-wave criteria was associated with decreased atrial arrhythmia burden, recurrence, and de novo incidence compared with right atrial septal pacing and right atrial appendage pacing.
Participatory family workshops in psychosocial health and illness research: experiences from Danish health promotion projects
Authors: Grabowski Dan , Pals Regitze Anne Saurbrey , Hoeeg Didde , Ingersgaard Marianne Vie , DeCosta Patricia , Jespersen Louise Norman
Published: February 2022

Family involvement in health and illness research is a complex matter, often characterized by unclear structural relations and contrasting needs and expectations within the family. As the family is a setting in which health and illness behaviors are developed, maintained and potentially changed, gaining knowledge about family dynamics and how to approach familial health promotion is essential. But which methodological approaches are best suited to collecting data for generating such knowledge? We propose using participatory family workshops as a method to generate in-depth data on health-related psychosocial family dynamics, the goal is to improve the field of familial health promotion. We have used family workshops in a variety of settings among various target groups in different research and development projects. In the present article, we re-visit and discuss three research projects focusing on (i) families living with type 2 diabetes, (ii) family-based prevention of childhood obesity and (iii) families with a child with type 1 diabetes. We present experiences with all phases involved in planning and facilitating research workshops. Key points are discussed in relation to implications and perspectives for practice and research. Family workshops are complex and sometimes unpredictable. However, when family workshops are successful, they provide rich and dynamic in-depth data that cannot be produced using more traditional forms of data collection. The article provides an outline of experiences as well as hands-on recommendations for working with family workshops.
Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation
Authors: Geertsma Haley M , Suk Terry R , Ricke Konrad M , Horsthuis Kyra , Parmasad Jean-Louis A , Fisk Zoe A , Callaghan Steve M , Rousseaux Maxime W C
Published: February 2022

A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson’s disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.
The Magnitude of Crohn’s Disease Direct Costs in Health Care Systems (from Different Perspectives): A Systematic Review
Authors: Santiago Mafalda , Dias Cláudia Camila , Alves Catarina , Ministro Paula , Gonçalves Raquel , Carvalho Diana , Portela Francisco , Correia Luís , Lago Paula , Magro Fernando
Published: February 2022

Background

The prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, causing high impact on the quality of life of patients and an increasing burden for health care systems. In this systematic review, we reviewed the literature concerning the direct costs of Crohn’s disease (CD) for health care systems from different perspectives: regional, economic, and temporal.

Methods

We searched for original real-world studies examining direct medical health care costs in Crohn’s disease. The primary outcome measure was the mean value per patient per year (PPY) of total direct health care costs for CD. Secondary outcomes comprised hospitalization, surgery, CD-related medication (including biologics), and biologics mean costs PPY.

Results

A total of 19 articles were selected for inclusion in the systematic review. The studies enrolled 179 056 CD patients in the period between 1997 and 2016. The pooled mean total cost PPY was €6295.28 (95% CI, €4660.55-€8503.41). The pooled mean hospitalization cost PPY for CD patients was €2004.83 (95% CI, €1351.68-€2973.59). The major contributors for the total health expenditure were biologics (€5554.58) and medications (€3096.53), followed by hospitalization (€2004.83) and surgery (€1883.67). No differences were found between regional or economic perspectives, as confidence intervals overlapped. However, total costs were significantly higher after 2010.

Conclusions

Our review highlighted the burden of CD for health care systems from different perspectives (regional, economic, and temporal) and analyzed the impact of the change of IBD treatment paradigm on total costs. Reducing the overall burden can depend on the increase of remission rates to further decrease hospitalizations and surgeries.
Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study
Authors: Nakken Ola , Holmøy Trygve , Stigum Hein , Myhr Kjell-Morten , Dahl Jesper , Heldal Einar , Meyer Haakon E
Published: February 2022

Background

Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk.

Methods

Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship.

Results

Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST.

Conclusion

A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.
Effect of calcination on the adsorption of Chifeng zeolite on Pb2+ and Cu2+
Authors: Chen Xiaolong , Tao Jieshi , Sun Pengliang , Yu Fujia , Li Bin , Dun Linan
Published: February 2022

As an important non-metallic mineral resource, zeolite is widely used in many fields. In this paper, natural zeolite from Chifeng, Inner Mongolia, was selected as the experimental material, and the calcination effect of the sample was studied in detail. The zeolite sample undergoes complex changes during the calcination process. The higher the calcination temperature, the smaller the specific surface area of the sample. When calcined at 150°C for 1 h, zeolite samples with granularity ranging from 0.050 to 0.075 mm show relatively good removal of Cu2+ and Pb2+from aqueous solution. After the zeolite is calcined, the solution with an initial concentration of 100 mg/l of heavy metal ions can reduce the concentration of Pb2+ and Cu2+ to 25 mg/l and 60 mg/l, respectively, with a removal rate of 75% and 40%. In addition, this article also focuses on its removal mechanism.
Domestic Workers, the ‘Family Worker’ Exemption from Minimum Wage, and Gendered Devaluation of Women’s Work
Authors: Sedacca Natalie
Published: February 2022

Domestic workers, who work in private households carrying out tasks such as cooking, cleaning, and care for children and the elderly, are overwhelmingly women and often from migrant and/ or ethnic minority backgrounds. This article examines a stark example of domestic workers’ exclusion from labour law protection, regulation 57(3) of the National Minimum Wage Regulations, which exempts employers from paying the minimum wage where a worker lives in their employer’s family home and is treated ‘as a member of the family’ in relation to accommodation, meals, tasks and leisure activities. Drawing on feminist theory on the divisions between ‘productive’ work outside the home versus ‘reproductive’ work within it, it argues that the exemption’s application has reflected gendered devaluation of domestic labour, stemming from its conflation with work normally performed for free by women in the ‘private sphere’ of the home. Focusing on the December 2020 Employment Tribunal (ET) judgment in Puthenveettil v Alexander & ors, which held that the exemption was unlawful and indirectly discriminatory on the grounds of sex, the article provides timely and in-depth analysis of the prospects for challenging the devaluation of domestic work in light of the limitations of legal protections for domestic workers in the UK.
Cost-effectiveness of Respiratory Syncytial Virus Disease Prevention Strategies: Maternal Vaccine Versus Seasonal or Year-Round Monoclonal Antibody Program in Norwegian Children
Authors: Li Xiao , Bilcke Joke , Vázquez Fernández Liliana , Bont Louis , Willem Lander , Wisløff Torbjørn , Jit Mark , Beutels Philippe ,   REspiratory Syncytial virus Consortium in EUrope (RESCEU) Investigators, Beutels Philippe , Bont Louis , Nair Harish , Campbell Harry , Pollard Andrew , Openshaw Peter , Martinon-Torres Federico , Heikkinen Terho , Meijer Adam , Fischer Thea K , van den Berge Maarten , Giaquinto Carlo , Abram Michael , Swanson Kena , Rizkalla Bishoy , Vernhes Charlotte , Gallichan Scott , Aerssens Jeroen , Kumar Veena , Molero Eva
Published: February 2022

Background

Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs.

Methods

Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease.

Results

We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb.

Conclusions

Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential.
Longitudinal Systemic and Mucosal Immune Responses to SARS-CoV-2 Infection
Authors: Wright Peter F , Prevost-Reilly Alejandra C , Natarajan Harini , Brickley Elizabeth B , Connor Ruth I , Wieland-Alter Wendy F , Miele Anna S , Weiner Joshua A , Nerenz Robert D , Ackerman Margaret E
Published: February 2022

Background

A longitudinal study was performed to determine the breadth, kinetics, and correlations of systemic and mucosal antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods

Twenty-six unvaccinated adults with confirmed coronavirus disease 2019 (COVID-19) were followed for 6 months with 3 collections of blood, nasal secretions, and stool. Control samples were obtained from 16 unvaccinated uninfected individuals. SARS-CoV-2 neutralizing and binding antibody responses were respectively evaluated by pseudovirus assays and multiplex bead arrays.

Results

Neutralizing antibody responses to SARS-CoV-2 were detected in serum and respiratory samples for 96% (25/26) and 54% (14/26), respectively, of infected participants. Robust binding antibody responses against SARS-CoV-2 spike protein and S1, S2, and receptor binding (RBD) domains occurred in serum and respiratory nasal secretions, but not in stool samples. Serum neutralization correlated with RBD-specific immunoglobulin (Ig)G, IgM, and IgA in serum (Spearman ρ = 0.74, 0.66, and 0.57, respectively), RBD-specific IgG in respiratory secretions (ρ = 0.52), disease severity (ρ = 0.59), and age (ρ = 0.40). Respiratory mucosal neutralization correlated with RBD-specific IgM (ρ = 0.42) and IgA (ρ = 0.63).

Conclusions

Sustained antibody responses occurred after SARS-CoV-2 infection. Notably, there was independent induction of IgM and IgA binding antibody and neutralizing responses in systemic and respiratory compartments. These observations have implications for current vaccine strategies and understanding SARS-CoV-2 reinfection and transmission.
Disulfiram enhances meropenem activity against NDM- and IMP-producing carbapenem-resistantAcinetobacter baumanniiinfections
Authors: Dubey Vineet , Devnath Kuldip , Gupta Vivek K , Kalyan Gazal , Singh Mangal , Kothari Ashish , Omar Balram Ji , Pathania Ranjana
Published: February 2022

Objectives

To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.

Methods

Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time–kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.

Results

Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time–kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.

Conclusions

These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
Vancomycin-arginine (STM-001) abrogates ESBL carrier and carbapenem-resistant Escherichia coli burden in a murine complicated urinary tract infection model
Authors: Neville Lewis F. , Shalit Itamar , Warn Peter A. , Rendell Jacob T.
Published: February 2022

Objectives

STM-001, a retargeted glycopeptide, is active against MDR E. coli expressing ESBLs including carbapenemases. Herein, we assessed its capability to combat E. coli complicated urinary tract infections (cUTI) in mice driven by clinically important serine (CTX-M-15) and metallo-β-lactamases (NDM-1).

Methods

Plasma and urine pharmacokinetics following IV administration of STM-001 (1–50 mg/kg) were determined in mice via LC-MS/MS. The effects on bacterial burden (kidney, bladder and urine) were determined in a 7 day mouse cUTI model whereby STM-001 was administered q12h or q24h at 2–100 mg/kg/day from Day 4. Efficacy was assessed by the change in log10 cfu/g or log10 cfu/mL from vehicle-treated infected mice.

Results

MICs of STM-001 for CTX-M-15 and NDM-1 E. coli were 8 and 16 mg/L, respectively. Blood pharmacokinetic profile was linear and dose-dependent with low clearance of 9.49 ± 0.31 mL/min/kg, V = 0.63 ± 0.02 L/kg and t½ = 1.16 ± 0.03 h. High STM-001 concentrations were recovered in urine 0–8 h post-administration, reaching up to 120-fold above its MIC. In cUTI efficacy studies, STM-001 (1–50 mg/kg, q12h) reduced CTX-M-15 burden by log10 4.31 (kidney), 3.95 (bladder) and 4.82 (urine) compared with vehicle-treated animals (P < 0.0001). STM-001 also reduced NDM-1 burden by log10 3.89 (kidney), 3.76 (bladder) and 3.08 (urine) (P < 0.0001), with similar inhibitory effects following q24h dosing.

Conclusions

STM-001 was highly effective in reducing E. coli burden in kidney, bladder and urine in mouse cUTI models. The observed efficacy with either dosing regimen indicates potential low humanized doses of 1–5 mg/kg. These data support further development of STM-001 as an innovative, carbapenem-sparing antibiotic to combat human cUTIs.
GARDE: a standards-based clinical decision support platform for identifying population health management cohorts
Authors: Bradshaw Richard L , Kawamoto Kensaku , Kaphingst Kimberly A , Kohlmann Wendy K , Hess Rachel , Flynn Michael C , Nanjo Claude J , Warner Phillip B , Shi Jianlin , Morgan Keaton , Kimball Kadyn , Ranade-Kharkar Pallavi , Ginsburg Ophira , Goodman Melody , Chambers Rachelle , Mann Devin , Narus Scott P , Gonzalez Javier , Loomis Shane , Chan Priscilla , Monahan Rachel , Borsato Emerson P , Shields David E , Martin Douglas K , Kessler Cecilia M , Del Fiol Guilherme
Published: February 2022

Population health management (PHM) is an important approach to promote wellness and deliver health care to targeted individuals who meet criteria for preventive measures or treatment. A critical component for any PHM program is a data analytics platform that can target those eligible individuals.

Objective

The aim of this study was to design and implement a scalable standards-based clinical decision support (CDS) approach to identify patient cohorts for PHM and maximize opportunities for multi-site dissemination.

Materials and Methods

An architecture was established to support bidirectional data exchanges between heterogeneous electronic health record (EHR) data sources, PHM systems, and CDS components. HL7 Fast Healthcare Interoperability Resources and CDS Hooks were used to facilitate interoperability and dissemination. The approach was validated by deploying the platform at multiple sites to identify patients who meet the criteria for genetic evaluation of familial cancer.

Results

The Genetic Cancer Risk Detector (GARDE) platform was created and is comprised of four components: (1) an open-source CDS Hooks server for computing patient eligibility for PHM cohorts, (2) an open-source Population Coordinator that processes GARDE requests and communicates results to a PHM system, (3) an EHR Patient Data Repository, and (4) EHR PHM Tools to manage patients and perform outreach functions. Site-specific deployments were performed on onsite virtual machines and cloud-based Amazon Web Services.

Discussion

GARDE’s component architecture establishes generalizable standards-based methods for computing PHM cohorts. Replicating deployments using one of the established deployment methods requires minimal local customization. Most of the deployment effort was related to obtaining site-specific information technology governance approvals.
Foot Burns in Persons With Diabetes: Outcomes From the National Trauma Data Bank
Authors: Perrault David , Cobert Jason , Gadiraju Veda , Sharma Ayushi , Gurtner Geoffrey , Pham Tam , Sheckter Clifford C
Published: February 2022

Diabetes mellitus (DM) complicates the treatment of burn injuries. Foot burns in diabetic patients are challenging problems with unfavorable outcomes. National-scale evaluations are needed, especially with regard to limb salvage. We aim to characterize lower-extremity burns in persons with DM and evaluate the likelihood of amputation. The National Trauma Data Bank (NTDB) was queried from 2007 to 2015 extracting encounters with primary burn injuries of the feet using International Classification of Diseases (ICD) 9th edition codes. Logistic regression modeled predictors of lower-extremity amputation. Covariables included age, sex, race/ethnicity, comorbidities including DM, % burn TBSA, mechanism, and region of burn center. Poisson regression evaluated temporal incidence rate changes in DM foot burns. Of 116,796 adult burn encounters, 7963 (7%) had foot burns. Of this group, 1308 (16%) had DM. 5.6% of encounters with DM foot burns underwent amputation compared to 1.5% of non-DM encounters (P < .001). Independent predictors of lower-extremity amputation included DM (odds ratio 3.70, 95% confidence interval 2.98–4.59), alcohol use, smoking, chronic kidney disease, and burn size >20%, African-American/black race, male sex, and age >40 years (all P < .01). The incidence of DM foot burns increased over the study period with an incidence rate ratio of 1.07 (95% confidence interval 1.05–1.10, P < .001). In conclusion, DM was associated with nearly a 4-fold increase in amputation after adjusting for covariables. Furthermore, the incidence of DM foot burns is increasing. Strategies for optimizing care in persons with DM foot burns are need to improve limb salvage.
The Special Tribunal for Lebanon and its Outreach Programme
Authors: Kavran Olga
Published: February 2022

Not only did the Special Tribunal Lebanon face the same challenges as many other international tribunals, but arguably it was situated in a uniquely politicized context. Perhaps for this reason, the importance of outreach was recognized from the outset, as part of its legal framework. While the STL may not have concluded its operations in the manner originally envisaged, its approach to outreach and public information — including an emphasis on meta-normative truths and the importance of education — may offer valuable insights for the future, both for international and, with the increasing number of universal jurisdiction cases, also national, jurisdictions.
Versatile functions of RNA m6A machinery on chromatin
Authors: Song Tanjing , Lv Suli , Li Neng , Zhao Xuefeng , Ma Xianyun , Yan Yingying , Wang Weixia , Sun Lidong
Published: February 2022

m6A, a conserved and abundant modification on RNA, regulates RNA processing and function. RNA m6A machinery, including writers, erasers, and readers of m6A, is indispensable for m6A installation and function. Intriguingly, recent studies have revealed that m6A machinery can be recruited to chromatin by pleiotropic factors, including nascent RNA, transcription factors, regulatory RNA, histone modifications, and epigenetic machinery. Consequently, recruitment of m6A machinery can directly regulate chromatin biology, such as transcription, DNA damage repair, and DNA recombination beyond installation of m6A on nascent mRNA. Here, we discuss recent evidence showing that m6A machinery is targeted to chromatin and the direct biological consequences along with the underlying mechanisms.
A rare case report of pigment gallstones and a concomitant gastric gastrointestinal stromal tumour
Authors: Pillay Yagan
Published: February 2022

Gastric gastrointestinal stromal tumours (GISTs) with cholelithiasis in the English literature are quite rare with a few published case reports. Their concurrent surgical management has also been debated as the clinical symptoms are often ascribed to one of the pathologies. All case reports to date have reported on cholesterol cholelithiasis. We would like to present a first case report of pigment cholelithiasis and a gastric GIST and their concurrent laparoscopically management. This was facilitated due to the patient’s request to deal with both pathologies as well as the nebular signs concerning the symptoms that she presented with. We were able to undertake the dual surgeries without compromising her oncological outcomes.
The profit petroleum-sharing arrangement: legal complications of profit petroleum-sharing provisions of the Kurdistan Region production sharing contracts
Authors: Salih Rdhwan S
Published: February 2022

The method for sharing the profit petroleum between the host State and the contractor is one of the major topics in Production Sharing Contracts (PSCs). Profit petroleum generally can be split between a contractor and the host State based on fixed shares or the sliding scale method. This study has the principal aim of critically analysing and arguing the provisions of the Kurdistan Region utilized PSCs regarding profit petroleum-sharing arrangement in order to ascertain its legal complications. This study also aims to seek some alternatives that can be useful and adopted by the Kurdistan Regional Government (KRG) to make more profit and reduce the burden on the government. The Study has clarified that the KRG’s Model PSC and most of its PSCs have adopted the R-factor formula for sharing of profit petroleum that derives from the Kurdistan Region Oil and Gas Law No (22) of 2007. The adopted R-factor is not an appropriate method and its calculation and the contractor percentage share of profit petroleum varies in the signed PSCs. On the other hand, a number of the KRG’s PSCs, contrary to the stipulated R-factor formula in the Kurdistan Region Oil and Gas Law 2007, have adopted different formulas. Finally, the study propounds numerous recommendations for the Kurdistan Region to minimize legal contentions relating to the profit petroleum-sharing arrangement of the Kurdistan Region.
The Class II KNOX family members KNAT3 and KNAT7 redundantly participate in Arabidopsis seed coat mucilage biosynthesis
Authors: Zhang Yuanyuan , Yin Qi , Qin Wenqi , Gao Han , Du Jinge , Chen Jiajun , Li Huiling , Zhou Gongke , Wu Hong , Wu Ai-Min
Published: February 2022

The production of Arabidopsis seed mucilage involves complex polysaccharide biosynthetic pathways and developmental processes in seed epidermal cells. Although the polysaccharide components of Arabidopsis seed mucilage have been identified, their regulatory mechanism requires further investigation. Here, we show that Class II KNOX gene family members KNAT3 and KNAT7 play an essential role in regulating mucilage production in the early developmental stages of Arabidopsis seeds. Double mutant knat3knat7 resulted in defective seed mucilage production and columellae formation, whereas knat3 showed a normal phenotype compared with wild type, and the mucilage thickness in knat7 was slightly disturbed. Rhamnogalacturonan I (RG-I) and its biosynthetic substrates galacturonic acid and rhamnose were reduced in both the adherent and soluble mucilage of knat3knat7. Comparative transcriptome analysis on whole seeds suggested that polysaccharide, glucosinolate and anthocyanin biosynthetic pathways were specifically repressed in knat3knat7. Transient co-expression of KNAT3 and KNAT7 with promoter regions of candidate genes in Arabidopsis protoplasts revealed that both KNAT3 and KNAT7 act as positive regulators of the RG-I biosynthetic gene MUCILAGE-MODIFIED 4 (MUM4, AT1G53500). Collectively, our results demonstrate that KNAT3 and KNAT7 are multifunctional transcription factors in secondary cell wall development and redundantly modulate mucilage biosynthesis in Arabidopsis seeds.
Nitrogen deficiency- and sucrose-induced anthocyanin biosynthesis is modulated by HISTONE DEACETYLASE15 in Arabidopsis
Authors: Liao Hong-Sheng , Yang Chien-Chih , Hsieh Ming-Hsiun
Published: February 2022

Anthocyanin accumulation is a hallmark response to nitrogen (N) deficiency in Arabidopsis. Although the regulation of anthocyanin biosynthesis has been extensively studied, the roles of chromatin modification in this process are largely unknown. In this study we show that anthocyanin accumulation induced by N deficiency is modulated by HISTONE DEACETYLASE15 (HDA15) in Arabidopsis seedlings. The hda15-1 T-DNA insertion mutant accumulated more anthocyanins than the wild-type when the N supply was limited, and this was caused by up-regulation of anthocyanin biosynthetic and regulatory genes in the mutant. The up-regulated genes also had increased levels of histone acetylation in the mutant. The accumulation of anthocyanins induced by sucrose and methyl jasmonate, but not that induced by H2O2 and phosphate starvation, was also greater in the hda15-1 mutant. While sucrose increased histone acetylation in the hda15-1 mutant in genes in a similar manner to that caused by N deficiency, methyl jasmonate only enhanced histone acetylation in the genes involved in anthocyanin biosynthesis. Our results suggest that different stresses act through distinct regulatory modules to activate anthocyanin biosynthesis, and that HDA15-mediated histone modification modulates the expression of anthocyanin biosynthetic and regulatory genes to avoid overaccumulation in response to N deficiency and other stresses.
Transcription factor OsSGL is a regulator of starch synthesis and grain quality in rice
Authors: Liu Zhenming , Jiang Shun , Jiang Lingli , Li Wanjing , Tang Yuqin , He Wei , Wang Manling , Xing Junjie , Cui Yanchun , Lin Qinlu , Yu Feng , Wang Long
Published: February 2022

Starch biosynthesis during rice endosperm development is important for grain quality, as it influences grain size and physico-chemical properties, which together determine rice eating quality. Cereal starch biosynthetic pathways have been comprehensively investigated; however, their regulation, especially by transcriptional repressors remains largely unknown. Here, we identified a DUF1645 domain-containing protein, STRESS_tolerance and GRAIN_LENGTH (OsSGL), that participates in regulating rice starch biosynthesis. Overexpression of OsSGL reduced total starch and amylose content in the endosperm compared with the wild type. Chromatin immunoprecipitation sequencing and RNA-seq analyses indicated that OsSGL targets the transcriptional activity of several starch and sucrose metabolism genes. In addition, ChIP-qPCR, yeast one-hybrid, EMSA and dual-luciferase assays demonstrated that OsSGL directly inhibits the expression of SUCROSE SYNTHASE 1 (OsSUS1) in the endosperm. Furthermore, OsSUS1 interacts with OsSGL to release its transcriptional repression ability. Unexpectedly, our results also show that knock down and mutation of OsSGL disrupts the starch biosynthetic pathway, causing lower starch and amylose content. Therefore, our findings demonstrate that accurate control of OsSGL homeostasis is essential for starch synthesis and grain quality. In addition, we revealed the molecular mechanism of OsSGL in regulating starch biosynthesis-related genes, which are required for grain quality.
TRIPTYCHON-LIKE regulates aspects of both fruit flavor and color in citrus
Authors: He Jiaxian , Xu Yuantao , Huang Ding , Fu Jialing , Liu Ziang , Wang Lun , Zhang Yin , Xu Rangwei , Li Li , Deng Xiuxin , Xu Qiang
Published: February 2022

Deciphering the genetic basis of organoleptic traits is critical for improving the quality of fruits, which greatly shapes their appeal to consumers. Here, we characterize the citrus R3-MYB transcription factor TRIPTYCHON-LIKE (CitTRL), which is closely associated with the levels of citric acid, proanthocyanidins (PAs), and anthocyanins. Overexpression of CitTRL lowered acidity levels and PA contents in citrus calli as well as anthocyanin and PA contents in Arabidopsis leaves and seeds. CitTRL interacts with the two basic helix–loop–helix (bHLH) proteins CitbHLH1 and ANTHOCYANIN 1 (CitAN1) to regulate fruit quality. We show that CitTRL competes with the R2R3-MYB CitRuby1 for binding to CitbHLH1 or CitAN1, thereby repressing their activation of anthocyanin structural genes. CitTRL also competes with a second R2R3-MYB, CitPH4, for binding to CitAN1, thus altering the expression of the vacuolar proton-pump gene PH5 and Leucoanthocyanidin reductase, responsible for vacuolar acidification and proanthocyanidins biosynthesis, respectively. Moreover, CitPH4 activates CitTRL transcription, thus forming an activator–repressor loop to prevent the overaccumulation of citric acid and PAs. Overall, this study demonstrates that CitTRL acts as a repressor of the accumulation of citric acid, PAs, and anthocyanins by a cross-regulation mechanism. Our results provide an opportunity to simultaneously manipulate these key traits as a means to produce citrus fruits that are both visually and organoleptically appealing.
An Eddington ratio-driven origin for the LX − M* relation in quiescent and star-forming active galaxies
Authors: Carraro Rosamaria , Shankar Francesco , Allevato Viola , Rodighiero Giulia , Marsden Christopher , Arévalo Patricia , Delvecchio Ivan , Lapi Andrea
Published: February 2022

A mild correlation exists in active galaxies between the mean black hole accretion, as traced by the mean X-ray luminosity  and the host galaxy stellar mass M*, characterised by a normalization steadily decreasing with cosmic time and lower in more quiescent galaxies. We create comprehensive semi-empirical mock catalogues of active black holes to pin down which parameters control the shape and evolution of the  − M* relation of X-ray-detected active galaxies. We find that the normalization of the  − M* relation is largely independent of the fraction of active galaxies (the duty cycle), but strongly dependent on the mean Eddington ratio, when adopting a constant underlying MBH − M* relation as suggested by observational studies. The data point to a decreasing mean Eddington ratio with cosmic time and with galaxy stellar mass at fixed redshift. Our data can be reproduced by black holes and galaxies evolving on similar MBH − M* relations but progressively decreasing their average Eddington ratios, mean X-ray luminosities, and specific star formation rates, when moving from the starburst to the quiescent phase. Models consistent with the observed  − M* relation and independent measurements of the mean Eddington ratios are characterised by MBH − M* relations lower than those derived from dynamically measured local black holes. Our results point to the  − M* relation as a powerful diagnostic to: (1) probe black hole–galaxy scaling relations and the level of accretion on to black holes; (2) efficiently break the degeneracies between duty cycles and accretion rates in cosmological models of black holes.
Low-frequency observations of giant pulses from ordinary pulsars
Authors: Kazantsev A N , Basalaeva M Yu
Published: February 2022

We present the results of an investigation of the giant radio pulse (GRP) generation rate from five radio pulsars (B0301+19, B0950+08, B1112+50, B1133+16, and B1237+25) and anomalous intensity pulse generation rate from B0809+74. All data used were obtained with the Large Phased Array radio telescope at the Pushchino Radio Astronomy Observatory at 111 MHz from 2012 to 2021. In addition to the analysis of the rate of generation of bright pulses, we analyse the distribution of bright pulses in the phase of the pulsar period and search for clusters of bright pulses – several bright pulses emitted in adjacent pulsar periods. It is found that pulsars B0301+19, B1112+50, B1133+16, and B1237+25 demonstrate different generation rates and generation of clusters. Pulsar B1112+50 generates GRP clusters more often than the other pulsars studied. The longest cluster of GRPs containing four single pulses is detected from this pulsar. GRPs from the pulsars studied are distributed along the longitudes of the main components of the average pulses of these pulsars. This distribution is 1.5–2 times narrower than the phase distribution of non-giant pulses. It is found that the distance between the components of the average GRP profile and the distance between the components of the average non-giant profile differ substantially for pulsars with multicomponent average profiles.