bluuebunny/crossref_metadata_2025 huggingface dataset:
676 - Dupilumab increases levels of bone growth biomarker irrespective of prior use of systemic corticosteroids in children with moderate-to-severe atopic dermatitis
Authors: Irvine Alan D , Paller Amy S , Hamon Sara , Horowitz Julie , Farrell Annamaria , Hatsell Sarah , Ehmann Peter , Marco Ainara Rodríguez , Bansal Ashish , Chen Zhen , Levy Stephane , Cyr Sonya L
Published: August 2024

Introduction/Background

Children with moderate-to-severe atopic dermatitis (AD) are at increased risk of lower bone mineral density (BMD) and fractures. Peak bone mass achieved during prepubescence is a major determinant of lifetime risk of fractures and osteoporosis. Bone alkaline phosphatase (BALP) promotes bone mineralization and contributes to density and linear growth in children. Systemic corticosteroids (SCS) negatively impact growth and bone health.

Objectives

To describe the impact of dupilumab treatment on BALP in children aged 6–11 years with moderate-to-severe AD and prior history of SCS use.

Methods

BALP levels in sera from participants receiving dupilumab 300 mg every 4 weeks (q4w) or placebo in LIBERTY AD PEDS (NCT03345914) and dupilumab 300 mg q4w in LIBERTY AD PED-OLE (NCT02612454) were analyzed at baseline and at 8, 12, 16 (PEDS), and 52 weeks (PED-OLE). Serum BALP levels (mcg/L) were stratified by prior use (with SCS; n = 42) or with no prior use of SCS (without SCS; n = 203), as captured in PEDS patient history at baseline.

Results

Regardless of prior SCS use, dupilumab treatment led to significant increase in BALP levels in children with moderate-to-severe AD at Week 16 compared with the placebo group (with SCS: 300 mg q4w [n = 25] vs placebo [n = 17], mean change [standard deviation] in BALP levels of 15.1 mcg/L [16.5] vs −5.5 mcg/L [16.0], P = 0.0099; without SCS: 300 mg q4w [n = 97] vs placebo [n = 106], 11.8 mcg/L [18.8] vs 2.2 mcg/L [16.3], P = 0.0074). By Week 52, BALP levels further increased vs baseline regardless of prior SCS use and were comparable with reference intervals (with SCS: 24.5 mcg/L [16.8], P = 0.0044; without SCS: 13.4 mcg/L [19.4], P = 0.0002). Patients in the placebo group who switched to dupilumab in PED-OLE had improved to levels similar to those of patients continuing treatment by Week 52 (with SCS: 23.3 mcg/L [19.3], P = 0.0067 [vs baseline]; without SCS: 18.4 mcg/L [20.4], P < 0.0001 [vs baseline]).

Conclusions

Dupilumab treatment increased BALP levels in children aged 6-11 years with moderate-to-severe AD irrespective of prior history of SCS use. These results add to the body of evidence that moderate-to-severe AD can negatively impact BALP levels, and that this effect may be improved with dupilumab in this age group, regardless of history of SCS use. The increase in BALP levels suggests that dupilumab may help improve bone mineralization in children with moderate-to-severe AD when treated during prepubescence.
691 - Understanding patient and physician preferences when choosing between biologic and oral systemic treatment options for moderate-to-severe atopic dermatitis: a discrete choice experiment
Authors: Puelles Jorge , Arija Pablo , Durno Nicholas , Pantiri Krystallia , Subramanian Ramkumar , Jack Katrin , Chambenoit Olivier , Boeri Marco , van Hout Ben , Silverberg Jonathan I
Published: August 2024

Background

A growing number of treatment options are becoming available for moderate-to-severe atopic dermatitis (AD), including biologic therapies. As these treatments have different efficacy, safety, and tolerability profiles, it is important to understand patient and physician preferences for informed treatment decision making.

Objective

To discover the importance of different attributes, including efficacy, safety, and mode of administration, and to provide insights into whether patient preferences concur or conflict with those of physicians.

Methods

We conducted a cross-sectional, online discrete choice experiment involving 306 patients with AD and 206 physicians in the UK and Germany. Qualitative interviews identified key attributes influencing treatment preferences, including efficacy (itch relief, sleep disturbance, time-to-itch relief, and total body surface area affected by eczema), safety (special warnings and risks of eye problems and shingles), and treatment administration. Data were analyzed using a random parameters logit model to calculate the conditional relative importance of each attribute.

Results

Both groups placed significant emphasis on efficacy, with reducing sleep disturbance ranking first for patients and second for physicians and itch ranking first for physicians and second for patients. Time to itch relief was the third most important efficacy attribute for both groups, although it was more important for patients. For both groups, the risk of eye problems was the most important safety concern. The mode of administration was not considered of great importance when compared with efficacy and safety attributes.

Conclusions

Our findings suggest patients prioritize sleep disturbance, an attribute not captured in other preference studies in AD, and itch. This emphasizes the importance of addressing sleep-related issues and itching to enhance patients’ well-being. The findings offer insights for prioritization strategies among healthcare providers, aiming to improve patient outcomes amidst a growing number of AD treatments.
701 - Dupilumab efficacy and safety up to 2 years in children aged 6 months to 5 years with atopic dermatitis
Authors: Paller Amy S , Simpson Eric L , Siegfried Elaine C , Cork Michael J , Arkwright Peter D , Pinter Andreas , Dubost-Brama Ariane , Laws Elizabeth , Chen Zhen , Bansal Ashish , Prescilla Randy , Nguyen Tien V
Published: August 2024

Introduction/Background

While previous studies into continuous long-term dupilumab treatment for adults with moderate-to-severe atopic dermatitis (AD) demonstrated sustained efficacy, further study into long-term safety and efficacy data regarding dupilumab in children is needed.

Objectives

To evaluate the impact of treatment with dupilumab and low-potency topical corticosteroids (TCS) for up to 2 years on efficacy and safety measures in children aged 6 months to 5 years with moderate-to-severe AD.

Methods

Children aged 6 months to 5 years with moderate-to-severe AD, who had participated in prior dupilumab pediatric AD studies were enrolled in a phase 3 open label extension (OLE) study. Patients received subcutaneous dupilumab every 4 weeks; 200 mg for children weighing 5 to <15 kg, 300mg for 15 to <30 kg. Topical AD treatments were allowed. Efficacy outcomes assessed include the proportion of patients who achieved 75% improvement from baseline in Eczema Area and Severity Index (EASI-75) score and the proportion of patients who achieved an Investigator Global Assessment (IGA) score of 0/1 as observed from OLE baseline to 2 years. Safety was also evaluated.

Results

A total of 180 patients were included in the 6 month to 5 years cohort; mean (±SD) age at OLE baseline was 3.9 (1.3) years with mean (SD) duration of AD of 3.5 (1.3) years. At OLE baseline, 29.4% of patients achieved EASI-75, improving to 85.1% at 52 weeks and 92.1% at 104 weeks. Similarly, 12.8% of patients achieved IGA 0/1 at OLE baseline, improving to 36.0% at Week 52 and 40.6% at Week 104. Total treatment-emergent adverse events (TEAEs) were observed in 87.8% of patients (intensity: mild 24.4%, moderate 52.2%, severe 11.1%). TEAEs assessed as related to dupilumab by the study investigators were reported in 18.3% of patients; the most prevalent were conjunctivitis (2.8%), allergic conjunctivitis (1.7%), nasopharyngitis (1.7%) and urticaria (1.7%). Serious TEAEs assessed as related to dupilumab by the study investigators were observed in 0.6% of patients.

Conclusions

Treatment with dupilumab for up to 2 years in young children with moderate-to-severe AD demonstrated efficacy outcomes, with sustained improvement in clinical signs reported in a large proportion of patients. Results are consistent with the known safety profile for dupilumab.
711 - Prolonged half-life and sustained inhibition of key inflammatory biomarkers: a phase 1 study of APG777, a high-affinity humanized IgG1 monoclonal antibody targeting IL-13
Authors: Lim Xiu Qin , Winter Erica , Nograles Kristine , Thankamony Sai , Dillinger Lukas , Dambkowski Carl
Published: August 2024

Introduction

APG777 is a high-affinity humanized anti-IL-13 IgG1 monoclonal antibody (mAb) that blocks formation of the IL-13/IL-13Rα1/IL-4Rα complex, preventing receptor heterodimerization and downstream signaling. APG777 contains a triple amino acid modification, YTE, in the Fc region that extends half-life (t1/2) by increasing binding to neonatal Fc receptor.

Objectives

This is a report of initial results of the first study of APG777 in humans, including safety, pharmacokinetics (PK), and pharmacodynamics (PD).

Methods

This first-in-human, randomized, double-blind, placebo (PBO)-controlled trial evaluated safety, tolerability, PK, and PD of APG777 in healthy participants. The study was conducted in Australia and consisted of single ascending dose (SAD) and multiple dose (MD) cohorts. Participants received single subcutaneous (SC) doses up to 1200 mg in the SAD and repeat doses of 300 mg SC in the MD. Each cohort consisted of 8 participants randomized 6:2 to APG777 or PBO. Safety assessments were conducted throughout the study and blood draws for PK and PD were obtained at multiple timepoints.

Results

Forty participants were enrolled. To date, adverse events (AEs) were mild and generally unrelated to study drug. There were no serious AEs or dose-dependent trends. APG777 pharmacokinetics were dose proportional, with t1/2 of approximately 75 days. Single doses of APG777 resulted in sustained inhibition of pSTAT6 and TARC for 12 weeks, the longest available follow-up.

Conclusions

APG777 was well-tolerated at doses up to 1200 mg, similar to other IL-13-targeted mAbs. The t1/2 of APG777, due to its YTE modification, is approximately 3 times longer than currently available mAbs and PD assessments confirm sustained inhibition of key biomarkers of atopic dermatitis. The favorable safety profile and optimized PK of APG777 support the initiation of a phase 2 study in adults with moderate-to-severe atopic dermatitis where every 3- to 6-month maintenance dosing will be evaluated.
728 - Evaluation of risk factors for dupilumab-associated ocular sequelae in the treatment of atopic dermatitis
Authors: Reddy Varsha , Lum Alexa , Kitsios Katerina , Shil Swarna , Nattis Alanna
Published: August 2024

Background

Dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signaling. It is used in the treatment of moderate-to-severe atopic dermatitis in those 6 months or older who are uncontrolled on or cannot tolerate topical treatments. Ocular surface disease is a recognized adverse effect of dupilumab use that has been highlighted in previous studies. Few studies describe the risk factors for developing such ocular adverse effects.

Objectives

This study aims to highlight the risk factors associated with the development of dupilumab-associated ocular surface disease (DAOSD) described in the literature.

Methods

The PubMed and ScienceDirect databases were searched in April 2024 using key search terms including “dupilumab”, “demographics”, “risk factors”, “ocular”, “keratitis”, “conjunctivitis”, “side effects”, and “atopic dermatitis”. Nine articles were included after deduplication, title/abstract screening, full-text review, and quality appraisal. Studies were included if they were written in English and discussed risk factors for ocular side effects of dupilumab. Studies were excluded if they discussed other biologic agents or ocular conditions of other origins.

Results

Out of the nine studies analyzed, six described prior history of ocular disease as a risk factor for developing DAOSD. Severe atopic dermatitis was highlighted as a risk factor in five out of nine studies. Elevated total IgE levels and eosinophil count were described as risk factors in four out of nine studies. Three studies cited facial or eyelid eczema and two studies highlighted family history of atopy as having an association with the development of DAOSD. One study described high levels of chemokines, as well as personal history of other atopic conditions. At least one patient needing to discontinue treatment with dupilumab due to ocular side effects was mentioned in six out of nine studies. Seven out of nine studies included a recommendation for ophthalmological evaluation prior to or during treatment with dupilumab.

Conclusions

While the etiology of DAOSD is not fully understood, past studies have elucidated potential risk factors for its development. Patients being treated with dupilumab for atopic dermatitis have higher severity or refractory disease, and the discontinuation of treatment due to ocular side effects may have implications on the quality of life of these patients. Additional studies are needed to better understand the risk factors for DAOSD and prevent further complications. Limitations include small sample size and lack of control group in some studies, inclusion of studies in non-US countries, and lack of gender and racial representation in some studies.
733 - Nemolizumab elicits fast itch response in atopic dermatitis within 2 days: a post hoc analysis of ARCADIA 1 and 2 data
Authors: Silverberg Jonathan I , Stein-Gold Linda , Thaçi Diamant , Pink Andrew E , Papp Kim A , Legat Franz J , Laquer Vivian T , Cheong Soo Yeon , Ulianov Liliana , Ryzhkova Anna , Piketty Christophe
Published: August 2024

Background

Itch is the most burdensome symptom of atopic dermatitis (AD) that severely affects sleep and overall and quality of life.1,2 Rapid control of itch could be instrumental in minimizing disease symptoms and the associated burden for patients.3,4 Nemolizumab, an interleukin-31 (IL-31) alpha antagonist, inhibits the IL-31 pathway of itch and inflammation in AD.5

Objectives

To evaluate speed of onset of itch relief and sleep improvements with nemolizumab in moderate-to-severe AD.

Methods

ARCADIA-1 and ARCADIA-2 were two identical, randomized, double-blinded, placebo-controlled studies. Patients (≥12 years) with moderate-to-severe AD and inadequate response to topical corticosteroids (TCS) were randomized (2:1) to receive nemolizumab 30mg every 4 weeks (60mg baseline loading dose) or matching placebo, both with background TCS of low/medium potency with/without topical calcineurin inhibitors (TCI).

Results

Significant improvements in itch (least squares [LS] mean±standard error [SE] change from baseline [CFB] in Peak Pruritus Numeric Rating Scale [PP-NRS]) were noted in nemolizumab-treated vs placebo-treated patients by Day 1 in ARCADIA-1 (-0.9±0.08 vs -0.4±0.10) and ARCADIA-2 (-1.1±0.09 vs -0.4±0.12), reaching -2.4±0.08 vs -1.2±0.11 and -2.3 ±0.09 vs -0.9±0.12 respectively at Day 14 (p<0.001 for all). Significantly greater proportions of nemolizumab-treated vs placebo-treated patients achieved ≥4-point improvement in PP-NRS by Day 2 in ARCADIA-1 (9.4% vs 3.4%, p<0.01) and Day 1 in ARCADIA-2 (8.2% vs 1.9%, p<0.001) and through Day 14 (ARCADIA-1: 22.7% vs 10.6%, p<0.0001; ARCADIA-2: 23.4% vs 6.8%, p<0.0001).

Conclusions

Treatment with nemolizumab plus TCS/TCI resulted in rapid, statistically and clinically significant improvements in itch in moderate-to-severe AD.
Non-contrast abbreviated MRI for the detection of hepatocellular carcinoma in patients with Liver Imaging Reporting and Data System LR-3 and LR-4 observations in MRI
Authors: Maung Soe Thiha , Tanpowpong Natthaporn , Satja Minchanat , Treeprasertsuk Sombat , Chaiteerakij Roongruedee
Published: August 2024

Background and aims

With ultrasound sensitivity limited in hepatocellular carcinoma (HCC) surveillance and few prospective studies on non-contrast abbreviated MRI (NC-AMRI), this study aimed to assess its diagnostic performance in detecting HCC.

Methods

This prospective study involved cirrhotic patients with contrast-enhanced MRI (CE-MRI) Liver Imaging Reporting and Data System (LI-RADS) LR-3 and LR-4 observations detected during HCC surveillance. Patients underwent average 3 complete CE-MRI rounds at 3-6 months interval, with approximately 12-month follow-up. NC-AMRI included diffusion-weighted (DWI), T2-weighted imaging (T2WI), and T1-weighted imaging (T1WI). NC-AMRI protocol images were analysed for diagnostic performance, with subgroup analyses. CE-MRI and NC-AMRI images were independently reviewed by 2 experienced radiologists, with inter-reader agreement assessed with Kappa coefficient. The reference standard was the American Association for the Study of Liver Diseases-defined presence of arterial hypervascularity and washout during the portal-venous or delayed phases on CE-MRI.

Results

In 166 CE-MRI follow-ups of 63 patients (median age: 63 years; 60.3% male, 39.7% female), 12 patients developed HCC, with average size of 19.6 mm. The NC-AMRI (DWI + T2WI + T1WI) showed 91.7% sensitivity (95%CI, 61.5-99.8) and 91.6% specificity (95%CI, 86.0-95.4), area under receiver operating characteristic 0.92 (95%CI, 0.83-1.00). Across different Body Mass Index categories, lesion size, Child-Turcotte-Pugh classes, Albumin-Bilirubin (ALBI) grades, and Model for End-Stage Liver Disease classes, sensitivity remained consistent. However, specificity differed significantly between ALBI grade 1 and 2 (86.7% vs. 98.4%, P = .010), and between viral and non-viral cirrhosis (93.8% vs. 80.8%, P = .010).

Conclusions

NC-AMRI proved clinically feasible, and exhibits high diagnostic performance in HCC detection.

Advances in knowledge

This study highlights efficacy of NC-AMRI in detecting HCC among cirrhotic patients with LR-3 and LR-4 observations, representing significant progress in HCC surveillance.
Dysfunction of the magnocellular subdivision of the visual thalamus in developmental dyslexia
Authors: Müller-Axt Christa , Kauffmann Louise , Eichner Cornelius , von Kriegstein Katharina
Published: August 2024

Developmental dyslexia (DD) is one of the most common learning disorders, affecting millions of children and adults worldwide. To date, scientific research has attempted to explain DD primarily based on pathophysiological alterations in the cerebral cortex. In contrast, several decades ago, pioneering research on five post-mortem human brains suggested that a core characteristic of DD might be morphological alterations in a specific subdivision of the visual thalamus—the magnocellular lateral geniculate nucleus (M-LGN). However, due to considerable technical challenges in investigating LGN subdivisions non-invasively in humans, this finding was never confirmed in vivo, and its relevance for DD pathology remained highly controversial.

Here, we leveraged recent advances in high resolution MRI at high field strength (7 T) to investigate the M-LGN in DD in vivo. Using a case-control design, we acquired data from a large sample of young adults with DD (n = 26; age 28 ± 7 years; 13 females) and matched control participants (n = 28; age 27 ± 6 years; 15 females). Each participant completed a comprehensive diagnostic behavioural test battery and participated in two MRI sessions, including three functional MRI experiments and one structural MRI acquisition. We measured blood oxygen level-dependent responses and longitudinal relaxation rates to compare both groups on LGN subdivision function and myelination. Based on previous research, we hypothesized that the M-LGN is altered in DD and that these alterations are associated with a key DD diagnostic score, i.e. rapid letter and number naming.

The results showed aberrant responses of the M-LGN in DD compared to controls, which was reflected in a different functional lateralization of this subdivision between groups. These alterations were associated with rapid letter and number naming performance, specifically in male DD. We also found lateralization differences in the longitudinal relaxation rates of the M-LGN in DD relative to controls. Conversely, the other main subdivision of the LGN, the parvocellular LGN (P-LGN), showed comparable blood oxygen level-dependent responses and longitudinal relaxation rates between groups.

The present study is the first to unequivocally show that M-LGN alterations are a hallmark of DD, affecting both the function and microstructure of this subdivision. It further provides a first functional interpretation of M-LGN alterations and a basis for a better understanding of sex-specific differences in DD with implications for prospective diagnostic and treatment strategies.
Synthesis of ɛ-NbN and δ-NbN by metathesis reaction of NaNbO3 and BN
Authors: Osaka Tenshin , Ikenobe Toshiya , Hiroi Zenji , Yamane Hisanori , Yamada Takahiro
Published: August 2024

δ-NbN powder with particles of ∼1 µm in size was obtained by heating a mixture of NaNbO3 and BN powders at 1373 K for 1 h, while agglomerates composed of ɛ-NbN platelet grains up to 50 µm in size were obtained by heating the mixture at the same temperature for 10 h. Metathesis reaction in which sodium borate was formed with replacement of the oxygen and nitrogen from NaNbO3 and BN occurred with the NbN formation. Wavelength-dispersive X-ray analysis showed that the molar ratios of Nb to N in the synthesized δ-NbN and ɛ-NbN were ∼1:1. Magnetic susceptibility measurements showed that the δ-NbN powder was a superconductor with a transition temperature of ∼16 K. In comparison, the ɛ-NbN agglomerates did not exhibit superconductivity above 2 K.
Single Monoclonal Antibodies Should Not Be Used for COVID-19 Therapy: A Call for Antiviral Stewardship
Authors: Casadevall Arturo , Focosi Daniele , Pirofski Liise-anne , Shoham Shmuel
Published: August 2024

The COVID-19 pandemic witnessed the greatest deployment of monoclonal antibody (mAb) therapies for an infectious disease, but all were defeated by SARS-CoV-2 evolution. As new mAbs are developed, the infectious disease community needs stewardship practices to reduce emergence of resistance.
Nuclear envelope lamin-related dilated cardiomyopathy: a case series including histopathology
Authors: O’Connor William , Arshia Asma , Prabakar Deipthan , Sabesan Vaishnavi , Spindel Jeffrey F
Published: August 2024

Background

Lamin A/C gene (LMNA) mutations cause myocardial fibrosis manifesting as arrhythmogenic, non-compaction, or dilated cardiomyopathies. Fibro-fatty replacement largely involves the conduction system and conduction disease commonly occurs prior to contractile dysfunction.

Case summary

Two young, unrelated Caucasian males, aged 34 and 25, were referred to our centre for treatment of advanced heart failure. Both patients had a family history of heart failure and sudden cardiac death among their first-degree relatives and were diagnosed with Lamin A/C mutations, but they had not been screened prior to disease onset. Although the initial phenotypes were dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy, both patients’ disease progressed rapidly to include ventricular arrhythmias, severe global left ventricular hypokinesis, and dependence on outpatient milrinone to complete activities of daily living. Both patients received heart transplantation within 2 years of initial disease onset. The surgical pathology of the explanted hearts revealed characteristic findings of fibro-fatty degeneration of the conduction system, and using light microscopy, they were found to have nuclear membrane thinning, bubbling, and convolution throughout all areas sampled.

Discussion

Lamin A/C–related cardiomyopathy is associated with sudden cardiac death early in the disease course, warranting early consideration of implantable cardioverter defibrillator implantation, and rapid progression to end-stage cardiomyopathy refractory to standard medical therapies, necessitating early referral to an advanced heart failure centre. We report a newly observed and recorded finding of morphologic nuclear alterations in late-stage disease using high-power light microscopy. These alterations underscore the pathophysiology of Lamin A/C–related cardiomyopathy and provide a basis for future research into disease-specific therapies.
Acute type B aortic dissection following transcatheter mitral valve edge-to-edge repair: a case report
Authors: Ma Guizhou , Zhou Linjie , Cai Dianyu , Wang Ying , Cai Zhixiong
Published: August 2024

Background

Transoesophageal echocardiography is rarely reported as a possible cause of aortic dissection during the transcatheter edge-to-edge repair procedure. Herein, we present a case of type B aortic dissection following the transcatheter mitral valve edge-to-edge repair procedure, most likely related to the transoesophageal echocardiography probe.

Case summary

A 68-year-old Chinese man complained of exertional dyspnoea lasting over 2 years and had been diagnosed with severe mitral regurgitation. He was admitted to our hospital for the treatment of severe mitral regurgitation with transcatheter edge-to-edge repair. One MitraClip XTR (Abbott Vascular) was successfully implanted under the guidance of active transoesophageal echocardiography, and the mitral regurgitation became trace. However, the patient complained of persistent back pain after the treatment, and computed tomography angiography revealed a type B aortic dissection in the descending aorta. After 2 weeks of unsuccessful conservative treatment, he successfully underwent endovascular stenting and was discharged from the hospital. The patient recovered well and remained event free during the 6-month follow-up.

Discussion

Herein, we presented a rare complication following transcatheter mitral valve edge-to-edge repair that was most likely related to the transoesophageal echocardiography probe—type B aortic dissection. We postulated that repetitive flexion of the transoesophageal echocardiography probe led to compression-induced injury to the descending aorta wall at the mid-oesophageal level, which was the most probable aetiology of type B aortic dissection. Although this complication is rare, it is potentially fatal and therefore needs attention.
Clinical and genetic associations of asymmetric apical and septal left ventricular hypertrophy
Authors: Yuan Victoria , Vukadinovic Milos , Kwan Alan C , Rader Florian , Li Debiao , Ouyang David
Published: August 2024

Aims

Increased left ventricular mass has been associated with adverse cardiovascular outcomes including incident cardiomyopathy and atrial fibrillation. Such associations have been studied in relation to total left ventricular hypertrophy, while the regional distribution of myocardial hypertrophy is extremely variable. The clinically significant and genetic associations of such variability require further study.

Methods and results

Here, we use deep learning–derived phenotypes of disproportionate patterns of hypertrophy, namely, apical and septal hypertrophy, to study genome-wide and clinical associations in addition to and independent from total left ventricular mass within 35 268 UK Biobank participants. Using polygenic risk score and Cox regression, we quantified the relationship between incident cardiovascular outcomes and genetically determined phenotypes in the UK Biobank. Adjusting for total left ventricular mass, apical hypertrophy is associated with elevated risk for cardiomyopathy and atrial fibrillation. Cardiomyopathy risk was increased for subjects with increased apical or septal mass, even in the absence of global hypertrophy. We identified 17 genome-wide associations for left ventricular mass, 3 unique associations with increased apical mass, and 3 additional unique associations with increased septal mass. An elevated polygenic risk score for apical mass corresponded with an increased risk of cardiomyopathy and implantable cardioverter-defibrillator implantation.

Conclusion

Apical and septal mass may be driven by genes distinct from total left ventricular mass, suggesting unique genetic profiles for patterns of hypertrophy. Focal hypertrophy confers independent and additive risk to incident cardiovascular disease. Our findings emphasize the significance of characterizing distinct subtypes of left ventricular hypertrophy. Further studies are needed in multi-ethnic cohorts.
Optimized estimation of marine deflection of the vertical from multibeam laser altimeter data of ICESat-2
Authors: Peng Huihui , Liu Xin , Li Zhen , Wei Xuyang , Fan Xin , Guo Jinyun
Published: August 2024

Satellite altimetry data, with its increasing density and quality, has become the primary source for marine deflection of the vertical (DOV) and gravity anomaly modelling. Limited by orbital inclinations, the precision of the meridian component of the gridded deflection of the vertical (GDOV) calculated by traditional altimetry satellites is significantly better than that of the prime vertical component, and the excessive precision difference between these two components restricts the inversion precision of marine gravity anomaly model. The study of cross-track deflection of the vertical (CTDOV) is enabled by the multibeam synchronous observation mode of the new laser altimetry satellite, Ice, Cloud and Land Elevation Satellite-2 (ICESat-2). Based on the remove-restore method, residual geoid gradients are first calculated in this paper using three approaches: along-track (A-T), cross-track (C-T) and an integration of along-track and cross-track. Vertical deflections are then computed on a 1′ × 1′ grid using the least squares collocation (LSC) method, and the precision is verified against the SIO V32.1_DOV model. An optimized combination is proposed to address the issue of precision differences between the meridian and prime vertical components, and to enhance the precision of DOV inversion. A new DOV combination is formed by combining the meridian component from along-track deflection of the vertical (ATDOV) with the prime vertical component from cross-track deflection of the vertical (CTDOV) based on the remove-restore method. The Philippine Sea (0°–35°N, 120°–150°E) is selected as the test area to verify the feasibility of the optimized combination. The results indicate that the optimized combination of the meridian and prime vertical components achieved test precision of 2.63 and 3.33 μrad, respectively, when compared against the SIO V32.1_DOV model. The precision gap between the components is effectively narrowed by this approach, which maintains the precision of the meridian component and enhances that of the prime vertical component, thereby achieving optimal inversion precision for gravity anomalies.
Impact of glycan depletion, glycan debranching and increased glycan charge on HIV-1 neutralization sensitivity and immunogenicity
Authors: D’Addabbo Alessio , Tong Tommy , Crooks Emma T , Osawa Keiko , Xu Jiamin , Thomas Alyssa , Allen Joel D , Crispin Max , Binley James M
Published: August 2024

Broadly neutralizing antibodies (bNAbs) isolated from HIV-1 infected donors are vaccine paradigms. These bNAbs recognize envelope glycoprotein trimers that carry 75–90 oligomannose and complex-type glycans. Although bNAbs and their precursors must navigate past glycans, they usually also make some glycan contacts. Glycan-modified vaccines may therefore be useful to initiate and guide bNAb development. Here, we describe two ways to modify Env glycans for possible vaccine use: 1) using a cocktail of glycosidases (termed “NGAF3” (Neuraminidase, β-Galactosidase, N-Acetylglucosaminidase, endoglycosidase F3 (endo F3)) to deplete complex glycans to try to minimize bNAb-glycan clashes and 2) co-expressing β-1,4-galactosyltransferase 1 (B4G) and β-galactoside α-2,6 sialyltransferase 1 (ST6) during Env biosynthesis, creating bNAb-preferred glycan structures. Mass spectrometry revealed that NGAF3 removed glycan heads at 3/7 sites occupied by complex glycans. B4G overexpression resulted in hybrid glycan development whenever complex glycans were closely spaced. The glycan at position 611 in of Env’s gp41 transmembrane subunit was uniquely isolated from the effects of both endo F3 and B4G. B4G and ST6 co-expression increased hybrid and sialylated glycan abundance, reducing glycan complexity. In rabbit vaccinations, B4G + ST6 virus-like particles (VLPs) induced less frequent, weaker titer NAbs, implying that ST6-mediated increased Env charge dampens vaccine antibodies. In some cases, vaccine sera preferentially neutralized B4G + ST6-modified pseudovirus. HIV-1+ donor plasma NAbs were generally more effective against B4G + ST6 modified pseudovirus, suggesting a preference for less complex and/or α-2,6 sialylated Env trimers. Collectively, our data suggest that B4G and ST6 Env modifications are best suited for intermediate or late vaccine shots.
Advancing the future of equitable access to health care: recommendations from international health care leaders
Authors: Boyer Beth , Huber Katie , Zimlichman Eyal , Saunders Robert , McClellan Mark , Kahn Charles , Noach Ryan , Salzberg Claudia
Published: August 2024

Disparities in access to health care are persistent and contribute to poor health outcomes for many populations around the world. Barriers to access are often similar across countries, despite differences in how health systems are structured. Health care leaders can work to address these barriers through bold, evidence-based actions. The Future of Health (FOH), an international community of senior health leaders, collaborated with the Duke-Margolis Institute for Health Policy to identify priority organizational and policy actions needed to improve equitable access to health care through a consensus-building exercise, a targeted literature review, and an expert discussion group. This paper describes four key action areas for health care leaders that FOH members identified as critical to enabling the future of equitable access to health care: ensuring prioritization of and accountability for equitable access to care; establishing comprehensive, organization-wide strategies to address barriers to access; clearly defining and incentivizing improvement on key measures related to reducing disparities in access; and establishing cross-sector partnerships to improve equitable access.
Production of structurally diverse sphingolipids by anaerobic marine bacteria in the euxinic Black Sea water column
Authors: Ding Su , von Meijenfeldt F A Bastiaan , Bale Nicole J , Sinninghe Damsté Jaap S , Villanueva Laura
Published: August 2024

Microbial lipids, used as taxonomic markers and physiological indicators, have mainly been studied through cultivation. However, this approach is limited due to the scarcity of cultures of environmental microbes, thereby restricting insights into the diversity of lipids and their ecological roles. Addressing this limitation, here we apply metalipidomics combined with metagenomics in the Black Sea, classifying and tentatively identifying 1623 lipid-like species across 18 lipid classes. We discovered over 200 novel, abundant, and structurally diverse sphingolipids in euxinic waters, including unique 1-deoxysphingolipids with long-chain fatty acids and sulfur-containing groups. Sphingolipids were thought to be rare in bacteria and their molecular and ecological functions in bacterial membranes remain elusive. However, genomic analysis focused on sphingolipid biosynthesis genes revealed that members of 38 bacterial phyla in the Black Sea can synthesize sphingolipids, representing a 4-fold increase from previously known capabilities and accounting for up to 25% of the microbial community. These sphingolipids appear to be involved in oxidative stress response, cell wall remodeling, and are associated with the metabolism of nitrogen-containing molecules. Our findings underscore the effectiveness of multi-omics approaches in exploring microbial chemical ecology.
Patient and public understanding of antimicrobial resistance: a systematic review and meta-ethnography
Authors: Wojcik Gosha , Afseth Janyne , Fagan Ross , Thomson Fiona , Ring Nicola
Published: August 2024

Objectives

To further develop an understanding of laypeople’s (adult patients and public) beliefs and attitudes toward antimicrobial resistance (AMR) by developing a conceptual model derived from identifying and synthesizing primary qualitative research.

Methods

A systematic search of 12 electronic databases, including CINAHL, MEDLINE, PsycINFO, PubMed and Web of Science to identify qualitative primary studies exploring patient and public understanding of AMR published between 2012 and 2022. Included studies were quality appraised and synthesized using Noblit and Hare’s meta-ethnographic approach and reported using eMERGe guidance.

Results

Thirteen papers reporting 12 qualitative studies were synthesized. Studies reported data from 466 participants aged 18–90 years. Five themes were identified from these original studies: the responsible patient; when words become meaningless; patient–prescriber relationship; past experience drives antibiotic use; and reframing public perception. These themes supported the development of a conceptual model that illustrates the tension between two different assumptions, that is, how can antibiotics be used for the collective good whilst balancing the immediate needs of individual patients.

Conclusions

Findings suggest that AMR is a distinct ethical issue and should not be viewed purely as a prescribing problem. The meta-ethnography-generated conceptual model illustrates many factors affecting the public’s perception of AMR. These include laypeople’s own knowledge, beliefs and attitudes around antibiotic use, the relationship with the healthcare provider and the wider context, including the overwhelming influence of the media and public health campaigns. Future research is needed to explore effective health messaging strategies to increase laypeople’s baseline awareness of AMR as a public threat.
Genomic characterization of carbapenemase-producing Enterobacterales from Dhaka food markets unveils the spread of high-risk antimicrobial-resistant clones and plasmids co-carrying blaNDM and mcr-1.1
Authors: Nisa Tania Tabassum , Sugawara Yo , Hamaguchi Shigeto , Takeuchi Dan , Abe Ryuichiro , Kuroda Eisuke , Morita Masatomo , Zuo Hui , Ueda Akiko , Nishi Isao , Hossain Nowrin , Hasan Md Mahmudul , Siddiqee Mahbubul H , Nakatani Daisaku , Nakata Ken , Akeda Yukihiro
Published: August 2024

Background

The transmission of carbapenemase-producing Enterobacterales (CPE) in the external environment, especially through food, presents a significant public health risk.

Objectives

To investigate the prevalence and genetic characteristics of CPE in food markets of Dhaka, Bangladesh, using WGS.

Methods

CPE isolates were obtained from different food and water samples collected from food markets in the southern part of Dhaka, Bangladesh. The isolates subsequently underwent molecular typing, WGS employing both short- and long-read sequencers, and plasmid analysis.

Results

This study unveiled an extensive spread of CPE, with no significant difference in contamination rates observed in samples (N = 136), including meat (n = 8), fish (n = 5), vegetables (n = 36) or various food-washed water (n = 65) from markets near hospitals or residential areas. Thirty-eight Enterobacterales from 33 samples carried carbapenemase genes (blaNDM-1, -4, -7, blaKPC-2, blaOXA-181 or blaIMI-1). Among these, the high-risk Escherichia coli ST410 clone was the most prevalent and distributed across various locations. Furthermore, the identification of IncHI2 plasmids co-harbouring resistance genes like blaNDM-5 and mcr-1.1, without discernible epidemiological connections, is a unique finding, suggesting their widespread dissemination.

Conclusions

The analysis unveils a dynamic landscape of CPE dissemination in food markets, underscored by the proliferation of novel IncHI2 hybrid plasmids carrying both colistin- and carbapenem-resistance genes. This illuminates the ever-evolving landscape of antimicrobial resistance in Dhaka, urging us to confront its emergent challenges.
IFN-α2 Autoantibody Screening and Functional Evaluation in Viral and Bacterial Infections
Authors: Cockx Maaike , Steels Sophie , Michiels Birthe , Van Elslande Jan , Vermeersch Pieter , Frans Glynis , Claeys Kristl G , Desmet Stefanie , De Munter Paul , Bossuyt Xavier
Published: August 2024

Background

The presence of anti-interferon (IFN)-α2 autoantibodies is a strong indicator of severe disease course during viral infections and is observed in autoimmune diseases (e.g., myasthenia gravis). Detection of these autoantibodies during severe bacterial infections is understudied. Multiple anti-IFN-α2 autoantibody screening assays are available. However, the results do not always correlate with the neutralizing capacity of the autoantibodies.

Methods

Anti-IFN-α2 antibodies were measured by a Luminex-based assay in serum samples from individuals admitted to the intensive care unit infected with influenza (n = 38), invasive bacteria (n = 152), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 52). Anti-IFN-α2 antibodies were also studied in individuals with myasthenia gravis (n = 22) and in healthy individuals (n = 37). Individuals testing positive by Luminex were subsequently tested by enzyme-linked immunosorbent assay (ELISA) and tested for nonspecific reactivity and neutralization.

Results

Three of 16 Luminex-positive samples had nonspecific reactivity, 11/16 were positive by ELISA, and 10/16 had neutralizing activity. Anti-IFN-α2 antibodies were found in individuals infected with SARS-CoV-2 (7/52), influenza (3/38), invasive bacteria [2/152, of which 1 was Legionella pneumophilia and was 1 Escherichia coli (E. coli) (out of 39 E. coli infections)], and in individuals with myasthenia gravis (2/22).

Conclusions

Anti-IFN-α2 autoantibodies were detected in viral infections, myasthenia gravis, and rarely in bacterial infections. ELISA and Luminex screening assays do not give similar results. Nonspecific reactivity and functional assays are necessary to validate the screening test result.
Molecular characterization, antimicrobial resistance and invasion of epithelial cells by Streptococcus agalactiae strains isolated from colonized pregnant women and newborns in Rio de Janeiro, Brazil
Authors: Pimentel Bruna Alves da Silva , Lannes-Costa Pamella Silva , Viana Alice Slotfeldt , Santos Gabriela da Silva , Leobons Maria Beatriz Gerardin Poirot , Ferreira-Carvalho Bernadete Teixeira , Nagao Prescilla Emy
Published: August 2024

Aims

To evaluate the prevalence, molecular characteristics, antimicrobial susceptibility, and epithelial invasion of Streptococcus agalactiae strains isolated from pregnant women and newborns in Rio de Janeiro, Brazil.

Methods and results

A total of 67 S. agalactiae isolates, 48 isolates from pregnant women and 19 from neonates, were analyzed. Capsular type Ia and V were predominant (35.8%/each). The multilocus sequence typing analysis revealed the presence of 19 STs grouped into 6 clonal complexes with prevalence of CC17/40.3% and CC23/34.3%. The lmb and iag virulence genes were found in 100% of isolates. Four S. agalactiae strains, belonging to CC17/ST1249 and CC23/ST23, were able to adhere to A549 respiratory epithelial cells. Antimicrobial resistance was verified mainly to tetracycline (85%), erythromycin (70.8%), and clindamycin (58.3%). Four S. agalactiae isolates were multidrug resistant. The resistance genes tested were found in 92.5% of isolates for tetM, 58.2% for ermB, 28.4% for mefAE, and 10.4% for tetO.

Conclusion

The study showed a high prevalence of virulence and antimicrobial genes in S. agalactiae strains isolated from pregnant women and newborns, supporting the idea that continued surveillance is necessary to identify risk factors and perform long-term follow-up in pregnant women and neonates in Rio de Janeiro.
Data sharing considerations to maximize the use of pathogen biological and genomics resources data for public health
Authors: Holden Nicola J
Published: August 2024

Public sector data associated with health are a highly valuable resource with multiple potential end-users, from health practitioners, researchers, public bodies, policy makers, and industry. Data for infectious disease agents are used for epidemiological investigations, disease tracking and assessing emerging biological threats. Yet, there are challenges in collating and re-using it. Data may be derived from multiple sources, generated and collected for different purposes. While public sector data should be open access, providers from public health settings or from agriculture, food, or environment sources have sensitivity criteria to meet with ethical restrictions in how the data can be reused. Yet, sharable datasets need to describe the pathogens with sufficient contextual metadata for maximal utility, e.g. associated disease or disease potential and the pathogen source. As data comprise the physical resources of pathogen collections and potentially associated sequences, there is an added emerging technical issue of integration of omics ‘big data’. Thus, there is a need to identify suitable means to integrate and safely access diverse data for pathogens. Established genomics alliances and platforms interpret and meet the challenges in different ways depending on their own context. Nonetheless, their templates and frameworks provide a solution for adaption to pathogen datasets.
Precision feeding as a tool to reduce the environmental footprint of pig production systems: a life-cycle assessment
Authors: Llorens Berta , Pomar Candido , Goyette Bernard , Rajagopal Rajinikanth , Andretta Ines , Latorre Maria Angeles , Remus Aline
Published: August 2024

Nitrogen and phosphorus excretion are major sources of environmental contamination in growing–finishing pig operations. Nutrient excretion can be reduced by feeding pigs daily-tailored diets to their estimated nutrient requirements using individual precision feeding (IPF) techniques. This study modeled and evaluated the environmental impact of moving from conventional group 3-phase feeding (CGF) to IPF systems in Quebec, Canada, using life-cycle assessment with SimaPro software. The cradle-to-farm model included inputs and outputs of each subphase: raw materials/feedstuffs production, feed mill processing, transport, animal rearing, and manure management. The model was identical for both treatments in all aspects except for the production of feeds and barn and manure emissions in the growing–finishing phases. All feed ingredients originated from Quebec, simulating agricultural practices using real management data from an average farm in Quebec. Based on observed pig growth data, the CGF and IPF systems were compared in the growing–finishing phase. IPF diets were modeled as the blend of 2 feeds (i.e., A and B), while CGF diets were stablished according to the industry. The evaluated impact categories were global warming potential (GWP), eutrophication potential (EP), and acidification potential (AP). The functional unit was 1 t of feed at the feed mill gate and 1 t of finished pig live weight at the farm gate. A Monte Carlo analysis determined the uncertainty of the growth performance results. Feeding programs were compared using analysis of variance. Corn was associated with elevated GWP and AP impacts, leading to higher impacts for diets with higher corn content. Feed B, which contained 83% corn, resulted in impacts of 645 kg of CO2-eq., 8.53 kg SO2-eq., and 4.89 kg PO4-eq. Diets with higher EP impact had a higher percentage of soybean meal. Feed A contained 25% of this ingredient and had an impact of 608 kg CO2-eq., 6.98 kg SO2-eq., and 5.57 kg PO4-eq. CGF diets had environmental impacts between those of feeds A and B. Compared to CGF, applying IPF programs during the growing–finishing phase decreased GWP by 7.6%, AP by 16.2% and EP by 13.0%. IPF significantly reduced the environmental impact in all categories through the more efficient use of nutritional resources by pigs. IPF could help to improve the sustainability of growing–finishing pig operations in Quebec and likely other regions using corn and soybean-based diets.