bluuebunny/crossref_metadata_2025 huggingface dataset:
Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia
Authors: Howard-Anderson Jessica , Hamasaki Toshimitsu , Dai Weixiao , Collyar Deborah , Rubin Daniel , Nambiar Sumathi , Kinamon Tori , Leister-Tebbe Heidi , Hill Carol , Geres Holly , Holland Thomas L , Doernberg Sarah B , Chambers Henry F , Fowler Vance G , Evans Scott R , Boucher Helen W ,   for the Antibacterial Resistance Leadership Group, Boucher Helen , Cosgrove Sara , Doernberg Sarah , Evans Scott , Hamasaki Toshi , Holland Tom , Howard-Anderson Jessica , Fowler Vance , King Heather , Nambiar Sumati , Tsalik Ephraim , Gopinath Ramya , Kim Peter , Natarajan Mukil , Needles Mark , Rubin Dan , Waack Ursula , Collyar Deborah
Published: September 2023

Background

Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation.

Methods

A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses.

Results

In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%­−55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%–52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid.

Conclusions

The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.
Vedolizumab in Mild-to-Moderate Crohn’s Disease Patients Naïve to Biological Therapy: A Multicentric Observational Study
Authors: Dotti Adriana Zanoni , Magro Daniela Oliveira , Vilela Eduardo Garcia , Chebli Julio Maria Fonseca , Chebli Liliana Andrade , Steinwurz Flavio , Argollo Marjorie , Carvalho Nayara Salgado , Parente Jose Miguel Luz , Lima Murilo Moura , Parra Rogério Serafim , Perin Ramir Luan , Flores Cristina , Morsoletto Eloá Marussi , da Costa Ferreira Sandro , Ludvig Juliano Coelho , Kaiser Junior Roberto Luiz , Faria Mikaell Alexandre Gouvea , Nicollelli Guilherme Mattioli , Andrade Adriana Ribas , Queiroz Natalia Sousa Freitas , Kotze Paulo Gustavo
Published: September 2023

Background

In real-world experience, the number of patients using vedolizumab as first-line biological therapy was low. We aimed to evaluate the effectiveness and safety of vedolizumab in mild-to-moderate Crohn’s disease (CD) biologic-naïve patients.

Methods

We performed a retrospective multicentric cohort study with patients who had clinical activity scores (Harvey–Bradshaw Index [HBI]) measured at baseline and weeks 12, 26, 52, as well as at the last follow-up. Clinical response was defined as a reduction ≥3 in HBI, whereas clinical remission as HBI ≤4. Mucosal healing was defined as the complete absence of ulcers in control colonoscopies. Kaplan–Meier survival analysis was used to assess the persistence with vedolizumab.

Results

From a total of 66 patients, 53% (35/66) reached clinical remission at week 12. This percentage increased to 69.7% (46/66) at week 26, and 78.8% (52/66) at week 52. Mucosal healing was achieved in 62.3% (33/53) of patients. Vedolizumab was well tolerated, and most adverse events were minor. During vedolizumab treatment, 3/66 patients underwent surgery.

Conclusions

This study demonstrates the effectiveness and safety of vedolizumab as a first-line biological agent in patients with mild-to-moderate CD.
Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/− long QT syndrome variant
Authors: Venkateshappa Ravichandra , Hunter Diana V , Muralidharan Priya , Nagalingam Raghu S , Huen Galvin , Faizi Shoaib , Luthra Shreya , Lin Eric , Cheng Yen May , Hughes Julia , Khelifi Rania , Dhunna Daman Parduman , Johal Raj , Sergeev Valentine , Shafaattalab Sanam , Julian Lisa M , Poburko Damon T , Laksman Zachary , Tibbits Glen F , Claydon Tom W
Published: September 2023

Aims

Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR–Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243.

Methods and results

The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1–S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness.

Conclusion

Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.
Cybersecurity in UK Universities: mapping (or managing) threat intelligence sharing within the higher education sector
Authors: Piazza Anna , Vasudevan Srinidhi , Carr Madeline
Published: September 2023

Higher education has recently been identified as a sector of concern by the UK National Cyber Security Centre (NCSC). In 2021, the NCSC reported that universities and higher education institutions (HEI) had been exponentially targeted by cyber-criminals. Existing challenges were amplified or highlighted over the course of the global pandemic when universities struggled to continue to function through hybrid and remote teaching provision that relied heavily on their digital estate and services. Despite the value of the sector and the vulnerabilities within it, higher education has received relatively little attention from the cybersecurity research community. Over 2 years, we carried out numerous interventions and engagements with the UK higher education sector. Through interviews with cybersecurity practitioners working in the sector as well as roundtables, and questionnaires, we conducted a qualitative and quantitative analysis of threat intelligence sharing, which we use as a proxy for measuring and analysing collaboration. In a unique approach to studying collaboration in cybersecurity, we utilized social network analysis. This paper presents the study and our findings about the state of cybersecurity in UK universities. It also presents some recommendations for future steps that we argue will be necessary to equip the higher education sector to continue to support UK national interests going forward. Key findings include the positive inclination of those working in university cybersecurity to collaborate as well as the factors that impede that collaboration. These include management and insurance constraints, concerns about individual and institutional reputational damage, a lack of trusted relationships, and the lack of effective mechanisms or channels for sectoral collaboration. In terms of the network itself, we found that it is highly fragmented with a very small number of the possible connections active, none of the organizations we might expect to facilitate collaboration in the network are playing a significant role, and some universities are currently acting as key information bridges. For these reasons, any changes that might be led by sectoral bodies such as Jisc, UCISA or government bodies such as NCSC, would need to go through these information brokers.
Education level and the use of coronary computed tomography, functional testing, coronary angiography, revascularization, and outcomes—a 10-year Danish, nationwide, registry-based follow-up study
Authors: Søndergaard Marc Meller , Freeman Phillip , Kristensen Anna Meta Dyrvig , Chang Su Min , Nassir Khurram , Mortensen Martin Bødtker , Nørgaard Bjarne Linde , Maeng Michael , Andersen Mikkel Porsborg , Søgaard Peter , Tayal Bhupendar , Pareek Manan , Johnsen Søren Paaske , Køber Lars , Gislason Gunnar , Torp-Pedersen Christian , Kragholm Kristian Hay
Published: September 2023

Background and aims

Coronary computed tomography angiography (CCTA) can guide downstream preventive treatment and improve patient prognosis, but its use in relation to education level remains unexplored.

Methods

This nationwide register-based cohort study assessed all residents in Denmark between 2008 and 2018 without coronary artery disease (CAD) and 50–80 years of age (n = 1 469 724). Residents were divided according to four levels of education: low, lower-mid, higher-mid, and high. Outcomes were CCTA, functional testing, invasive coronary angiography (ICA), revascularization, and major adverse cardiovascular and cerebrovascular events (MACCE).

Results

Individuals with the lowest education level underwent CCTA (absolute risk [AR] 3.95% individuals aged ≥50–59, AR 3.62% individuals aged ≥60–69, and AR 2.19% individuals aged ≥70–80) less often than individuals of lower-mid (AR 4.16%, AR 3.90%, and AR 2.41%), higher-mid (AR 4.38%, AR 4.30%, and AR 2.45%) and highest education level (AR 3.98%, AR 4.37%, and AR 2.30%). Similar differences were observed for functional testing. Conversely, use of ICA, and risks of revascularization and MACCE were more common among individuals of lowest education level. Among patients examined with CCTA (n = 50 234), patients of lowest education level less often underwent functional testing and more likely initiated preventive medication, underwent ICA, revascularization, and experienced MACCE.

Conclusion

Despite tax-financed healthcare in Denmark, individuals of lowest education level were less likely to undergo CCTA and functional testing than persons of higher education level. Invasive coronary angiography utilization, revascularization, and MACCE risks were higher for individuals of lowest education level. Among CCTA-examined patients, patients of lowest education level were more likely to initiate preventive medication and had the highest risks of revascularization and MACCE when compared to higher education level groups. These findings suggest that the preventive potential of CCTA is underutilized in individuals of lower education level, a proxy for socioeconomic status. Socioeconomic differences in CAD assessment, care, and outcomes are likely even larger without tax-financed healthcare.
Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis
Authors: Florsheim Natan , Naugolni Larisa , Zahdeh Fouad , Lobel Orit , Terespolsky Batel , Michaelson-Cohen Rachel , Gold Merav Y , Goldberg Michal , Renbaum Paul , Levy-Lahad Ephrat , Zangen David
Published: September 2023

Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519_1523del (64% of wild-type [WT], P = .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P = .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P < .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway's role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients.
Taxed fairly? How differences in perception shape attitudes towards progressive taxation
Authors: Kalleitner Fabian , Bobzien Licia
Published: September 2023

Empirically, the poor are more likely to support increases in the level of tax progressivity than the rich. Such income-stratified tax preferences can result from differences in preferences of what should be taxed as argued by previous literature. However, it may also result from income-stratified perceptions of what is taxed. This paper argues that the rich perceive higher levels of tax progressivity than the poor and that tax perceptions affect individuals’ support for progressive taxation. Using data from an Austrian survey experiment, we test this argument in three steps: First, in line with past research, we show that individuals’ income positions are connected to individuals’ tax preferences as a self-interest rationale would predict. However, second, we show that this variation is mainly driven by income-stratified tax perceptions. Third, randomly informing a subset of the sample about actual tax rates, we find that changing tax perceptions causally affects support for redistributive taxation among those who initially overestimated the level of tax progressivity. Our results indicate that tax perceptions are relevant for forming tax preferences and suggest that individuals are more polarized in their perceptions of who pays how much taxes than in their support for who should pay how much tax.
The effects of internet-based cognitive behaviour therapy for depression in cardiovascular disease on symptoms of anxiety: a secondary analysis of a randomized trial
Authors: Westas Mats , Mourad Ghassan , Andersson Gerhard , Lundgren Johan , Johansson Peter
Published: September 2023

Aims

The aims of this study were to evaluate: (i) the short- and long-term effects of the internet-based cognitive behaviour (iCBT) programme on symptoms of distress and fear disorder in cardiovascular disease (CVD) patients, and (ii) the association between changes in depression and changes in symptoms of distress and fear disorder from baseline to 12-month follow-up.

Methods and results

Secondary analysis of data collected in a randomized controlled study evaluating the effects on depression of an iCBT programme compared to an online discussion forum (ODF) in CVD patients (n = 144). Data were collected at baseline, at post-intervention (9 weeks), and at 6- and 12-month follow-ups.

The results showed that symptoms of distress disorder were statistically significantly more reduced in the iCBT group than in the ODF group. For symptoms of the fear disorder, no differences were found except for avoidance, which showed a statistically significant reduction in the iCBT group. The long-term analysis in the iCBT group showed that CAQ total score and fear decreased from baseline to 6- and 12-month follow-ups, respectively. Avoidance and attention both decreased statistically significantly from baseline to post-intervention, but not between post-intervention and 12-month follow-up.

Conclusion

The results suggest that the iCBT programme targeted depression in CVD patients successfully reduced symptoms of distress disorder and to a lesser extent symptoms of fear disorder. Change in depression was more strongly associated with a change in distress than a change in fear disorder.

Registration

ClinicalTrials.gov: NCT02778074
Ancestry estimation in forensic anthropology: accuracy of the AncesTrees software in a Brazilian sample
Authors: Jacometti Victor , Guimarães Marco Aurelio , de Moraes Luis Otávio Carvalho , Marques Sérgio Ricardo , Cunha Eugénia , da Silva Ricardo Henrique Alves
Published: September 2023

The objective of this study is to analyze the accuracy and applicability of the AncesTrees software with respect to a set of cranial measurements of a Brazilian sample consisting of 114 identified skulls from two osteological collections, predominantly composed of European (n = 59), African (n = 35), and admixed individuals (n = 20). Twenty-four different craniometric measurements are performed and input to AncesTrees via two algorithms, one of which is used in three configurations, with different ancestral groups integrated in the model. The software exhibits superior performance in the estimation of European individuals, reaching 73% accuracy, compared with 66% in the African individuals. Those individuals classified as admixed produce a variety of ancestral classifications, mainly European. Overall, the most accurate combination of AncesTrees is obtained using ancestralForest with only the European and African groups integrated into the algorithm, where the accuracy reaches 70%. The applicability of this software to a specific population is fragile because of the high admixing load, making it necessary to create a more representative anthropometric database of the Brazilian people.

Key points
Culture Change in Older Adult Care Settings: A Bibliometric Review
Authors: Ivanitskaya Lana V , Bogner Matthew P
Published: September 2023

Background and Objectives

We systematically analyzed research on the culture change movement, in the context of global efforts to transform the provision of older adult care in institutional settings.

Research Design and Methods

Using Web of Science and Scopus publications relevant to person-centered care, culture change, or older adult care settings, we built bibliometric networks for keywords and terms extracted from titles and abstracts. Overlays depicted corresponding authors’ countries, publication recency, funding, scientific impact, and concept use.

Results

The keyword network for 337 publications revealed variability in culture change settings and study indexing. Term network overlays showed geographical and chronological research variation. Corresponding authors from 14 countries contributed publications, mostly from the United States (69% of publications), Canada (9%), and Australia (5%). Social environment and person-centeredness studies, particularly in dementia care settings, were more recent than studies on physical environment, quality, organizational culture, turnover, and staffing. Scholars listed funding sources for 38% of publications; funding and scientific impact did not always overlap. Well-cited studies on standards of care and policy were funded at a lower rate than topics of lower impact. Over 60% of titles, abstracts, or keywords referred to quality and person-centeredness.

Discussion and Implications

Originating in the 1990s in the United States, culture change quickly became an international phenomenon, drawing researchers’ attention. Change research has deep roots in quality improvement and person-centered philosophy. We offered practical strategies for querying this hard to access literature. With some database-related limitations, empirical data on scientific impact can be used to allocate research funding.
Investigation of common genetic risk factors between thyroid traits and breast cancer
Authors: Lucotte Elise A , Asgari Yazdan , Sugier Pierre-Emmanuel , Karimi Mojgan , Domenighetti Cloé , Lesueur Fabienne , Boland-Augé Anne , Ostroumova Evgenia , de Vathaire Florent , Zidane Monia , Guénel Pascal , Deleuze Jean-François , Boutron-Ruault Marie-Christine , Severi Gianluca , Liquet Benoît , Truong Thérèse
Published: September 2023

Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 × 10−4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = −0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00–1.13, p-value = 2.8 × 10−2 and OR = 1.04, 95%CI: 1.00–1.08, p-value = 3.8 × 10−2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89–0.97, p-value = 2.0 × 10−3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 10−8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.
Higher incidence of embryonic defects in mouse offspring conceived with assisted reproduction from fathers with sperm epimutations
Authors: Karahan Gurbet , Martel Josée , Rahimi Sophia , Farag Mena , Matias Fernando , MacFarlane Amanda J , Chan Donovan , Trasler Jacquetta
Published: September 2023

Assisted reproductive technologies (ART) account for 1–6% of births in developed countries. While most children conceived are healthy, increases in birth and genomic imprinting defects have been reported; such abnormal outcomes have been attributed to underlying parental infertility and/or the ART used. Here, we assessed whether paternal genetic and lifestyle factors, that are associated with male infertility and affect the sperm epigenome, can influence ART outcomes. We examined how paternal factors, haploinsufficiency for Dnmt3L, an important co-factor for DNA methylation reactions, and/or diet-induced obesity, in combination with ART (superovulation, in vitro fertilization, embryo culture and embryo transfer), could adversely influence embryo development and DNA methylation patterning in mice. While male mice fed high-fat diets (HFD) gained weight and showed perturbed metabolic health, their sperm DNA methylation was minimally affected by the diet. In contrast, Dnmt3L haploinsufficiency induced a marked loss of DNA methylation in sperm; notably, regions affected were associated with neurodevelopmental pathways and enriched in young retrotransposons, sequences that can have functional consequences in the next generation. Following ART, placental imprinted gene methylation and growth parameters were impacted by one or both paternal factors. For embryos conceived by natural conception, abnormality rates were similar for WT and Dnmt3L+/− fathers. In contrast, paternal Dnmt3L+/− genotype, as compared to WT fathers, resulted in a 3-fold increase in the incidence of morphological abnormalities in embryos generated by ART. Together, the results indicate that embryonic morphological and epigenetic defects associated with ART may be exacerbated in offspring conceived by fathers with sperm epimutations.
Vascular Disease Is Associated With Differences in Brain Structure and Lower Cognitive Functioning in Inflammatory Bowel Disease: A Cross-Sectional Study
Authors: Patel Ronak , Marrie Ruth Ann , Bernstein Charles N , Bolton James M , Graff Lesley A , Marriott James J , Figley Chase R , Kornelsen Jennifer , Mazerolle Erin L , Helmick Carl , Uddin Md Nasir , Fisk John D
Published: September 2023

Background

Vascular disease and cognitive impairment have been increasingly documented in inflammatory bowel disease (IBD), and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning.

Methods

Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression–based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling.

Results

Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure.

Conclusions

Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.
Childhood Socioeconomic Characteristics and Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study
Authors: Sigvardsson Ida , Størdal Ketil , Östensson Malin , Guo Annie , Ludvigsson Johnny , Mårild Karl
Published: September 2023

Background

Ecological observations suggest a negative relationship between childhood socioeconomic status (SES) and inflammatory bowel disease (IBD) risk. Individual-level analyses have been inconsistent and mostly lacked refined assessments of SES. We aimed to comprehensively study the association between early-life SES and later IBD.

Methods

This study included 117 493 participants from the Norwegian Mother, Father and Child cohort and Swedish All Babies in Southeast Sweden cohorts. Participants were followed from birth (1997-2009) through 2021. IBD was identified through national patient registers. Questionnaire and register data were used to define parental educational level, employment, and household income level. Cox regression estimated adjusted hazard ratios (aHRs), accounting for other SES exposures and covariates (eg, parental IBD). Cohort-specific estimates were pooled using a random-effects model.

Results

During 2 024 299 person-years of follow-up, 451 participants were diagnosed with IBD (All Babies in Southeast Sweden cohort, n = 113 and Norwegian Mother, Father and Child cohort, n = 338). Early-life maternal, but not paternal, educational level was associated with later IBD (low vs high educational level; pooled aHR, 1.81; 95% confidence interval [CI], 1.16-2.82; and pooled aHR, 1.20; 95% CI, 0.80-1.80; respectively). Having a nonworking mother or father was not significantly associated with IBD (pooled aHR, 0.69; 95% CI, 0.47-1.02; pooled aHR, 0.79; 95% CI, 0.45-1.37). High vs low household income level yielded a pooled aHR of 1.33 (95% CI, 0.94-1.89). Overall, results were largely consistent across cohorts.

Conclusions

In this prospective Scandinavian cohort study, low maternal educational level was, independent of other SES and covariates, significantly associated with later IBD in her child. Further research is needed to elucidate factors that may mediate this relationship.
Staged endoscopic mitral valve repair for active infective endocarditis with a mitral annular abscess
Authors: Kato Riku , Hosoba Soh , Maeda Shogo , Ito Toshiaki
Published: September 2023

The presence of an annular abscess complicates the operation for infective endocarditis. We report a case of a totally endoscopic repair of a mitral annular abscess using a staged strategy. A 28-year-old woman underwent endoscopic mitral valve repair for active infective endocarditis with Staphylococcus aureus. At the index operation, the mitral annular abscess was completely debrided, yielding an annular defect. The mitral valve was repaired with the autologous pericardial patch and an annuloplasty. Primary repair of the annular defect was not performed because of the fragility of oedematous tissues. Two weeks after index surgery, when the infection was under control, and the scar tissue had formed around the annulus, we performed the second stage operation involving repair of the annular abscess. The scar formation enabled annular reconstruction and additional repair of the mitral valve in a totally endoscopic fashion. The postoperative course was uneventful, and there was no recurrence at 5 months. An annular abscess may be repaired with staged surgery in select situations.
Near-Optimal Restriction Estimates for Cantor Sets on the Parabola
Authors: Ryou Donggeun
Published: September 2023

For any $0 < \alpha <1$, we construct Cantor sets on the parabola of Hausdorff dimension $\alpha $ such that they are Salem sets and each associated measure $\nu $ satisfies the estimate $\left \| \widehat {f d\nu } \right \|_{L^{p}({\mathbb {R}}^{2})} \leq C_{p} \left \| f \right \|_{L^{2}(\nu )}$ for all $p>6/\alpha $ and for some constant $C_{p}>0$,which may depend on $p$ and $\nu $. The range $p>6/\alpha $ is optimal except for the endpoint. The proof is based on the work of Łaba and Wang on restriction estimates for random Cantor sets and the work of Shmerkin and Suomala on Fourier decay of measures on random Cantor sets. They considered fractal subsets of ${\mathbb {R}}^{d}$, while we consider fractal subsets of the parabola.
Tools Needed to Support Same-Day Diagnosis and Treatment of Current Hepatitis C Virus Infection
Authors: Fricker Gregory P , Ghany Marc G , Mera Jorge , Pinsky Benjamin A , Ward John W , Chung Raymond T
Published: September 2023

The current multiday diagnosis and treatment paradigm for hepatitis C virus (HCV) infection results in far fewer patients receiving treatment with direct-acting antiviral agents than those with diagnosed HCV infection. To achieve HCV elimination, a paradigm shift in access to HCV treatment is needed from multiday testing and treatment algorithms to same-day diagnosis and treatment. This shift will require new tools, such as point-of-care (POC) antigen tests or nucleic acid tests for HCV and hepatitis B virus (HBV) and nucleic acid tests for human immunodeficiency virus (HIV) that do not require venous blood. This shift will also require better use of existing resources, including expanded access to HCV treatment and available POC tests, novel monitoring approaches, and removal of barriers to approval. A same-day diagnosis and treatment paradigm will substantially contribute to HCV elimination by improving HCV treatment rates and expanding access to treatment in settings where patients have brief encounters with healthcare.
Maximizing Reflexive Hepatitis C Virus (HCV) RNA Testing of HCV Antibody-Reactive Samples Within United States Public Health Laboratories
Authors: Johnson Lauren N , Gaynor Anne M , Wroblewski Kelly , Buss Sarah N
Published: September 2023

Hepatitis C virus (HCV) infection can have serious consequences when untreated and diagnosis is the first step in any treatment regimen. In the Unites States a 2-step algorithm consisting of HCV antibody screening and HCV RNA testing of HCV antibody-reactive specimens is recommended for detection of current HCV infection. We conducted a survey of HCV diagnostic practices in US public health laboratories and convened a meeting of HCV subject matter experts to identify opportunities for improvement in HCV diagnosis. Automatic reflexive HCV RNA testing of HCV antibody-reactive specimens was identified as a gap in laboratory practice. Only 54% of respondent laboratories always automatically reflexed or referred an anti-HCV-reactive specimen to an HCV RNA test. To facilitate diagnosis and ensure patients are not lost to follow-up, laboratories should ensure that the entire HCV testing algorithm can be completed with a sample(s) collected during a single patient visit.
What Hepatitis C Virus (HCV) Diagnostic Tools Are Needed to Advance Diagnosis of Current HCV Infection in Outreach Settings and in a Nonclinical Setting?
Authors: Page Kimberly , Feinberg Judith
Published: September 2023

Given the growing hepatitis C virus (HCV) epidemic in the United States, it is imperative to implement a coordinated, equitable public health approach to HCV testing that will facilitate immediate access to treatment, especially for individuals with limited healthcare access and those who inject drugs. Point-of-care RNA diagnostic tests have the greatest potential to address this need. Future regulatory approval has been facilitated by a recent change in the US Food and Drug Administration's approach to evaluating point-of-care diagnostic tests that have been developed and validated.
Down-Classification of Hepatitis C Virus Diagnostics: Implications for Screening and Diagnosis
Authors: Terrault Norah
Published: September 2023

In November 2021, the United States Food and Drug Administration reclassified 2 types of hepatitis C virus (HCV) diagnostic tests (HCV antibody and HCV nucleic acid) from class III to class II, providing a less burdensome pathway to market for diagnostic companies. This down-classification is anticipated to facilitate innovation in HCV diagnostics, particularly for new point-of-care viral detection assays, and ultimately support HCV elimination efforts by increasing the ease of screening as well as test-and-treat models of HCV care.
Development and Validation of Three Automated High-Throughput Molecular Tests to Detect Monkeypox Virus Infections
Authors: Anderson Mark , Hodges Austin , Luk Ka-Cheung , Olivo Ana , Forberg Kenn , Meyer Todd V , Strobel Carolyn , Kim Mark , Toolsie Dan , Moore Nicholas M , Goldstein Yitzchak , Rodgers Mary , Lucic Danijela , Cloherty Gavin
Published: September 2023

Background

The 2022 outbreak of the clade IIb monkeypox virus and subsequent global spread lead to an urgent need for the development of high-throughput, sensitive, and reproducible diagnostic tests.

Methods

We developed 3 assays to detect monkeypox virus, 2 (MPXV+ and MPXV) for m2000 RealTime and 1 (MPXV) for Alinity m platforms. Dual targets in E9L and B6R (MPXV+) and J2L and B7R (MPXV) increased mutation resistance. In silico prediction indicates MPXV+ cross-reactivity with orthopox viruses and specific monkeypox virus detection with MPXV.

Results

m2000 RealTime MPXV+ and MPXV assay sensitivity was determined to be 3.2 plaque-forming units/mL using a reference virus culture diluted into universal transport medium (UTM). Alinity m MPXV lower limit of detection was 200 copies/mL using monkeypox virus plasmids in pooled UTM matrix. m2000 RealTime MPXV+ and MPXV assays were validated with lesion swabs in UTM and 1:1 saliva to UTM mixtures. Commercially available and remnant clinical lesion specimens in UTM were tested with RealTime MPXV+, RealTime MPXV and Alinity m MPXV assays and demonstrated high agreement to known mpox (MPX)-positive specimens.

Conclusions

RealTime MPXV+, RealTime MPXV, and Alinity MPXV are high throughput and sensitive assays used for the detection of monkeypox virus. These assays maybe useful during MPX outbreaks.
Oral Favipiravir Exposure and Pharmacodynamic Effects in Adult Outpatients With Acute Influenza
Authors: Hayden Frederick G , Lenk Robert P , Epstein Carol , Kang Lih Lisa
Published: September 2023

Background

The pharmacokinetics of oral favipiravir and the relationships of plasma concentrations to antiviral effects are incompletely studied in influenza.

Methods

Serial plasma samples were collected from adults with uncomplicated influenza who were randomized to favipiravir (1800 mg twice a day on day 1, 800 mg twice a day on days 2 to 5; n = 827) or placebo (n = 419) in 2 phase 3 trials. Post hoc analyses assessed the frequency of reaching an average minimum concentration (Cmin) ≥20 µg/mL, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure.

Results

Wide interindividual variability existed in favipiravir concentrations, and this regimen failed to reach an average Cmin>20 µg/mL in 41%–43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 and lower viral titer area under the curve compared to those who did not. Those with average Cmin <20 µg/mL had over 2-fold higher mean ratios of the metabolite T-705M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh >80 kg (61.5%–64%).

Conclusions

Higher favipiravir levels with average Cmin>20 µg/mL were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average Cmin values in uncomplicated influenza.

Clinical Trials Registration . NCT1068912 and NCT01728753.
Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis
Authors: Abdelgawad Noha , Wasserman Sean , Abdelwahab Mahmoud Tareq , Davis Angharad , Stek Cari , Wiesner Lubbe , Black John , Meintjes Graeme , Wilkinson Robert J , Denti Paolo
Published: September 2023

Background

Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM.

Methods

In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits.

Results

Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27–56) and 58 kg (range, 30–96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours.

Conclusions

Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.

Clinical Trials Registration.  ClinicalTrials.gov (NCT03927313).
Fair-Weather Abusers? Civil War Dynamics and the Onset of State-Sponsored Violence
Authors: Keels Eric , Greig J Michael
Published: September 2023

Despite decades of rigorous research on the use of government-sponsored violence in armed conflicts, there remains significant uncertainty as to when and where leaders choose to target civilians in war. We argue that the variation in the use of state repression is explained in part by how soldiers perceive battlefield gains by rebel forces. Specifically, while strong opposition forces are often a necessary condition for elites convincing agents to engage in state-sponsored brutality, this is modified by the soldiers’ beliefs surrounding the outcome of the war. If government soldiers believe that rebels are likely to win the war, we posit that they will likely shirk orders to target civilians, fearing post-war accountability. We test this argument by examining subnational variation in battlefield dynamics and the use of government one-sided violence from 1992 to 2010.
Investigation of genomic mutations and their association with phenotypic resistance to new and repurposed drugs in Mycobacterium tuberculosis complex clinical isolates
Authors: Mok Simone , Roycroft Emma , Flanagan Peter R , Wagener Johannes , Fitzgibbon Margaret M
Published: September 2023

Background

WGS has the potential to detect resistance-associated mutations and guide treatment of MDR TB. However, the knowledge base to confidently interpret mutations associated with the new and repurposed drugs is sparse, and phenotypic drug susceptibility testing is required to detect resistance.

Methods

We screened 900 Mycobacterium tuberculosis complex genomes from Ireland, a low TB incidence country, for mutations in 13 candidate genes and assessed their association with phenotypic resistance to bedaquiline, clofazimine, linezolid, delamanid and pretomanid.

Results

We identified a large diversity of mutations in the candidate genes of 195 clinical isolates, with very few isolates associated with phenotypic resistance to bedaquiline (n = 4), delamanid (n = 4) and pretomanid (n = 2). We identified bedaquiline resistance among two drug-susceptible TB isolates that harboured mutations in Rv0678. Bedaquiline resistance was also identified in two MDR-TB isolates harbouring Met146Thr in Rv0678, which dated back to 2007, prior to the introduction of bedaquiline. High-level delamanid resistance was observed in two isolates with deletions in ddn, which were also resistant to pretomanid. Delamanid resistance was detected in two further isolates that harboured mutations in fbiA, but did not show cross-resistance to pretomanid. All isolates were susceptible to linezolid and clofazimine, and no mutations found were associated with resistance.

Conclusions

More studies that correlate genotypic and phenotypic drug susceptibility data are needed to increase the knowledge base of mutations associated with resistance, in particular for pretomanid. Overall, this study contributes to the development of future mutation catalogues for M. tuberculosis complex isolates
Siderophore-producingBacillus amyloliquefaciensBM3 mitigate arsenic contamination and suppressFusariumwilt in brinjal plants
Authors: Pradhan Smriti , Choudhury Abhinandan , Dey Sovan , Hossain Md Firoj , Saha Aniruddha , Saha Dipanwita
Published: September 2023

Aim

Arsenic contamination in agricultural soils poses a serious health risk for humans. Bacteria that produce siderophores, primarily for iron acquisition, can be relevant in combating arsenic toxicity in agricultural soils and simultaneously act as biocontrol agents against plant diseases. We evaluated the arsenic bioremediation and biocontrol potential of the rhizosphere isolate Bacillus amyloliquefaciens BM3 and studied the interaction between the purified siderophore bacillibactin and arsenic.

Methods and results

BM3 showed high arsenic resistance [MIC value 475 and 24 mM against As(V) and As(III), respectively] and broad spectrum in-vitro antagonism against several phytopathogenic fungi. BM3 was identified by biochemical characterization and 16S rRNA gene sequencing. Scanning electron microscopy (SEM) analysis revealed increased cell size of BM3 when grown in presence of sub-lethal arsenic concentrations. Bioremediation assays showed a 74% and 88.1% reduction in As(V) and As(III) concentrations, respectively. Genetic determinants for arsenic resistance (arsC and aoxB) and antifungal traits (bacAB and chiA) were detected by PCR. Arsenic chelating ability of bacillibactin, the siderophore purified from culture filtrate of BM3 and identified through spectroscopic data analysis, was observed in CAS assay and fluorescence spectrometry. In-vivo application of talc-based formulation of BM3 in brinjal seedlings showed significant reduction in Fusarium wilt disease.

Conclusion

Strain B. amyloliquefaciens BM3 may be useful in arsenic bioremediation and may be considered for large field trials as an alternative to chemical fungicides by inhibiting soil borne pathogens.
The relationship between electronic health records user interface features and data quality of patient clinical information: an integrative review
Authors: Madandola Olatunde O , Bjarnadottir Ragnhildur I , Yao Yingwei , Ansell Margaret , Dos Santos Fabiana , Cho Hwayoung , Dunn Lopez Karen , Macieira Tamara G R , Keenan Gail M
Published: September 2023

Objectives

Electronic health records (EHRs) user interfaces (UI) designed for data entry can potentially impact the quality of patient information captured in the EHRs. This review identified and synthesized the literature evidence about the relationship of UI features in EHRs on data quality (DQ).

Materials and methods

We performed an integrative review of research studies by conducting a structured search in 5 databases completed on October 10, 2022. We applied Whittemore & Knafl’s methodology to identify literature, extract, and synthesize information, iteratively. We adapted Kmet et al appraisal tool for the quality assessment of the evidence. The research protocol was registered with PROSPERO (CRD42020203998).

Results

Eleven studies met the inclusion criteria. The relationship between 1 or more UI features and 1 or more DQ indicators was examined. UI features were classified into 4 categories: 3 types of data capture aids, and other methods of DQ assessment at the UI. The Weiskopf et al measures were used to assess DQ: completeness (n = 10), correctness (n = 10), and currency (n = 3). UI features such as mandatory fields, templates, and contextual autocomplete improved completeness or correctness or both. Measures of currency were scarce.

Discussion

The paucity of studies on UI features and DQ underscored the limited knowledge in this important area. The UI features examined had both positive and negative effects on DQ. Standardization of data entry and further development of automated algorithmic aids, including adaptive UIs, have great promise for improving DQ. Further research is essential to ensure data captured in our electronic systems are high quality and valid for use in clinical decision-making and other secondary analyses.