bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerated hypertension following mavacamten introduction in severe obstructive hypertrophic cardiomyopathy with hypertension: a case report
Authors: Maurizi Niccolò , Antiochos Panagiotis , Muller Olivier , Wuerzner Gregory , Monney Pierre
Published: August 2024

Background

Mavacamten in Phase 2 and 3 clinical trials was well tolerated, reduced left ventricular outflow tract obstruction (LVOTO), and improved exercise capacity and symptoms. However, due to its recent introduction in the market, there is limited evidence from real-world patients with severe/multiple comorbidities and/or who are exposed to potential treatment interactions. Hypertension is common in patients with hypertrophic cardiomyopathy (HCM), but its impact on the treatment of LVOTO is undefined.

Case summary

A 55-year-old man with severely obstructive symptomatic HCM and Grade I arterial hypertension underwent treatment with mavacamten 5 mg. He presented an accelerated hypertension from Day 10 of treatment. On admission, he reported improvement of his dyspnoea [New York Heart Association (NYHA) Class II] and NT-pro BNP decreased to 1646 ng/L. Echocardiography showed a left ventricular ejection fraction of 60% with reduced systolic anterior motion and LVOTO (max 21 mmHg). Causes of secondary hypertension were excluded, and blood pressure (BP) was controlled by eplerenone and amlodipine introduction. Accelerated hypertension was concluded as a final diagnosis, and a potential causal link with the introduction of mavacamten was made. Evolution up to Day 135 proved a stabilization of the BP profile and of the LVOT gradient (max 36 mmHg) as well as improvement in functional capacity (NYHA Class I).

Discussion

We hypothesize that rapid relief of excess afterload may induce alterations potentially leading to high BP in patients with impaired peripheral vascular resistances. Patients with severe obstructive HCM and hypertension should be given special attention during mavacamten titration and should self-monitor the BP during this phase.
War, the State and Local Office-Holders in Britain, 1689–1750
Authors: Smith Hannah
Published: August 2024

Research on the British ‘fiscal-military state’ has placed great emphasis on the development of a financial infrastructure and professional bureaucracy in explaining Britain’s rise to superpower status in the eighteenth century. This article argues instead that, to appreciate fully the extent of the British state’s involvement in warfare, historians need to acknowledge the crucial and varied roles that local office-holders played in raising manpower for the army and supporting many of its requirements. Such an emphasis allows for a more nuanced understanding of the nature of the British fiscal-military state and the relations between centre and localities. This article illuminates the impact of war at a local level by examining how local office-holders, principally justices of the peace and parish constables, found and enlisted men into the army, secured deserters, intervened in mutinies, organised quarters for soldiers and transport for the army, and assisted former and injured soldiers and soldiers’ families. This work added to their burdens of office, it could jeopardise their authority and create bitter tensions within communities. Nevertheless, there was a high level of co-operation from local office-holders. The article analyses why local office-holders complied with the demands of central government and stresses their importance within the British ‘fiscal-military state’.
Atrial tachyarrhythmia prevention by Shensong Yangxin after catheter ablation for persistent atrial fibrillation: the SS-AFRF trial
Authors: Huang He , Liu Yu , Shuai Wei , Jiang Chenyang , Zhang Menghe , Qu Xiufen , Zheng Wenqing , Yang Hao , Liu Fan , Yu Bo , Chen Manhua , Mu Bin , Yao Chen , Tang Yanhong , Huang Congxin , Ouyang Feifan , Jia Zhenhua
Published: August 2024

Background and Aims

Despite advances in technology and techniques, the recurrence rate of persistent atrial fibrillation (AF) following catheter ablation remains high. The Shensong Yangxin (SSYX) capsule, a renowned traditional Chinese medicine formula, is used in the treatment of cardiac arrhythmias. This trial aimed to investigate whether the SSYX can improve clinical outcomes in patients who have undergone catheter ablation for persistent AF.

Methods

A multi-centre, randomized, double-blind, placebo-controlled clinical trial was conducted at 66 centres in China among 920 patients with persistent AF undergoing first ablation. Participants were randomized to oral SSYX, 1.6 g (.4 g/granule) thrice daily (n = 460), or matched placebo (n = 460) for 12 months. The primary endpoint was recurrent atrial tachyarrhythmias lasting for ≥30 s following a blanking period of 3 months. Secondary endpoints included time to first documented atrial tachyarrhythmias, AF burden, cardioversion, stroke/systemic embolism, changes in echocardiographic parameters, and quality-of-life (QoL) score. Analyses were performed according to the intention-to-treat principle.

Results

A total of 920 patients underwent randomization (460 assigned to SSYX group and 460 assigned to placebo group). During the follow-up of 12 months, patients assigned to SSYX had a higher event-free rate from recurrent atrial tachyarrhythmias when compared with the placebo group (12-month Kaplan–Meier event-free rate estimates, 85.5% and 77.7%, respectively; hazard ratio, .6; 95% confidence interval .4–.8; P = .001). Patients assigned to receive SSYX had a better QoL score at 12 months compared to those randomized to placebo. There was no significant difference in the incidence of serious adverse events between the two groups.

Conclusions

Treatment with SSYX following radiofrequency catheter ablation for persistent AF reduced the incidence of recurrent atrial tachyarrhythmias and led to clinically significant improvements in QoL during a 12-month follow-up in a Chinese population.
In vivo dissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1
Authors: Rivest Jean-François , Carter Sophie , Goupil Claudia , Antérieux Pénélope , Cyr Denis , Ung Roth-Visal , Dal Soglio Dorothée , Mac-Way Fabrice , Waters Paula J , Paganelli Massimiliano , Doyon Yannick
Published: August 2024

Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related “modifier’ genes (i.e. genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases. In vivo somatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressing Staphylococcus aureus Cas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of using in vivo genome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.
Contrast-Enhanced Ultrasound Imaging Detects Anatomical and Functional Changes in Rat Cervical Spine Microvasculature With Normal Aging
Authors: Harmon Jennifer N , Chandran Preeja , Chandrasekaran Abarajithan , Hyde Jeffrey E , Hernandez Gustavo J , Reed May J , Bruce Matthew F , Khaing Zin Z
Published: August 2024

Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. Although these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24–26 months, N = 6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4–6 months, N = 6; tortuosity index 2.20 ± 0.15 vs 4.74 ± 0.45, p < .05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14 ± 1.37e13 vs 3.66e14 ± 2.64e13 CEUS bolus area under the curve, p < .05). To elucidate functional differences, animals were exposed to a hypoxia challenge, whereas adult rats exhibited significant functional hyperemia in both gray matter (GM) and white matter (WM) (GM: 1.13 ± 0.10-fold change from normoxia, p < .05; WM: 1.16 ± 0.13, p < .05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the first in vivo description of age-related hemodynamic differences in the cervical spinal cord.
Resilience and Hassles Trajectories Among Older Adults During the COVID-19 Pandemic
Authors: Kurth Maria L , Segerstrom Suzanne C , Chandler Kelly D , Hooker Karen , Aldwin Carolyn M
Published: August 2024

Objectives

Despite higher physical vulnerability to coronavirus disease 2019 (COVID-19), older adults reported less psychological stress than younger and midlife adults during the pandemic. However, little is known about age differences in stress within later life, and most COVID-19 studies have been cross-sectional. We examined weekly hassles exposure and severity trajectories and whether these trajectories differed by age, resilience factors (higher trait resilience and education), and vulnerability factors (identifying as a woman, being a person of color, and having chronic health conditions).

Methods

Community-dwelling adults aged 50+ in Oregon (Mage = 71.1, standard deviation = 7.3; 74% women, 89% non-Hispanic White) completed weekly online surveys across 8 weeks (April 28–June 22, 2020) during the COVID-19 stay-at-home mandate. A 2-part model estimated how age, resilience, and vulnerability factors predicted weekly odds of any hassle exposure and level of severity.

Results

Across time, hassles exposure decreased and the rate of severity declined, but these patterns differed by age and other demographics. The old-old (estimated at age 78) remained stable in odds of any exposure, whereas the young-old (estimated at age 64) evidenced a J-shaped curve; age did not moderate the severity slopes. Furthermore, both resilience factors were associated with exposure trajectories, whereas vulnerability factors (race/ethnicity and chronic illness) were associated with levels of hassles severity.

Discussion

There were age differences in patterns of hassles during the COVID-19 pandemic. Furthermore, resilience and vulnerability factors also showed complex patterns, underscoring the need for future studies to focus on age differences in well-being in later life.
Does Religion Mitigate the Effect of Neighborhood Disorder on Cognitive Decline?: Evidence From a National Longitudinal Study of U.S. Older Adults
Authors: Lee Haena , Choi Yeon Jin , Jung Jong Hyun
Published: August 2024

Objectives

This paper examines whether perceived neighborhood disorder is associated with trajectories of cognitive functioning and whether religion mitigates this association among U.S. older adults.

Methods

Data are drawn from the 2006–2016 Health and Retirement Study (N = 12,669). Religious belief and religious attendance are assessed as potential moderators. Growth curve models are used to estimate trajectories of cognitive functioning over time.

Results

We find that perceived neighborhood disorder is associated with lower cognitive functioning at baseline; however, religious belief mitigates the impact of perceived neighborhood disorder on the level of cognitive functioning. For instance, individuals with high religious belief, despite experiencing high perceived neighborhood disorder, show better cognitive functioning at baseline compared to those with high disorder but low belief. While frequent religious attendance is associated with higher cognitive functioning at baseline, it does not moderate the impact of perceived neighborhood disorder on cognitive functioning.

Discussion

This study underscores the protective role of religious belief against cognitive aging in the face of neighborhood disorder, suggesting that personal faith may provide a cognitive reserve or coping mechanism. Our findings also imply that the absence of religious belief, combined with high perceived neighborhood disorder, may produce a compounded negative impact on cognitive aging.
Relationship between Cole–Cole model parameters in permittivity and conductivity formulation
Authors: Limbrock Jonas K , Kemna Andreas
Published: August 2024

For the analysis of spectral induced polarization (SIP) measurements and for the description of frequency-dependent electrical relaxation responses, so-called Cole–Cole models (CCMs) are widely used. Typically, CCM formulations in terms of complex electrical conductivity or complex electrical resistivity are used in geophysical applications. The differences between these model descriptions, in particular between the respective time constants, and their conversion have been studied. A third variant of the model is formulated in terms of complex permittivity, commonly used in materials science. In general, all these model formulations can be used equivalently for fitting SIP data, which, however, results in differing values for some of the model parameters. For a meaningful comparison of CCM parameters of different samples or measurements, it is necessary that they are based on the same model formulation. In this work, the relationships between the Debye model (DM) and CCM parameters in the formulation for complex permittivity and complex conductivity are studied. A direct analytical conversion is possible for generalized DM formulations, both in single- and multi-term model formulations, resulting in relationships between the respective relaxation time distributions (RTDs). Such a direct conversion for CCM formulations is not possible. We however derived an approximate relationship between $\log$-normal RTD and CCM formulations and respective permittivity and conductivity parameter values. Our study also highlights the significance of using consistent model formulations when experimental data are compared in terms of DM or CCM parameters, as parameters used to predict ice temperature are incorrect if the conductivity time constant is used to predict the temperature from interpolation of a permittivity time constant-temperature relationship.
Developing community resilience in the face of COVID-19: case study from the Estrie region, Canada
Authors: Shareck Martine , Badji Marie Suzanne , Picard Karine , Allaire Jean-François , Roy Philippe , Généreux Mélissa , Lévesque Julie , Lapierre-Fortin Émanuèle
Published: August 2024

The COVID-19 pandemic undeniably impacted population health and several aspects of community organization, including service delivery and social cohesion. Intersectoral collaboration and equity, two key dimensions of community resilience, proved central to an effective and equitable response to the pandemic. Yet the factors that enabled or constrained communities’ capacity to enact intersectoral collaboration and equity-focused action in such times of urgency and uncertainty remain poorly understood. This descriptive qualitative study aimed to (1) describe the processes through which intersectoral collaboration and equity-focused action were deployed during the first wave of COVID-19 and (2) identify factors enabling and constraining these processes. We conducted semi-directed interviews with 35 representatives of the governmental, institutional, and public and third sectors from four municipal regional counties of the Estrie region (Québec, Canada). We coded detailed interview notes following a codebook thematic analysis approach. We identified three processes through which intersectoral collaboration and equity-focused action were deployed: (1) networking; (2) adaptation, creation and innovation; and (3) human-centred action. Examples of levers which supported the deployment of these processes included capitalizing on pre-existing networks, adapting practices and services, and investing in solidarity and mutual aid. The influencing factors we describe represent concrete targets for resilience-building action. Although focused on the COVID-19 pandemic, our findings are relevant to other types of health, social, environmental or economic crises, and may guide health promotion and community development practitioners towards more effective community resilience-building responses.
Validating the short-version European Health Literacy Survey Questionnaire for community-dwelling older adults in Japan
Authors: Matsuo Rika , Fujita Kimie , Miyazono Mami , Miyasaka Keiko , Yamanaka Tomi , Yakushiji Kanako , Nagai Atsushi
Published: August 2024

The European Health Literacy Survey Questionnaire (HLS-EU-Q47) is available in multiple languages, and shortened versions have also been developed. This study aimed to examine the reliability and validity of the short version of the questionnaire (HLS-Q12) developed for community-dwelling older adults in Japan. The HLS-Q12 was developed using 12 of the 47 items of the Japanese version of the HLS-EU-Q47. In this study, the survey was conducted by distributing self-administered questionnaires to community-dwelling individuals aged 65 years and older who consented to participate; their responses were collected by mail. The correlation between the HLS-Q12 and the HLS-EU-Q47 was tested to assess criterion validity. To test construct validity, nine novel hypotheses were proposed. We also conducted a confirmatory factor analysis of the HLS-Q12. Based on a resurvey after 5–7 days, test–retest reliability was examined using interclass correlation coefficients (ICCs) and Bland–Altman analysis. In total, 118 individuals provided valid responses to the questionnaire. The Spearman rank correlation coefficient between the HLS-Q12 and the HLS-EU-Q47 was r = 0.98 (p < 0.001), and eight of the nine hypotheses were supported. The ICC was 0.96 (p < 0.001), and the 95% limit of agreement was −0.26 ± 5.9, suggesting no systematic error. Thus, the Japanese version of the HLS-Q12 was found to be reliable with high criterion validity and reproducibility. Hence, the HLS-Q12 is a useful scale for measuring health literacy among older adults in Japan.
Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours
Authors: Martin Samantha , Katainen Riku , Taira Aurora , Välimäki Niko , Ristimäki Ari , Seppälä Toni , Renkonen-Sinisalo Laura , Lepistö Anna , Tahkola Kyösti , Mattila Anne , Koskensalo Selja , Mecklin Jukka-Pekka , Rajamäki Kristiina , Palin Kimmo , Aaltonen Lauri A
Published: August 2024

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.
Feasibility of veno-arterial extracorporeal life support in awake patients with cardiogenic shock
Authors: Feng Iris , Singh Sameer , Kobsa Serge S , Zhao Yanling , Kurlansky Paul A , Zhang Ashley , Vaynrub Anna J , Fried Justin A , Takeda Koji
Published: August 2024

OBJECTIVES

This study sought to demonstrate outcomes of veno-arterial extracorporeal life support (VA-ECLS) in non-intubated (‘awake’) patients with cardiogenic shock, as very few studies have investigated safety and feasibility in this population.

METHODS

This was a retrospective review of 394 consecutive VA-ECLS patients at our institution from 2017 to 2021. We excluded patients cannulated for indications definitively associated with intubation. Patients were stratified by intubation status at time of cannulation and baseline differences were balanced by inverse probability of treatment weighting. The primary outcome was in-hospital mortality while secondary outcomes included adverse events during ECLS and destination at discharge.

RESULTS

Out of 135 patients in the final cohort, 79 were intubated and 56 were awake at time of cannulation. All awake patients underwent percutaneous femoral cannulation with technical success of 100% without intubation. Indications for VA-ECLS in awake patients included acute decompensated heart failure (64.3%), pulmonary hypertension or massive pulmonary embolism (12.5%), myocarditis (8.9%) and acute myocardial infarction (5.4%). After adjustment, awake and intubated patients had similar ECLS duration (7 vs 6 days, P = 0.19), in-hospital mortality (39.6% vs 51.7%, P = 0.28), and rates of various adverse events. Intubation status was not a significant risk factor for 90-day mortality (hazard ratio [95% confidence interval]: 1.26 [0.64, 2.45], P = 0.51) in multivariable analysis. Heart transplantation (15.1% vs 4.9%) and ventricular assist device (17.4% vs 2.2%) were more common destinations at discharge in awake patients than intubated patients (P = 0.02).

CONCLUSIONS

Awake VA-ECLS is safe and feasible with comparable outcomes as intubated counterparts in select cardiogenic shock patients.
Disentangling discordant vitamin D associations with prostate cancer incidence and fatality in a large, nested case–control study
Authors: Etiévant Lola , Gail Mitchell H , Albanes Demetrius
Published: August 2024

Background

Published analyses of prostate cancer nested case–control and survival data in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort suggested that men with higher baseline vitamin D [25(OH)D] concentrations have both (i) increased prostate cancer risk and (ii) decreased prostate cancer-specific fatality.

Methods

To investigate possible factors responsible for a spurious association with prostate cancer fatality, we reanalysed baseline serum vitamin D associations with prostate cancer risk and prostate cancer-specific fatality in case–control data nested within the ATBC Study (1000 controls and 1000 incident prostate cancer cases). Conditional logistic regression and Cox proportion hazard models were used, respectively, to estimate odds ratios for risk and hazard ratios for prostate cancer-specific fatality, overall and by disease aggressiveness. We replicated these case–control analyses using baseline serum measurements of alpha-tocopherol (vitamin E), beta-carotene and retinol (vitamin A), and used the entire ATBC Study cohort (n = 29 085) to estimate marginal associations between these baseline vitamins and prostate cancer incidence and fatality following blood collection.

Results

Vitamin D analyses agreed closely with those originally published, with opposite risk and fatality associations. By contrast, the analyses of alpha-tocopherol, beta-carotene and retinol yielded concordant associations for prostate cancer incidence and prostate cancer-specific fatality.

Conclusions

We found evidence of neither artefacts in the nested prostate cancer case–control data set nor detection or collider biases in the fatality analyses. The present findings therefore support a valid inverse (i.e. beneficial) association between vitamin D and prostate cancer-specific survival that warrants further evaluation, including possibly in controlled trials.
GluN2A: A Promising Target for Developing Novel Antidepressants
Authors: Wang Gang , Qi Wang , Liu Qiu-Hua , Guan Wei
Published: August 2024

Background

Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems regarding mental health care. It is now well established that N-methyl D-aspartate receptor (NMDAR) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS), and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated.

Methods

We reviewed several past studies to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression.

Results

These evidence suggests that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods.

Conclusions

Specific inhibition of the GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.
Residency in Long-Term Care Facilities: An Important Risk Factor for Respiratory Syncytial Virus Hospitalization
Authors: Branche Angela R , Falsey Ann R , Finelli Lyn , Walsh Edward E
Published: August 2024

Older age and comorbid conditions increase risk for severe for respiratory syncytial virus (RSV). Skilled nursing facilities (SNFs) and assisted living (AL) facilities represent an intersection of risk factors. In a 3-year prospective study in Rochester, New York, we compared the population-based incidence of RSV-associated hospitalization for community-dwelling (CD), SNF, and AL adults aged ≥65 years. Their median ages were 76, 83 and 86 years, respectively, and dementia and congestive heart failure (CHF) were more prevalent among SNF and AL residents. The average annual incidences were 117 (95% confidence interval, 104–132), 440 (307–629) and 740 per 100 000 persons (523–1045), respectively, for CD, SNF, and AL adults aged ≥65 years, demonstrating a need for unequivocal RSV vaccine recommendations in SNF and AL residents.
Spatial diversity of in vivo tissue immunity
Authors: Miyamoto Yu , Ishii Masaru
Published: August 2024

The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases.
Gut microbiota dysbiosis deteriorates immunoregulatory effects of tryptophan via colonic indole and LBP/HTR2B-mediated macrophage function
Authors: Jiang Lili , Hao Youling , Han Dandan , Dong Wenjian , Yang Aoyu , Sun Zhiyuan , Ge Yao , Duan Shuai , Zhang Xiuwen , Dai Zhaolai
Published: August 2024

Tryptophan (Trp) has been shown to regulate immune function by modulating gut serotonin (5-HT) metabolism and signaling. However, the mechanisms underlying the microbial modulation of gut 5-HT signaling in gut inflammation with gut microbiota dysbiosis require further investigation. Here, we investigated the effects of Trp supplementation on the composition and metabolism of the gut microbiome and 5-HT signaling-related gut immune function using a dextran sodium sulfate (DSS)-induced colitis mouse model coupled with antibiotic exposure. The results showed that antibiotic treatment before but not during DSS treatment decreased the immunoregulatory effects of Trp and aggravated gut inflammation and body weight loss in mice. Metagenomic analysis revealed that the fecal microbiota transplantation of Trp-enriched gut microbiota to recipient mice subject to antibiotic pre-exposure and DSS treatment alleviated inflammation by increasing the relative abundances of Lactobacillus and Parabacteroides and the microbial production of indole coupled with the activation of the 5-HT receptor 2B (HTR2B) in the colon. Transcriptomic analysis showed that HTR2B agonist administration strengthened the beneficial effects of Trp in DSS-induced colitis mice with antibiotic exposure by reducing gut lipopolysaccharide-binding protein (LBP) production, IκB-α/nuclear factor-κB signaling, and M1 macrophage polarization. Indole treatment reduced LBP production and M1 macrophage polarization both in mice with DSS-induced colitis and in lipopolysaccharide-treated mouse macrophages; however, the HTR2B antagonist reversed the effects of indole. Our findings provide the basis for developing new dietary and therapeutic interventions to improve gut microbiota dysbiosis-associated inflammatory gut disorders and diseases.
Role of volume and inoculum in MIC assessment: a study with meropenem and Klebsiella pneumoniae
Authors: Alieva Kamilla N , Golikova Maria V , Zinner Stephen H
Published: August 2024

Objectives

Pharmacodynamic parameters evaluated under conditions that simulate an infection site volume and microbial load might reveal hidden risks of resistance selection and subsequent treatment failure. The study aimed to investigate the predictive potential of MICs determined at various conditions on the antimicrobial effect and emergence of resistance.

Methods

We assessed meropenem MICs (microdilution: 0.2 mL, 5 × 105 cfu/mL; macrodilution: 2 mL, 5 × 105 cfu/mL), MICHVs (220 mL, 5 × 105 cfu/mL), MICHIs (0.2 mL, 5 × 107 cfu/mL) and MICHVIs (220 mL, 5 × 107 cfu/mL) for five Klebsiella pneumoniae strains and analysed these values alongside the results of experiments in a dynamic in vitro model. A clinically relevant meropenem dosing regimen was simulated and the starting bacterial inocula were 106 and 108 cfu/mL.

Results

The effectiveness of meropenem agreed with MICHVs for the 106 cfu/mL inoculum and with MICHIs or MICHVIs for the 108 cfu/mL inoculum. Strains characterized as resistant according to these values grew during meropenem exposure, and resistant mutants were selected.

Conclusions

Our results suggest that MICHV-based parameters may be suitable for predicting antibacterial effects and the risk of resistance development when the inoculum is 106 cfu/mL, while MICHI- or MICHVI-based parameters are suitable for these purposes when the inoculum is 108 cfu/mL. Also, the correlation between resistance selection and the MICHI-based parameter was as high as one that corresponds with a mutant prevention concentration (MPC)-based parameter; this suggests that the MPC can be replaced by the more easily determined alternative parameter MICHI.
Fluoroquinolones in orthopaedic infection: balancing risks and rewards
Authors: Azamgarhi Tariq , Scarborough Matthew , Peter-Akhigbe Viola , Scobie Antonia , Dunsmure Louise , Warren Simon
Published: August 2024

This article discusses the recent regulatory restrictions on the use of fluoroquinolones and their impact on treating orthopaedic infections. We focus on the balance between the benefits and risks of fluoroquinolones in scenarios involving severe infections where alternative antibiotics may be less effective. The discussion includes a summary of recent evidence on adverse effects and the implications for clinical practice.
Determination of Taurine in Infant Formula and Adult/Pediatric Nutritionals by Ultra High-Performance Liquid Chromatography with Multiple Reaction Monitoring-Mass Spectrometry: Single-Laboratory Validation, First Action 2022.08
Authors: ten Kate Geert A , Popma Bertus , van der Pruik Gerrit , Roeleveld Martin , van Gool Martine P
Published: August 2024

Background

Taurine (2-aminoethanesulfonic acid) is an essential β-amino acid, which is one of the most abundant intracellular amino acid component in humans. The level of free taurine in human milk is higher than in bovine milk. Since taurine is considered important for the development of a newborn, fortification of infant nutrition with taurine is common. This publication describes a rapid method for the determination of taurine in infant formula and adult/pediatric nutritionals.

Objective

This publication demonstrates the suitability and applicability of the method to determine taurine content in infant formula and adult/pediatric nutritionals.

Methods

Test portions are deproteinized by acid in an aqueous environment prior to analysis. The level of taurine is analyzed by hydrophilic interaction chromatography (HILIC) coupled with multiple reaction monitoring MS (MRM-MS). Quantitation is accomplished using a stable isotope-labeled internal standard (SILS) for taurine.

Results

The accuracy of the method was validated using standard reference materials and spike recovery studies. The average recoveries ranged between 92% and 105%. The relative standard deviation repeatability (RSDr) and relative standard deviation intermediate precision (RSDiR) were in the range of 0.7–4.6% (RSDr) and 1.3–6.7% (RSDiR). The limit of quantitation (LOQ) was below the requirement of 0.5 mg/100 g.

Conclusion

The single-laboratory validation (SLV) of the method for determination of taurine content in infant formula and adult/pediatric nutritionals demonstrates that it meets the requirements per AOAC INTERNATIONAL Standard Method Performance Requirements (SMPR) 2014.013.

Highlights

A fast method to selectively determine the content of taurine in infant formula and adult/pediatric nutritionals was evaluated and found to be fit for purpose for routine product compliance testing. Based on the results of this SLV, the method was approved by the AOAC Stakeholder Program on Infant Formula and Adult Nutritionals (SPIFAN) Expert Review Panel for SPIFAN Nutrient Methods for First Action Official MethodsSM status.
Prevalence of HIV-associated osteoporosis and fracture risk in midlife women: a cross-sectional study in Zimbabwe
Authors: Madanhire Tafadzwa , Ó Breasail Mícheál , Kahari Cynthia , Kowo-Nyakoko Farirayi , Ebeling Peter R , Ferrand Rashida A , Ward Kate A , Gregson Celia L
Published: August 2024

Antiretroviral therapy roll-out has dramatically reduced HIV-related mortality; more women are living to reach menopause. Menopausal estrogen loss causes bone loss, as does HIV and some of its treatments. However, data describing HIV’s impact on osteoporosis prevalence and fracture risk are scarce in southern Africa. A cross-sectional study of women aged 40-60 years (49% women with HIV [WLH]) was conducted in Harare, Zimbabwe. Menopause, fracture, and HIV history were collected, and anthropometry and BMD (by DXA) measured, and FRAX 10-year fracture probabilities quantified. The FRAX probability of a major osteoporotic fracture (MOF) included HIV as a risk factor for secondary osteoporosis. Linear and Poisson regression determined the relationships between clinical risk factors and both femoral neck (FN) BMD and the 10-year FRAX probability of MOF respectively. The 393 participants had a mean (SD) age of 49.6 (5.8) years and mean (SD) BMI of 29.1 (6.0) kg/m2. 95% of WLH were antiretroviral therapy (ART) established (85% tenofovir disoproxil fumarate) and 81% had a viral load <50 copies/mL. A BMD T-score ≤ –2.5 was more common in WLH than those without, at both FN and lumbar spine (LS) (FN, 22 [11.4%] vs 5 [2.5%]; LS, 40 [20.8%] vs 9 [4.5%], respectively). Prior fracture was more prevalent in WLH: any fracture type (27 [14%] vs 14 [7%]); MOF (14 [7.3%] vs 5 [2.5%]). WLH had a higher 10-year MOF probability (median, 1.2%; IQR, 0.9-1.8) compared with those without HIV (1.0%; IQR, 0.9-1.5) (p < .001), although probabilities were low. Older age, low weight, and HIV infection were strongly associated with lower FN BMD. Higher probability of MOF was associated with older age, HIV infection, parental hip fracture and prior fracture, although adjustment attenuated the association with HIV. No woman reported anti-osteoporosis medication use. While osteoporosis and previous fractures were common and untreated in this relatively young population, particularly in WLH, the FRAX-predicted 10-year MOF risk was low. Clinical risk factors considered in fracture risk prediction tools in Zimbabwe may need contextual modification.
HR-pQCT cross-calibration using standard vs. Laplace-Hamming binarization approach
Authors: Sadoughi Saghi , Subramanian Aditya , Ramil Gabriella , Zhou Minhao , Burghardt Andrew J , Kazakia Galateia J
Published: August 2024

High-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as a powerful imaging technique for characterizing bone microarchitecture in the human peripheral skeleton. The second-generation HR-pQCT scanner provides improved spatial resolution and a shorter scan time. However, the transition from the first-generation (XCTI) to second-generation HR-pQCT scanners (XCTII) poses challenges for longitudinal studies, multi-center trials, and comparison to historical data. Cross-calibration, an established approach for determining relationships between measurements obtained from different devices, can bridge this gap and enable the utilization and comparison of legacy data. The goal of this study was to establish cross-calibration equations to estimate XCTII measurements from XCTI data, using both the standard and Laplace-Hamming (LH) binarization approaches. Thirty-six volunteers (26–85 yr) were recruited and their radii and tibiae were scanned on both XCTI and XCTII scanners. XCTI images were analyzed using the manufacturer’s standard protocol. XCTII images were analyzed twice: using the manufacturer’s standard protocol and the LH segmentation approach previously developed and validated by our team. Linear regression analysis was used to establish cross-calibration equations. Results demonstrated strong correlations between XCTI and XCTII density and geometry outcomes. For most microstructural outcomes, although there were considerable differences in absolute values, correlations between measurements obtained from different scanners were strong, allowing for accurate cross-calibration estimations. For some microstructural outcomes with a higher sensitivity to spatial resolution (eg, trabecular thickness, cortical pore diameter), XCTII standard protocol resulted in poor correlations between the scanners, while our LH approach improved these correlations and decreased the difference in absolute values and the proportional bias for other measurements. For these reasons and due to the improved accuracy of our LH approach compared with the standard approach, as established in our previous study, we propose that investigators should use the LH approach for analyzing XCTII scans, particularly when comparing to XCTI data.
Status of incremental costs of first-line treatment recommended in Japanese clinical guidelines for metastatic breast cancer patients
Authors: Iwatani Tsuguo , Sasaki Keita , Machida Ryunosuke , Shien Tadahiko , Hara Fumikata , Fujisawa Tomomi , Takano Yuko , Kobayashi Yoshie , Saimura Michiyo , Koizumi Kei , Terada Mitsuo , Sasada Shinsuke , Saito Kanako , Sumiyoshi Miwa , Iwata Hiroji
Published: August 2024

Background

The increasing incidence and prevalence of breast cancer alongside diagnostic and treatment technology advances have produced a debate about the financial burden cancer places on the healthcare system and concerns about access.

Methods

This study was conducted at 51 hospitals belonging to the Breast Cancer Study Group of the Japan Clinical Oncology Group using a web-based survey. The survey period conducted from July 2021 to June 2022. The study population included patients with metastatic breast cancer who received the related treatment as their first-line therapy. The proportion of patients who selected that regimen as their first-line treatment was tabulated. The total cost increase for each current standard therapy in comparison to conventional treatments was calculated.

Results

A total of 702 patients (pts) were surveyed. Of those enrolled, 342 (48.7%) received high-cost treatment [estimated monthly drug costs exceeding ~500 000 Japanese Yen (JPY)]. Of these, 16 pts (4.7%) were receiving very high-cost treatment, amounting to more than 1 000 000 JPY per month. Fifty three (15.5%) of the patients who received high-cost treatment were 75 years of age or older. Of these, 1 pt (0.3%) were receiving very high-cost treatment. Analyses of incremental costs by current drugs showed that abemaciclib was costly with total additional cost of 6 365 670 JPY per patient. The total additional cost of the regimen per patient that included palbociclib was the second highest at 4011248 JPY, followed by atezolizumab at 3209033 JPY.

Conclusions

The findings indicate that evaluating the financial implications of high-cost treatments requires considering not only drug prices but also analysis of total cost increase.
Association of stromal type IV collagen and prognosis in neoadjuvant chemotherapy-treated pancreatic cancer
Authors: Nakamura Yasuhiro , Yasukawa Takehiro , Fukumura Yuki , Takeda Yoshinori , Imamura Hiroshi , Shi Yang , Li Mu , Abe Masaaki , Uyama Saya , Kajino Kazunori , Ishijima Muneaki , Saiura Akio , Orimo Akira
Published: August 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to its low surgical eligibility and resistance to chemotherapy. Abundant stroma is characteristic of PDAC, and cancer-associated fibroblasts (CAFs) are a major stromal constituent, contributing to chemoresistance. Because neoadjuvant chemotherapy (NAC) is included in PDAC treatment as a standard regimen, the role of CAFs in NAC resistance must be studied. Although type IV collagen (COLIV) is present in the tumor of PDAC, the association between COLIV and disease advancement of NAC-treated PDAC is unclear.

Methods

Using a cohort of NAC-treated patients with PDAC, we examined clinicopathological data and conducted immunohistochemical analysis of COLIV in tissue specimens prepared from surgically resected pancreas.

Results and Conclusions

Our analysis revealed that ~50% of the cases were positive for COLIV in the stroma and diffuse COLIV staining was an independent poor prognosis factor alongside high serum CA19-9 before NAC treatment (>37 U/mL) and postsurgical residual tumors. Based on these findings, we propose that stromal COLIV staining can be used to predict prognosis in NAC-treated patients with PDAC after surgery. Additionally, these findings suggest a possibility that stromal COLIV staining indicates resistance to anticancer drugs and/or contributes to malignancy in PDAC.
The beneficial impact of curcumin on cardiac lipotoxicity
Authors: Abolfazli Sajad , Butler Alexandra E , Kesharwani Prashant , Sahebkar Amirhossein
Published: August 2024

Lipotoxicity is defined as a prolonged metabolic imbalance of lipids that results in ectopic fat distribution in peripheral organs such as the liver, heart, and kidney. The harmful consequences of excessive lipid accumulation in cardiomyocytes cause cardiac lipotoxicity, which alters the structure and function of the heart. Obesity and diabetes are linked to lipotoxic cardiomyopathy. These anomalies might be caused by a harmful metabolic shift that accumulates toxic lipids and shifts glucose oxidation to less fatty acid oxidation. Research has linked fatty acids, fatty acyl coenzyme A, diacylglycerol, and ceramide to lipotoxic stress in cells. This stress can be brought on by apoptosis, impaired insulin signaling, endoplasmic reticulum stress, protein kinase C activation, p38 Ras-mitogen-activated protein kinase (MAPK) activation, or modification of peroxisome proliferator–activated receptors (PPARs) family members. Curcuma longa is used to extract curcumin, a hydrophobic polyphenol derivative with a variety of pharmacological characteristics. Throughout the years, curcumin has been utilized as an anti-inflammatory, antioxidant, anticancer, hepatoprotective, cardioprotective, anti-diabetic, and anti-obesity drug. Curcumin reduces cardiac lipotoxicity by inhibiting apoptosis and decreasing the expression of apoptosis-related proteins, reducing the expression of inflammatory cytokines, activating the autophagy signaling pathway, and inhibiting the expression of endoplasmic reticulum stress marker proteins.
Barriers and backslides: How economic instability impedes refugee self-reliance in Kakuma refugee camp, Kenya
Authors: Sackett Blair
Published: August 2024

Studies reveal that refugees develop a wide range of economic activity in displacement. In recent years, priorities of refugee self-reliance have had a resurgence among humanitarian organizations and policymakers. Within these programs, models of self-reliance have focused on employment and income for individual refugee households. Based on ethnographic observations, interviews, and longitudinal questionnaires in Kakuma refugee camp in Kenya, I demonstrate the need to broaden our models of self-reliance to incorporate the role economic shocks, or exogenous and unpredictable events that affect household resources. Rather than rare events, economic shocks were common across sectors and compounded by cuts to humanitarian support. Nor were shocks isolated events. Households faced multiple intersecting shocks, which rippled across communities as households were affected by shocks to others in their social networks. Across employment type and income, shocks destabilized the economic trajectories of refugee households and impeded progress toward self-reliance.