bluuebunny/crossref_metadata_2025 huggingface dataset:
Opportunities to Improve the Quality of Beef Produced under Smallholder Mixed Crop and Rangeland Livestock Production Systems
Authors: Mummed Yesihak Yusuf
Published: November 2023

East African countries contain a substantial proportion of cattle (9.3%, 136.4 million) and small ruminants (12%, 253.4 million) compared to the world’s total livestock population. In this region, more than 70% of the land surface is conducive to raise red meat animals. However, the region has limited share (approximately 1%) of meat products to the world market due to the failure to satisfy the minimal quality standard. Most of livestock farmers in this region are smallholders operating pastoral and mixed crop-livestock production systems. This study looked at reports on the quality of beef produced by smallholder production systems using Ethiopia as an example in order to identify potential and determinants in quality beef production under smallholders production system. In order to achieve this, research station beef quality reports were considered as a standard to compare the instrumental quality of beef reported from oxen and bulls raised by smallholders in mixed crop-livestock systems, ranches, and Hararghe cattle fattening systems. According to the analysis, oxen in the smallholders in the mixed crop-livestock systems produced comparatively lower-quality beef than oxen reared by the smallholders in the Hararghe fattening and bulls reared in the ranch systems, which produced good-quality beef. Improved feed resources are used in the Hararghe cattle fattening systems; oxen are used for draft service for a brief period of time (2.85 ± 0.58 years) and then sold for slaughter relatively at a young age. In pastoral settings, ranches offer options for the effective use of scare feed resources. The primary factors that determine the quality of beef produced from oxen raised in the mixed crop-livestock system were poor-quality feed resources, long-term draft service (6.62 ± 1.92 years), and old age at slaughter. To improve the quality of beef produced from the oxen raised in the mixed crop-livestock system, the practice of smallholder farmers in the Hararghe cattle fattening system needs to be adopted. The adoption of the practice also contributes to reduce the greenhouse gas emissions from the system and convert the subsistence mixed crop-livestock into a market-oriented system.
The Effect of Various Combinations of Peripheral Nerve Blocks on Postoperative Pain in Laparoscopic Cholecystectomy: A Comparative Prospective Study
Authors: Haitov Ben Zikri Zoya , Volis Maryna , Mazur Andrei , Orlova Tatjana , Alon Hana , Bar Yehuda Sara , Gofman Vladislav
Published: November 2023

Objectives. Most patients who undergo laparoscopic cholecystectomy (LC) experience moderate to severe pain in the first 24 hours after surgery. The transversus abdominal plane (TAP) is currently used for post-LC analgesia. Posterior, subcostal, or rectus sheath TAP blocks are the conventional approaches used. The aim of the current study was to compare the efficacy of combinations of various peripheral blocks on pain intensity and the use of pain killers, shortly after LC. Methods. This was a prospective, double-blind study, in which 200 patients who were about to undergo a LC procedure were recruited and randomized into 4 groups: patients receiving one of the following: TAP block alone, subcostal Tap block alone, subcostal TAP block with a TAP block, or subcostal TAP with a rectus sheath block. The intensity of pain (VAS score) and the use of painkillers were monitored in the recovery unit and in the department for up to 24 hours after surgery. Results. Pain levels decreased with time from 3.6 ± 3.2 at 30 minutes to 0.9 ± 2.0 at 24 hours after the surgery. Nevertheless, no difference between the various block types groups was noted. The percentage of patients who consumed analgesic medications decreased over time, from 83% at 30 to 21% at 24 hours after surgery. The mean/median number of medications consumed by each of the patients was lower among the patients who received a combination of 2 blocks compared to those who received a single one (mean/median of 2.7/3 and 2.8/3 for the TAP or subcostal TAP blocks, respectively; 2.5/2 and 2.3/2 for the subcostal TAP + TAP or subcostal TAP + rectus sheath blocks, respectively). Conclusion. A combination of peripheral nerve blocks reduced the use of analgesic consumption during the 24 hours after LC surgery, compared to standalone blocks.
Astragaloside IV-PESV Repressed T Cell Immunosuppression by Inhibiting PD-L1 Expression in Prostate Cancer through STAT3 Pathway
Authors: You Xujun , Qiu Junfeng , Li Qixin , Zhang Qing , Sheng Wen , Fu Wei , Cao Yiguo
Published: November 2023

Background. Prostate cancer (PCa) is a major threat to men’s health worldwide, and there is an urgent need to find a supportive strategy to improve traditional PD-1/PD-L1 targeted immunotherapy. Our previous research identified astragaloside IV and polypeptide extract from scorpion venom (PESV) as the main active components of the astragalus-scorpion drug pair for treating PCa. In this study, we wanted to continue exploring the modulatory effect of astragaloside IV-PESV on the immune microenvironment of tumors further to investigate the antitumor efficacy mechanism of astragaloside IV-PESV. Methods. First, molecular docking was performed to verify whether astragaloside IV and PESV could bind to STAT3 and PD-L1. Next, we performed mouse tumorigenesis experiments to explore the role of astragaloside IV-PESV. Additionally, we further validated the effects of astragaloside IV-PESV on the STAT3/PD-L1 pathway and immunity by in vitro cellular experiments. Furthermore, we overexpressed STAT3 and validated the effects of overexpression of STAT3 on cellular function, T cell activation, and immune escape in vitro and in vivo. Results. Molecular docking revealed astragaloside IV and PESV bound to STAT3 and PD-L1. Astragaloside IV-PESV led to notable tumor tissue volume and weight repression and inhibited tumor immunity and STAT3/PD-L1 pathway-related protein expressions. In vitro, astragaloside IV-PESV suppressed PD-L1 expression by inhibiting STAT3 signaling to modulate immunity. In contrast, overexpression of STAT3 restored PCa cell proliferation, migration, and invasion inhibition by astragaloside IV-PESV. In addition, overexpression of STAT3 restored the promoting effect of astragaloside IV-PESV on T cell activation. Finally, in vivo experiments further illuminated that overexpression of STAT3 restored the immune escape effect of astragaloside IV-PESV on the tumor. Conclusion. Astragaloside IV-PESV improved T cell immune escape by inhibiting PD-L1 expression in PCa through the STAT3 pathway.
Frequencies of VKORC1-1639G>A and rs397509427 in Patients on Warfarin and Healthy Syrian Subjects
Authors: Altawil Yara , Youssef Lama A.
Published: November 2023

Background. Vitamin K epoxide reductase complex subunit 1 (VKORC1) gene encodes a key enzyme with multiple cellular activities, namely, the reduction of vitamin K to its active form. VKORC1-1639G>A (rs9923231) is a common single nucleotide polymorphism with a crucial impact on warfarin dosing and possibly other physiological functions. This study aimed at investigating the frequencies of VKORC1-1639G>A alleles and genotypes in Syrian healthy subjects and patients on warfarin for different indications. Methods. A total of 138 individuals were enrolled in this cross-sectional study. Genomic DNA was extracted from both patients on warfarin and healthy subjects, and polymerase chain reaction (PCR) specific amplicons were genotyped via standard sequencing which also allowed the detection of rs397509427. Comparisons of -1639G>A frequency with other populations were drawn. Results. Of 94 patients on warfarin, 53 (56.38%) were with idiopathic venous thromboembolism (VTE). Despite comparable frequencies of the -1639A allele (47% and 50%), the AA and GA genotypes were at disparate frequencies of 93.2% versus 79.8% in the healthy subjects (

n
=
44

) versus patients on warfarin, respectively. Carriers of the GG genotype were at a four-fold increased risk of VTE in comparison with those of the AA and GA genotypes (odds ratio

OR

=
4

, 95%

CI
=
1.105
−
13.6

,

P
=
0.0469

). All study subjects were wild-type for the rs397509427 variant. Conclusions. Our results prove a high -1639A prevalence in Syrian healthy subjects and patients on warfarin at frequencies comparable to other Mediterranean and Middle Eastern populations. The A allele carriers are at a lower VTE risk, whereas a global prevalence gradient of the G allele is suggested to be associated with VTE risk.
Relationship between Indoor Living Environment and Housing Prices: A Case Study of the Taojinjiayuan Residential Quarter in Guangzhou, China
Authors: Wang Yang , Wang Min , Wu Yingmei , Yue Xiaoli , Li Xueying , Zhang Hong’ou
Published: November 2023

The indoor living environment of residential buildings is an important part of the habitat environment, affecting the living experience and well-being of the residents, which in turn influences the price of housing. However, few existing studies systematically concentrate on the integrated influence of the various elements of the indoor living environment on prices, and even fewer analyze the relationship between the indoor living environment and housing prices of different houses within the same residential quarter from a microperspective. Therefore, we use the Taojinjiayuan Residential Quarter, located in central Guangzhou City, China, as a case study area and analyze the extent and direction of the effect of the indoor living environment on housing prices. The study found that the quantitative evaluation results of the indoor living environment were reasonable. The integrated indoor living environment factors are closely related to housing prices. Orientation, view, and acoustic environment are significantly and positively related to housing prices, which have a different intensity of influence. These findings are beneficial to real estate developers, building designers, and residential users in quantitatively understanding the value of the indoor living environment.
Point-by-Point Pulsed Field Ablation Using a Multimodality Generator and a Contact Force–Sensing Ablation Catheter: Comparison With Radiofrequency Ablation in a Remapped Chronic Swine Heart
Authors: Di Biase Luigi , Marazzato Jacopo , Zou Fengwei , Lin Aung , Grupposo Vito , Chowdhuri Nilarun , Maffre Jennifer , Farshchi-Heydari Salman , Sharma Tushar , Beeckler Christopher , Govari Assaf , Bhardwaj Rahul , Mohanty Sanghamitra , Natale Andrea , Nakagawa Hiroshi , Zhang Xiaodong
Published: November 2023

Background:

Pulsed field ablation (PFA) has emerged as an alternative to radiofrequency ablation. However, data on focal point-by-point PFA are scarce. The aim of this study was to compare lesion durability and collateral damage between focally delivered unipolar/biphasic PFA versus radiofrequency in swine.

Methods:

Eighteen swine were randomized to low-dose PFA, high-dose PFA, and radiofrequency using a multimodality generator. Radiofrequency delivered by market-available generator served as control group. A contact force–sensing catheter was used to focally deliver PFA/radiofrequency at the pulmonary veins and other predefined sites in the atria. Animals were remapped postprocedurally and 28 days postablation to test lesion durability followed by gross necroscopy and histology.

Results:

All targeted sites were successfully ablated (contact force value, 13.9±4.1 g). Follow-up remapping showed persistent pulmonary vein isolation in all animals (100%) with lesion durability at nonpulmonary vein sites proven in most (98%). Regardless of the energy source used, the lesion size was similar across the study groups. Transmurality was achieved in 95% of targeted sites and 100% at pulmonary veins. On histology, PFA animals showed more mature scar formation than their radiofrequency counterpart without myocardial necrosis or inflammation. Finally, no sign of collateral damage was observed in any of the groups.

Conclusions:

In a randomized preclinical study, focally delivered unipolar/biphasic PFA guided by contact force values was associated with durable lesions on chronic remapping and with mature scar formation on histology without signs of collateral injury on necroscopy. Further studies are needed to investigate the long-term feasibility of this new approach to atrial fibrillation treatment.
Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model
Authors: Higuchi Satoshi , Voskoboinik Aleksandr , Im Sung Il , Lee Adam , Olgin Jeffrey , Arbil Ayla , Afzal Junaid , Marcus Gregory M. , Stillson Carol , Bibby Dwight , Abraham Theodore , Wilson Emily , Gerstenfeld Edward P.
Published: November 2023

BACKGROUND:

Frequent premature atrial complexes (PACs) are associated with future incident atrial fibrillation (AF), but whether PACs contribute to development of AF through adverse atrial remodeling has not been studied. This study aimed to explore the effect of frequent PACs from different sites on atrial remodeling in a swine model.

METHODS:

Forty swine underwent baseline electrophysiologic studies and echocardiography followed by pacemaker implantations and paced PACs (50% burden) at 250-ms coupling intervals for 16 weeks in 4 groups: (1) lateral left atrium (LA) PACs by the coronary sinus (Lat-PAC; n=10), (2) interatrial septal PACs (Sep-PAC; n=10), (3) regular LA pacing at 130 beats/min (Reg-130; n=10), and (4) controls without PACs (n=10). At the final study, repeat studies were performed, followed by tissue histology and molecular analyses focusing on fibrotic pathways.

RESULTS:

Lat-PACs were associated with a longer P-wave duration (93.0±9.0 versus 74.2±8.2 and 58.8±7.6 ms;
P
<0.001) and greater echocardiographic mechanical dyssynchrony (57.5±11.6 versus 35.7±13.0 and 24.4±11.1 ms;
P
<0.001) compared with Sep-PACs and controls, respectively. After 16 weeks, Lat-PACs led to slower LA conduction velocity (1.1±0.2 versus 1.3±0.2 [Sep-PAC] versus 1.3±0.1 [Reg-130] versus 1.5±0.2 [controls] m/s;
P
<0.001) without significant change in atrial ERP. The Lat-PAC group had a significantly increased percentage of LA fibrosis and upregulated levels of extracellular matrix proteins (lysyl oxidase and collagen 1 and 8), as well as TGF-β1 (transforming growth factor–β1) signaling proteins (latent and monomer TGF-β1 and phosphorylation/total ratio of SMAD2/3;
P
<0.05). The Lat-PAC group had the longest inducible AF duration (terminal to baseline: 131 [interquartile range 30, 192] seconds versus 16 [6, 26] seconds [Sep-PAC] versus 22 [11, 64] seconds [Reg-130] versus −1 [−16, 7] seconds [controls];
P
<0.001).

CONCLUSIONS:

In this swine model, frequent PACs resulted in adverse atrial structural remodeling with a heightened propensity to AF. PACs originating from the lateral LA produced greater atrial remodeling and longer induced AF duration than the septal-origin PACs. These data provide evidence that frequent PACs can cause adverse atrial remodeling as well as AF, and that the location of ectopic PACs may be clinically meaningful.
Chan Texts in Practice
Authors: van Schaik Sam
Published: November 2023

Research into early Chan has relied heavily on the manuscripts found in Cave 17 in Dunhuang, which generally date from before the eleventh century. However this research has often abstracted texts from their context as part of the varied and multilingual collection that was found in the cave. Furthermore, the date, form and original use of the manuscripts containing early Chan texts is often forgotten in the discussion. This brief paper looks at early Chan practice from a historical and local perspective, that is, as a kind of social history. Taking one text, The Record of the Masters and Students of the Lanka (Lengqie shizi ji 楞伽師資記) I discuss some of the meditation practices that it contains and compare these to manuscripts from the Dunhuang collection that fall outside the usual concept of ‘Chan Buddhism’. I conclude that first, early Chan texts should be understood as existing in specific social and ritual settings, such as group initiation rituals, educational settings with teachers and students, or indeed solitary meditation. Second, in the social setting that produced the Dunhuang manuscript cache, distinctions between what we tend to think of as ‘Chan meditation’ and other forms of meditation from tantric or pure land contexts, meant little in practice.
Doctrinal Engagements and Disengagements: Yongming Yanshou and His Legacies
Authors: Welter Albert
Published: November 2023

This paper looks at the vexed relationship of doctrine, or teaching (C. jiao/K. kyo/J. kyō 教) in the three kindred traditions subsumed under the rubric of the Sino-East Asian graph 禪, known through their distinctive pronunciations in modern languages as Chan, Sŏn, and Zen. While the stipulation of these traditions as ‘a special/separate transmission outside the teachings’; (jiaowai biechuan 教外別傳) presumes independence from Mahayana doctrinal teachings, the reality, as we know, was much more complicated. In this paper, I use Yongming Yanshou 永明延壽 (904–975/6), one of the most prominent Chan figures to promote doctrinal engagement, as a barometer to look at how doctrinal engagements and disengagements are regarded throughout each tradition. Perspectives on Yanshou, a figure at once revered and marginalized, unlock key features of each of these three interconnected traditions, what they share and how they disagree. Fundamentally, perspectives on doctrinal engagements and disengagements are rooted in seminal Chan disputes over the nature and value of Buddhist teaching, and Yanshou is a conduit for these disputes. Given the theme of the conference, ‘How Zen Became Chan’; I also look at the discrepancies these disputes reveal between modern Rinzai Zen orthodoxy’s defining of Zen in the modern world and the practice of Chan in China and Sŏn in Korea. The options that these discrepancies reveal are indicative of the relevance of doctrinal entanglements and disentanglements to the contemporary Chan, Sŏn, and Zen worlds.
Global Attribution of Precipitation to Weather Features
Authors: Konstali Kjersti , Spensberger Clemens , Spengler Thomas , Sorteberg Asgeir
Published: November 2023

Weather features, such as extratropical cyclones (ETCs), atmospheric rivers (ARs), and fronts, contribute to substantial amounts of precipitation globally. However, previous estimates of how much these individual features contribute to precipitation are very sensitive to subjectively chosen metrics. Furthermore, there is no information on how these weather features contribute to precipitation poleward of 60° latitude. To alleviate these shortcomings, we introduce a more robust attribution method applicable at all latitudes. Based on ERA5, we present the first global climatology of the contributions from cyclones, fronts, moisture transport axes (MTAs; AR-like features), and cold air outbreaks, as well as their combinations, to summer and winter precipitation as well as extreme precipitation. Most of the precipitation in the midlatitudes relates to the combination of ETC, fronts, and MTAs (28%), while in polar regions most precipitation occurs within the ETC-only category (27%). Extreme precipitation events in all extratropical regions are predominantly associated with the combination of ETCs, fronts, and MTAs (46%). In the midlatitudes, the combination of ETCs, fronts, and MTAs occurs almost 4 times as often during extreme events compared to regular events.
Two Large-Scale Meteorological Patterns are Associated with Short-Duration Dry Spells in the Northeastern United States
Authors: Sukhdeo Raymond , Grotjahn Richard , Ullrich Paul A.
Published: November 2023

Large-scale meteorological pattern (LSMP)–based analysis is used in a novel way to understand meteorological conditions before and during short-duration dry spells over the northeastern United States. These LSMPs are useful to assess models and select better-performing models for future projections. Dry-spell events are identified from histograms of consecutive dry days below a daily precipitation threshold. Events lasting 12 days or longer, which correspond to ∼10% of dry-spell events, are examined. The 500-hPa streamfunction anomaly fields for the first 12 days of each event are time averaged, and k-means clustering is applied to isolate the dry-spell-related LSMPs. The first cluster has a strong low pressure anomaly over the Atlantic Ocean, southeast of the region, and is more common in winter and spring. The second cluster has strong high pressure over east-central North America and is most common during autumn. Over the region, both clusters have negative specific humidity anomalies, negative integrated vapor transport from the north, and subsidence associated with a midlatitude jet stream dipole structure that reinforces upper-level convergence. Subsidence is supported by cold-air advection in the first cluster and the location on the east side of the lower-level high pressure in the second cluster. Extratropical cyclone storm tracks are generally shifted southward of the region during the dry spells. Individual events lie on a continuum between two distinct clusters. These clusters have similar local, but different remote, properties. Although dry spells occur with greater frequency during drought months, most dry spells occur during nondrought months.

Significance Statement

This study examines the large-scale weather patterns and meteorological conditions associated with dry-spell events lasting at least 2 weeks while affecting the northeastern United States. A statistical approach groups events together on the basis of similar atmospheric features. We find two distinct sets of patterns that we call large-scale meteorological patterns. These patterns reduce moisture, foster localized sinking, and shift the storm track southward along the Atlantic seaboard, all of which reduce precipitation. Besides greater understanding, knowing the meteorological patterns during short-term dryness in the region provides an important tool to assess how well atmospheric models reproduce these specific patterns. More dry spells occur in nondrought months than in drought months, which means that dry spells can occur without preexisting drought conditions.
A Review of Theoretical Frameworks for the Determinants of Growth of SMEs
Authors: Raparla Krishna Veni , Modh Satish
Published: November 2023

Small- and medium-sized enterprises (SMEs) are undeniably the backbone of a country's manufacturing sector, with an inherent desire for export orientation, leading to the exponential growth of emerging economies. Digital technologies have been heralded as a solution for SMEs, to increase their productivity and competitiveness. The paper tries to collate various important theories that advocate digital innovations and promote internationalisation in SMEs. The research aims to examine how researchers use existing or a combination of theories to investigate various aspects that augment the growth of SMEs. This paper reviews how multiple theories complement one another by adding rigour and usefulness to the emerging research in the field of entrepreneurship. As some of the relevant theories are collated and analysed in one place, they provide academicians with a platform for analysing various determinants in the growth of entrepreneurial activities in SMEs.
Integrated small RNA, mRNA and protein omics reveal a miRNA network orchestrating metabolic maturation of the developing human heart
Authors: Aharon-Yariv Adar , Wang Yaxu , Ahmed Abdalla , Delgado-Olguín Paul
Published: November 2023

Background

As the fetal heart develops, cardiomyocyte proliferation potential decreases while fatty acid oxidative capacity increases in a highly regulated transition known as cardiac maturation. Small noncoding RNAs, such as microRNAs (miRNAs), contribute to the establishment and control of tissue-specific transcriptional programs. However, small RNA expression dynamics and genome-wide miRNA regulatory networks controlling maturation of the human fetal heart remain poorly understood.

Results

Transcriptome profiling of small RNAs revealed the temporal expression patterns of miRNA, piRNA, circRNA, snoRNA, snRNA and tRNA in the developing human heart between 8 and 19 weeks of gestation. Our analysis demonstrated that miRNAs were the most dynamically expressed small RNA species throughout mid-gestation. Cross-referencing differentially expressed miRNAs and mRNAs predicted 6200 mRNA targets, 2134 of which were upregulated and 4066 downregulated as gestation progressed. Moreover, we found that downregulated targets of upregulated miRNAs, including hsa-let-7b, miR-1-3p, miR-133a-3p, miR-143-3p, miR-499a-5p, and miR-30a-5p predominantly control cell cycle progression. In contrast, upregulated targets of downregulated miRNAs, including hsa-miR-1276, miR-183-5p, miR-1229-3p, miR-615-3p, miR-421, miR-200b-3p and miR-18a-3p, are linked to energy sensing and oxidative metabolism. Furthermore, integrating miRNA and mRNA profiles with proteomes and reporter metabolites revealed that proteins encoded in mRNA targets and their associated metabolites mediate fatty acid oxidation and are enriched as the heart develops.

Conclusions

This study presents the first comprehensive analysis of the small RNAome of the maturing human fetal heart. Our findings suggest that coordinated activation and repression of miRNA expression throughout mid-gestation is essential to establish a dynamic miRNA-mRNA-protein network that decreases cardiomyocyte proliferation potential while increasing the oxidative capacity of the maturing human fetal heart. Our results provide novel insights into the molecular control of metabolic maturation of the human fetal heart.
Use of a novel pressure distribution system for severely ill neonates: a clinical pilot study carried out by the PREPICare consortium
Authors: Schlüer Anna-Barbara , Müller Adrian Yves , Fromme Nicolas Philip , Camenzind Martin , Riener Robert , Rossi René Michel , Aufdenblatten Barbara Brotschi
Published: November 2023

Background

Pressure Injuries are not exclusively an adult phenomenon; various risk factors contribute to a high prevalence rate of 43% in the neonatal and pediatric intensive care population. Effective preventive measures in this population are limited.

Methods

We performed a pilot study to analyze the distribution and localization of support surface interface pressures in neonates in a pediatric intensive care unit (PICU). The hypothesis was that pressure redistribution by a novel air mattress would reduce pressure peaks in critical neonates. The measurements were conducted in a 27-bed level III PICU between November and December 2020. This included measuring pressure distribution and pressure peaks for five neonates positioned on either a state-of-the-art foam mattress or a new prototype air mattress.

Results

We confirmed that the pressure peaks were significantly reduced using the prototype air mattress, compared with the state-of-the-art foam mattress. The reduction of mean pressure values was 9–29%, while the reduction of the highest 10% of pressure values was 23–41%.

Conclusions

The journey to an effective, optimal, and approved product for severely ill neonates to reduce Pressure Injuries is challenging. However, a crucial step was completed by this pilot study with the first pressure measurements in a real-world setting and the successful realization of a decrease in pressure peaks obtained using a prototype air mattress.
Screening for ELANE, HAX1 and GFI1 gene mutations in children with neutropenia and clinical characterization of two novel mutations in ELANE gene
Authors: Komvilaisak Patcharee , Yudhasompop Najwa , Kanchanakamhaeng Kittima , Hongeng Suradej , Pakakasama Samart , Anurathapan Usanarat , Pongphitcha Pongpak , Songdej Duantida , Sasanakul Werasak , Sirachainan Nongnuch
Published: November 2023

Background

Congenital neutropenia is a rare disease. Recurrent infections since young age are the presentation. The most common mutation causing severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) is the ELANE gene. The objectives of this study were to screen the three common genetic mutations of ELANE, HAX1 and GFI1 in children with chronic neutropenia and to describe the clinical characteristics of children who had the mutations.

Methods

Infants having ANC < 1,000/cu mm or children aged > 1 year having ANC < 1,500/cu mm at least 3 times in 3 months were enrolled in the study. Patients who had acquired neutropenia due to infection, immune deficiency, or drugs were excluded. The ELANE gene was first studied; and if mutations were not identified, the HAX1 and GFI1 genes were further examined.

Results

A total of 60 patients were enrolled in the study. The median (range) age, ratio of female to male, ANC, and last follow-up age were 9.2 (0.5–45.2) months, 1:1.2, 248 (0–1,101) /cu mm, and 19.9 (3.5–202.3) months, respectively. Infections were noted in 67.3% of all patients. ELANE gene mutation was found in only four patients (6.7%), and the rest (56 patients) showed no mutations in the HAX1 and GFI1 genes. In patients without mutations, 66.0% had normal ANC during the follow-up, with a median (range) age for normal ANC of 19.8 (4.0–60.0) months. Two novel mutations p. Ala79del (c.234_236del) and p. Val197GlufsTer18 (c.589_590insAGGCCGGC) were identified, and they respectively cause SCN and CyN. Patients with the two novel mutations presented with several episodes of infection, including pneumonia, sepsis, abscess, otitis media, and gum infection.

Conclusion

The genetic screening for ELANE, HAX1, and GFI1 gene mutations in 60 patients with chronic neutropenia could identify four patients (6.7%) with ELANE gene mutation and two novel mutations, p. Ala79del in exon 3 and p. Val197GlufsTer18 in exon 4 causing SCN; and CyN, respectively.
Risk factors associated with newly diagnosed attention-deficit/hyperactivity disorder in adults: a retrospective case-control study
Authors: Schein Jeff , Cloutier Martin , Gauthier-Loiselle Marjolaine , Bungay Rebecca , Arpin Emmanuelle , Guerin Annie , Childress Ann
Published: November 2023

Background

Knowledge of risk factors for attention-deficit/hyperactivity disorder (ADHD) may facilitate early diagnosis; however, studies examining a broad range of potential risk factors for ADHD in adults are limited. This study aimed to identify risk factors associated with newly diagnosed ADHD among adults in the United States (US).

Methods

Eligible adults from the IQVIA PharMetrics® Plus database (10/01/2015-09/30/2021) were classified into the ADHD cohort if they had ≥ 2 ADHD diagnoses (index date: first ADHD diagnosis) and into the non-ADHD cohort if they had no observed ADHD diagnosis (index date: random date) with a 1:3 case-to-control ratio. Risk factors for newly diagnosed ADHD were assessed during the 12-month baseline period; logistic regression with stepwise variable selection was used to assess statistically significant association. The combined impact of selected risk factors was explored using common patient profiles.

Results

A total of 337,034 patients were included in the ADHD cohort (mean age 35.2 years; 54.5% female) and 1,011,102 in the non-ADHD cohort (mean age 44.0 years; 52.4% female). During the baseline period, the most frequent mental health comorbidities in the ADHD and non-ADHD cohorts were anxiety disorders (34.4% and 11.1%) and depressive disorders (27.9% and 7.8%). Accordingly, a higher proportion of patients in the ADHD cohort received antianxiety agents (20.6% and 8.3%) and antidepressants (40.9% and 15.8%). Key risk factors associated with a significantly increased probability of ADHD included the number of mental health comorbidities (odds ratio [OR] for 1 comorbidity: 1.41; ≥2 comorbidities: 1.45), along with certain mental health comorbidities (e.g., feeding and eating disorders [OR: 1.88], bipolar disorders [OR: 1.50], depressive disorders [OR: 1.37], trauma- and stressor-related disorders [OR: 1.27], anxiety disorders [OR: 1.24]), use of antidepressants (OR: 1.87) and antianxiety agents (OR: 1.40), and having ≥ 1 psychotherapy visit (OR: 1.70), ≥ 1 specialist visit (OR: 1.30), and ≥ 10 outpatient visits (OR: 1.51) (all p < 0.05). The predicted risk of ADHD for patients with treated anxiety and depressive disorders was 81.9%.

Conclusions

Mental health comorbidities and related treatments are significantly associated with newly diagnosed ADHD in US adults. Screening for patients with risk factors for ADHD may allow early diagnosis and appropriate management.
Usage and health perception of cannabidiol-containing products among the population in Germany: a descriptive study conducted in 2020 and 2021
Authors: Geppert Johanna , Lietzow Julika , Hessel-Pras Stefanie , Kirsch Fabian , Schäfer Bernd , Sachse Benjamin
Published: November 2023

Background

Cannabidiol (CBD), a non-intoxicating substance of Cannabis sativa L., is gaining consumer attention. Yet, legal regulations in the EU are complex and questions of potential health risks remain partly unanswered. In Germany, little is known about people who use CBD products. The aim of this cross-sectional study was to gain insight into the user group of CBD, reasons for consumption and risk perception towards CBD-containing products.

Methods

The study consisted of two parts: In the first part of the study, the prevalence of CBD awareness and usage in Germany was estimated using a telephone survey and a population-representative sample of n = 1,011 respondents. Based on these results, n = 2,000 participants being aware of CBD were surveyed with an online questionnaire in the second part of the study to examine usage and perception of CBD in users and non-users.

Results

When the study was conducted at the end of 2020 and beginning of 2021, 40.2% of the German participants had already heard of products containing CBD, and 11.4% had actually used them. 42.1% of the users consumed such products regularly, at least once a week, primarily orally via oils or tinctures, and purchased them mainly online. Besides curiosity – addressed especially in young adults – anticipated health benefits including pain and stress relief were main reasons for use. More than half of the study participants perceived the health benefits of CBD use as high or very high. In contrast, the health risks were rated as low or very low by most respondents. Assumptions about official testing for safety as well as physical effects of CBD-containing products varied between users and non-users.

Conclusion

About one in nine people in Germany uses CBD-containing products. Given reasons for consumption and perception of potential health risks and benefits suggest that people are insufficiently informed about CBD-containing products. The results of the study indicate that risk communication is needed to raise awareness for the topic and to inform (potential) users.
PILLAR: ParaspInaL muscLe segmentAtion pRoject - a comprehensive online resource to guide manual segmentation of paraspinal muscles from magnetic resonance imaging
Authors: Anstruther Meagan , Rossini Bianca , Zhang Tongwei , Liang Terrance , Xiao Yiming , Fortin Maryse
Published: November 2023

Background

There is an increasing interest in assessing paraspinal morphology and composition in relation to low back pain (LBP). However, variations in methods and segmentation protocols contribute to the inconsistent findings in the literature. We present an on-line resource, the ParaspInaL muscLe segmentAtion pRoject (PILLAR, https://projectpillar.github.io/), to provide a detailed description and visual guide of a segmentation protocol by using the publicly available ITK-SNAP software and discuss related challenges when performing paraspinal lumbar muscles segmentations from magnetic resonance imaging (MRI).

Methods

T2-weighted and corresponding fat-water IDEAL axial MRI from 3 males and 3 females (2 chronic LBP and 1 control for each sex) were used to demonstrate our segmentation protocol for each lumbar paraspinal muscle (erector spinae, lumbar multifidus, quadratus lumborum and psoas) and lumbar spinal level (L1-L5).

Results

Proper segmentation requires an understanding of the anatomy of paraspinal lumbar muscles and the variations in paraspinal muscle morphology and composition due to age, sex, and the presence of LBP or related spinal pathologies. Other challenges in segmentation includes the presence and variations of intramuscular and epimuscular fat, and side-to-side asymmetry.

Conclusion

The growing interest to assess the lumbar musculature and its role in the development and recurrence of LBP prompted the need for comprehensive and easy-to-follow resources, such as the PILLAR project to reduce inconsistencies in segmentation protocols. Standardizing manual muscle measurements from MRI will facilitate comparisons between studies while the field is progressively moving towards the automatization of paraspinal muscle measurements for large cohort studies.
“We usually see a lot of delay in terms of coming for or seeking care”: an expert consultation on COVID testing and care pathways in seven low- and middle-income countries
Authors: Bonnet Gabrielle , Bimba John , Chavula Chancy , Chifamba Harunavamwe N. , Divala Titus , Lescano Andres G. , Majam Mohammed , Mbo Danjuma , Suwantika Auliya A. , Tovar Marco A. , Yadav Pragya , Corbett Elisabeth L. , Vassall Anna , Jit Mark
Published: November 2023

Background

Rapid diagnostic testing may support improved treatment of COVID patients. Understanding COVID testing and care pathways is important for assessing the impact and cost-effectiveness of testing in the real world, yet there is limited information on these pathways in low-and-middle income countries (LMICs). We therefore undertook an expert consultation to better understand testing policies and practices, clinical screening, the profile of patients seeking testing or care, linkage to care after testing, treatment, lessons learnt and expected changes in 2023.

Methods

We organized a qualitative consultation with ten experts from seven LMICs (India, Indonesia, Malawi, Nigeria, Peru, South Africa, and Zimbabwe) identified through purposive sampling. We conducted structured interviews during six regional consultations, and undertook a thematic analysis of responses.

Results

Participants reported that, after initial efforts to scale-up testing, the policy priority given to COVID testing has declined. Comorbidities putting patients at heightened risk (e.g., diabetes) mainly relied on self-identification. The decision to test following clinical screening was highly context-/location-specific, often dictated by local epidemiology and test availability. When rapid diagnostic tests were available, public sector healthcare providers tended to rely on them for diagnosis (alongside PCR for Asian/Latin American participants), while private sector providers predominantly used polymerase chain reaction (PCR) tests. Positive test results were generally taken at ‘face value’ by clinicians, although negative tests with a high index of suspicion may be confirmed with PCR. However, even with a positive result, patients were not always linked to care in a timely manner because of reluctance to receiving care or delays in returning to care centres upon clinical deterioration. Countries often lacked multiple components of the range of therapeutics advised in WHO guidelines: notably so for oral antivirals designed for high-risk mild patients. Severely ill patients mostly received corticosteroids and, in higher-resourced settings, tocilizumab.

Conclusions

Testing does not always prompt enhanced care, due to reluctance on the part of patients and limited therapeutic availability within clinical settings. Any analysis of the impact or cost-effectiveness of testing policies post pandemic needs to either consider investment in optimal treatment pathways or constrain estimates of benefits based on actual practice.
Body mass index and cancer risk among adults with and without cardiometabolic diseases: evidence from the EPIC and UK Biobank prospective cohort studies
Authors: Fontvieille Emma , Viallon Vivian , Recalde Martina , Cordova Reynalda , Jansana Anna , Peruchet-Noray Laia , Lennon Hannah , Heath Alicia K. , Aune Dagfinn , Christakoudi Sofia , Katzke Verena , Kaaks Rudolf , Inan-Eroglu Elif , Schulze Matthias B. , Mellemkjær Lene , Tjønneland Anne , Overvad Kim , Farràs Marta , Petrova Dafina , Amiano Pilar , Chirlaque María-Dolores , Moreno-Iribas Conchi , Tin Tin Sandar , Masala Giovanna , Sieri Sabina , Ricceri Fulvio , Panico Salvatore , May Anne M. , Monninkhof Evelyn M. , Weiderpass Elisabete , Gunter Marc J. , Ferrari Pietro , Freisling Heinz
Published: November 2023

Background

Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer.

Methods

This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI).

Results

In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m2) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m2) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09–0.47).

Conclusions

Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.
Integrated single-cell and bulk RNA sequencing analysis identifies a neoadjuvant chemotherapy-related gene signature for predicting survival and therapy in breast cancer
Authors: Zhang Xiaojun , Feng Ran , Guo Junbin , Pan Lihui , Yao Yarong , Gao Jinnan
Published: November 2023

Neoadjuvant chemotherapy (NAC) is a well-established treatment modality for locally advanced breast cancer (BC). However, it can also result in severe toxicities while controlling tumors. Therefore, reliable predictive biomarkers are urgently needed to objectively and accurately predict NAC response. In this study, we integrated single-cell and bulk RNA-seq data to identify nine genes associated with the prognostic response to NAC: NDRG1, CXCL14, HOXB2, NAT1, EVL, FBP1, MAGED2, AR and CIRBP. Furthermore, we constructed a prognostic risk model specifically linked to NAC. The clinical independence and generalizability of this model were effectively demonstrated. Additionally, we explore the underlying cancer hallmarks and microenvironment features of this NAC response-related risk score, and further assess the potential impact of risk score on drug response. In summary, our study constructed and validated a nine-gene signature associated with NAC prognosis, which was accomplished through the integration of single-cell and bulk RNA data. The results of our study are of crucial significance in the prediction of the efficacy of NAC in BC, and may have implications for the clinical management of this disease.
CDK5: an oncogene or an anti-oncogene: location location location
Authors: Nikhil Kumar , Shah Kavita
Published: November 2023

Recent studies have uncovered various physiological functions of CDK5 in many nonneuronal tissues. Upregulation of CDK5 and/or its activator p35 in neurons promotes healthy neuronal functions, but their overexpression in nonneuronal tissues is causally linked to cancer of many origins. This review focuses on the molecular mechanisms by which CDK5 recruits diverse tissue-specific substrates to elicit distinct phenotypes in sixteen different human cancers. The emerging theme suggests that CDK5’s role as an oncogene or anti-oncogene depends upon its subcellular localization. CDK5 mostly acts as an oncogene, but in gastric cancer, it is a tumor suppressor due to its unique nuclear localization. This indicates that CDK5’s access to certain nuclear substrates converts it into an anti-oncogenic kinase. While acting as a bonafide oncogene, CDK5 also activates a few cancer-suppressive pathways in some cancers, presumably due to the mislocalization of nuclear substrates in the cytoplasm. Therefore, directing CDK5 to the nucleus or exporting tumor-suppressive nuclear substrates to the cytoplasm may be promising approaches to combat CDK5-induced oncogenicity, analogous to neurotoxicity triggered by nuclear CDK5. Furthermore, while p35 overexpression is oncogenic, hyperactivation of CDK5 by inducing p25 formation results in apoptosis, which could be exploited to selectively kill cancer cells by dialing up CDK5 activity, instead of inhibiting it. CDK5 thus acts as a molecular rheostat, with different activity levels eliciting distinct functional outcomes. Finally, as CDK5’s role is defined by its substrates, targeting them individually or in conjunction with CDK5 should create potentially valuable new clinical opportunities.
Implications of TDP-43 in non-neuronal systems
Authors: Ke Hao , Liu Kang , Jiao Baowei , Zhao Limin
Published: November 2023

TAR DNA-binding protein 43 (TDP-43) is a versatile RNA/DNA-binding protein with multifaceted processes. While TDP-43 has been extensively studied in the context of degenerative diseases, recent evidence has also highlighted its crucial involvement in diverse life processes beyond neurodegeneration. Here, we mainly reviewed the function of TDP-43 in non-neurodegenerative physiological and pathological processes, including spermatogenesis, embryonic development, mammary gland development, tumor formation, and viral infection, highlighting its importance as a key regulatory factor for the maintenance of normal functions throughout life. TDP-43 exhibits diverse and sometimes opposite functionality across different cell types through various mechanisms, and its roles can shift at distinct stages within the same biological system. Consequently, TDP-43 operates in both a context-dependent and a stage-specific manner in response to a variety of internal and external stimuli.