bluuebunny/crossref_metadata_2025 huggingface dataset:
Axonal self-sorting without target guidance in
Drosophila
visual map formation
Authors: Agi Egemen , Reifenstein Eric T. , Wit Charlotte , Schneider Teresa , Kauer Monika , Kehribar Melinda , Kulkarni Abhishek , von Kleist Max , Hiesinger P. Robin
Published: March 2024

The idea of guidance toward a target is central to axon pathfinding and brain wiring in general. In this work, we show how several thousand axonal growth cones self-pattern without target-dependent guidance during neural superposition wiring in
Drosophila
. Ablation of all target lamina neurons or loss of target adhesion prevents the stabilization but not the development of the pattern. Intravital imaging at the spatiotemporal resolution of growth cone dynamics in intact pupae and data-driven dynamics simulations reveal a mechanism by which >30,000 filopodia do not explore potential targets, but instead simultaneously generate and navigate a dynamic filopodial meshwork that steers growth directions. Hence, a guidance mechanism can emerge from the interactions of the axons being guided, suggesting self-organization as a more general feature of brain wiring.
Adaptive optical imaging with entangled photons
Authors: Cameron Patrick , Courme Baptiste , Vernière Chloé , Pandya Raj , Faccio Daniele , Defienne Hugo
Published: March 2024

Adaptive optics (AO) has revolutionized imaging in fields from astronomy to microscopy by correcting optical aberrations. In label-free microscopes, however, conventional AO faces limitations because of the absence of a guide star and the need to select an optimization metric specific to the sample and imaging process. Here, we propose an AO approach leveraging correlations between entangled photons to directly correct the point spread function. This guide star–free method is independent of the specimen and imaging modality. We demonstrate the imaging of biological samples in the presence of aberrations using a bright-field imaging setup operating with a source of spatially entangled photon pairs. Our approach performs better than conventional AO in correcting specific aberrations, particularly those involving substantial defocus. Our work improves AO for label-free microscopy and could play a major role in the development of quantum microscopes.
Enhancing rice panicle branching and grain yield through tissue-specific brassinosteroid inhibition
Authors: Zhang Xiaoxing , Meng Wenjing , Liu Dapu , Pan Dezhuo , Yang Yanzhao , Chen Zhuo , Ma Xiaoding , Yin Wenchao , Niu Mei , Dong Nana , Liu Jihong , Shen Weifeng , Liu Yuqin , Lu Zefu , Chu Chengcai , Qian Qian , Zhao Mingfu , Tong Hongning
Published: March 2024

Crop yield potential is constrained by the inherent trade-offs among traits such as between grain size and number. Brassinosteroids (BRs) promote grain size, yet their role in regulating grain number is unclear. By deciphering the clustered-spikelet rice germplasm, we show that activation of the BR catabolic gene
BRASSINOSTEROID-DEFICIENT DWARF3
(
BRD3
) markedly increases grain number. We establish a molecular pathway in which the BR signaling inhibitor GSK3/SHAGGY-LIKE KINASE2 phosphorylates and stabilizes OsMADS1 transcriptional factor, which targets
TERMINAL FLOWER1
-like gene
RICE CENTRORADIALIS2
. The tissue-specific activation of
BRD3
in the secondary branch meristems enhances panicle branching, minimizing negative effects on grain size, and improves grain yield. Our study showcases the power of tissue-specific hormonal manipulation in dismantling the trade-offs among various traits and thus unleashing crop yield potential in rice.
Prophage proteins alter long noncoding RNA and DNA of developing sperm to induce a paternal-effect lethality
Authors: Kaur Rupinder , McGarry Angelina , Shropshire J. Dylan , Leigh Brittany A. , Bordenstein Seth R.
Published: March 2024

The extent to which prophage proteins interact with eukaryotic macromolecules is largely unknown. In this work, we show that cytoplasmic incompatibility factor A (CifA) and B (CifB) proteins, encoded by prophage WO of the endosymbiont
Wolbachia,
alter long noncoding RNA (lncRNA) and DNA during
Drosophila
sperm development to establish a paternal-effect embryonic lethality known as cytoplasmic incompatibility (CI). CifA is a ribonuclease (RNase) that depletes a spermatocyte lncRNA important for the histone-to-protamine transition of spermiogenesis. Both CifA and CifB are deoxyribonucleases (DNases) that elevate DNA damage in late spermiogenesis. lncRNA knockdown enhances CI, and mutagenesis links lncRNA depletion and subsequent sperm chromatin integrity changes to embryonic DNA damage and CI. Hence, prophage proteins interact with eukaryotic macromolecules during gametogenesis to create a symbiosis that is fundamental to insect evolution and vector control.
Build networked resilience across cities
Authors: Bai Xuemei
Published: March 2024

There is an increasing need for the world to be prepared for a myriad of shocks and hazards. Many parts of the world are already experiencing climate change–related extreme weather events such as heatwaves, floods, and wildfires, which are projected to worsen in both intensity and frequency. The World Health Organization (WHO) also warns of “
Disease X
”—a term that includes both known and unknown infectious diseases capable of posing considerable global public health risks.
Histone acetyltransferase Sas3 contributes to fungal development, cell wall integrity, and virulence in
Aspergillus fumigatus
Authors: Wang Yamei , Fan Jialu , Zhou Zhengyu , Goldman Gustavo H. , Lu Ling , Zhang Yuanwei
Published: March 2024

Histone acetyltransferase (HAT)-mediated epigenetic modification is essential for diverse cellular processes in eukaryotes. However, the functions of HATs in the human pathogen
Aspergillus fumigatus
remain poorly understood. In this study, we characterized the functions of
M
OZ,
Y
bf2/
S
as3, Sas2, and
T
ip60 (MYST)-family histone acetyltransferase something about silencing (Sas3) in
A. fumigatus
. Phenotypic analysis revealed that loss of Sas3 results in significant impairments in colony growth, conidiation, and virulence in the
Galleria mellonella
model. Subcellular localization and Western blot analysis demonstrated that Sas3 localizes to nuclei and is capable of acetylating lysine 9 and 14 of histone H3
in vivo
. Importantly, we found that Sas3 is critical for the cell wall integrity (CWI) pathway in
A. fumigatus
as evidenced by hypersensitivity to cell wall-perturbing agents, altered cell wall thickness, and abnormal phosphorylation levels of CWI protein kinase MpkA. Furthermore, site-directed mutagenesis studies revealed that the conserved glycine residues G641 and G643 and glutamate residue E664 are crucial for the acetylation activity of Sas3. Unexpectedly, only triple mutations of Sas3 (G641A/G643A/E664A) displayed defective phenotypes similar to the Δ
sas3
mutant, while double or single mutations did not. This result implies that the role of Sas3 may extend beyond histone acetylation. Collectively, our findings demonstrate that MYST-family HAT Sas3 plays an important role in the fungal development, virulence, and cell wall integrity in
A. fumigatus
.

IMPORTANCE

Epigenetic modification governed by HATs is indispensable for various cellular processes in eukaryotes. Nonetheless, the precise functions of HATs in the human pathogen
Aspergillus fumigatus
remain elusive. In this study, we unveil the roles of MYST-family HAT Sas3 in colony growth, conidiation, virulence, and cell wall stress response in
A. fumigatus
. Particularly, our findings demonstrate that Sas3 can function through mechanisms unrelated to histone acetylation, as evidenced by site-directed mutagenesis experiments. Overall, this study broadens our understanding of the regulatory mechanism of HATs in fungal pathogens.
Histone H2A variant H2A.B is enriched in transcriptionally active and replicating HSV-1 lytic chromatin
Authors: Flores Cortes Esteban , Saddoris Sarah M. , Owens Arryn K. , Gibeault Rebecca , Depledge Daniel P. , Schang Luis M.
Published: March 2024

Herpes simplex virus 1 (HSV-1) transcription is restricted in latently infected neurons and the genomes are in mostly silenced chromatin, whereas all viral genes are transcribed in lytically infected cells, in which the genomes are dynamically chromatinized. Epigenetic regulation modulates HSV-1 transcription during lytic, latent, and reactivating infections but the precise mechanisms are not fully defined. Nucleosomes are dynamic: they slide, breathe, assemble, and disassemble. We and others have proposed that the most dynamic HSV-1 chromatin is transcriptionally competent, whereas the least dynamic is silenced. However, the mechanisms yielding the unusually dynamic viral chromatin remain unknown. Histone variants affect nucleosome dynamics. The dynamics of H2A, H2A.X, and macroH2A were enhanced in infected cells, whereas those of H2A.B were uniquely decreased. We constructed stably transduced cells expressing tagged histone H2A, H2A.B, macroH2A, or H2B, which assembles the H2A/H2B nucleosome dimers with all H2A variants. All H2A variants, as well as ectopic and endogenous H2B were assembled into HSV-1 chromatin evenly throughout the genome but canonical H2A was relatively depleted whereas H2A.B was enriched, particularly in the most dynamic viral chromatin. When viral transcription and DNA replication were restricted, H2A.B became as depleted from the viral chromatin through the entire genome as H2A. We propose that lytic HSV-1 nucleosomes are enriched in the dynamic variant H2A.B/H2B dimers to promote HSV-1 chromatin dynamics and transcriptional competency and conclude that the dynamics of HSV-1 chromatin are determined in part by the H2A variants.

IMPORTANCE

Herpes simplex virus 1 (HSV-1) transcription is epigenetically regulated during latent and lytic infections, and epigenetic inhibitors have been proposed as potential antiviral drugs to modulate latency and reactivation. However, the detailed epigenetic mechanisms of regulation of HSV-1 transcription have not been fully characterized and may differ from those regulating cellular transcription. Whereas lytic HSV-1 chromatin is unusually dynamic, latent silenced HSV-1 chromatin is not. The mechanisms resulting in the unique dynamics of the lytic chromatin remain unknown. Here we identify the enrichment of the highly dynamic histone 2A variant H2A in the most dynamic viral chromatin, which provides a mechanistic understanding of its unique dynamics. Future work to identify the mechanisms of enrichment in H2A.B on the viral chromatin may identify novel druggable epigenetic regulators that modulate HSV-1 latency and reactivation.
Emergence and dissemination of equine-like G3P[8] rotavirus A in Brazil between 2015 and 2021
Authors: Gutierrez Meylin Bautista , Arantes Ighor , Bello Gonzalo , Berto Lúcia Helena , Dutra Leonardo Hermes , Kato Rodrigo Bentes , Fumian Tulio Machado
Published: March 2024

Rotavirus A (RVA) is a major cause of acute gastroenteritis globally that is classically genotyped by its two immunodominant outer capsid proteins, VP7 (G-) and VP4 (P-). Recent evidence suggests that the reassortant equine-like G3P[8] strain played a substantial role in RVA transmission in Brazil since 2015. To understand its global emergence and dissemination in Brazilian territory, stool samples collected from 11 Brazilian states (
n
= 919) were genotyped by RT-qPCR and proceeded to sequence the VP7 gene (
n
= 102, 79 being newly generated) of the G3P[8] samples with pronounced viral loads. Our phylogenetic genotyping showed that G3P[8] became the dominant strain in Brazil between 2017 and 2020, with equine-like variants representing 75%–100% of VP7 samples in this period. A Bayesian discrete phylogeographic analysis strongly suggests that the equine-like G3P[8] strain originated in Asia during the early 2010s and subsequently spread to Europe, the Caribbean, and South America. Multiple introductions were detected in Brazil between 2014 and 2017, resulting in five national clusters. The reconstruction of the effective population size of the largest Brazilian cluster showed an expansion until 2017, followed by a plateau phase until 2019 and subsequent contraction. Our study also supports that most mutations fixed during equine-like G3P[8] evolution were synonymous, suggesting that adaptive evolution was not an important driving force during viral dissemination in humans, potentially increasing its susceptibility to acquired immunity. This research emphasizes the need for comprehensive rotavirus genomic surveillance that allows close monitoring of its ever-shifting composition and informs more effective public health policies.

IMPORTANCE

Our original article demonstrated the origin and spread in a short time of equine-like G3P[8] in Brazil and the world. Due to its segmented genome, it allows numerous mechanisms including genetic drift and reassortment contribute substantially to the genetic diversity of rotavirus. Although the effectiveness and increasing implementation of vaccination have not been questioned, a matter of concern is its impact on the emergence of escape mutants or even the spread of unusual strains of zoonotic transmission that could drive epidemic patterns worldwide. This research emphasizes the need for comprehensive rotavirus genomic surveillance, which could facilitate the formulation of public policies aimed at preventing and mitigating its transmission.
Bacillus halotolerans
SW207 alleviates enterotoxigenic
Escherichia coli
-induced inflammatory responses in weaned piglets by modulating the intestinal epithelial barrier, the TLR4/MyD88/NF-κB pathway, and intestinal microbiota
Authors: Li Minghan , Zhao Dongyu , Guo Jialin , Pan Tianxu , Niu Tianming , Jiang Yanqi , Shi Chunwei , Huang Haibin , Wang Nan , Zhang Di , Zhang Shumin , Wang Chunfeng , Yang Guilian
Published: March 2024

Enterotoxigenic
Escherichia coli
(ETEC) is one of the major pathogens contributing to piglet diarrhea, with significant implications for both piglet health and the economic aspects of the livestock industry. SW207 is an isolate of
Bacillus halotolerans
isolated from the cold- and disease-resistant Leixiang pigs in Northeastern China. We have discovered that SW207 can survive in the pig’s gastrointestinal fluid and under conditions of high bile salt concentration, displaying potent antagonistic activity against ETEC. In this study, we established a weaned piglet diarrhea model infected with ETEC to investigate the role of SW207 in preventing diarrhea and improving intestinal health. Results indicate that SW207 upregulates the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1, at both the transcriptional and translational levels. Furthermore, SW207 reduces serum endotoxin, D-lactic acid, and various oxidative stress markers while enhancing piglet mechanical barrier function. In terms of immune barrier, SW207 suppressed the activation of the TLR4/MyD88/NF-κB pathway, reducing the expression of various inflammatory factors and upregulating the expression of small intestine mucosal sIgA. Concerning the biological barrier, SW207 significantly reduces the content of
E. coli
in the intestines and promotes the abundance of beneficial bacteria, thereby mitigating the microbiota imbalance caused by ETEC. In summary, SW207 has the potential to prevent weaned piglet diarrhea caused by ETEC, alleviate intestinal inflammation and epithelial damage, and facilitate potential beneficial changes in the intestinal microbiota. This contributes to elucidating the potential mechanisms of host-microbe interactions in preventing pathogen infections.

IMPORTANCE

Enterotoxigenic
Escherichia coli
(ETEC) has consistently been one of the significant pathogens causing mortality in weaned piglets in pig farming. The industry has traditionally relied on antibiotic administration to control ETEC-induced diarrhea. However, the overuse of antibiotics has led to the emergence of drug-resistant zoonotic bacterial pathogens, posing a threat to public health. Therefore, there is an urgent need to identify alternatives to control pathogens and reduce antibiotic usage. In this study, we assessed the protective effect of a novel probiotic in a weaned piglet model infected with ETEC and analyzed its mechanisms both
in vivo
and
in vitro
. The study results provide theoretical support and reference for implementing interventions in the gut microbiota to alleviate early weaned piglet diarrhea and improve intestinal health.
Antifungal potential of lipopeptides produced by the
Bacillus siamensis
Sh420 strain against
Fusarium graminearum
Authors: Hussain Sarfaraz , Tai Bowen , Ali Maratab , Jahan Israt , Sakina Suha , Wang Gang , Zhang Xinlong , Yin Yixuan , Xing Fuguo
Published: March 2024

Biological control is a more sustainable and environmentally friendly alternative to chemical fungicides for controlling
Fusarium
spp. infestations. In this work,
Bacillus siamensis
Sh420 isolated from wheat rhizosphere showed a high antifungal activity against
Fusarium graminearum
as a secure substitute for fungicides. Sh420 was identified as
B. siamensis
using phenotypic evaluation and 16S rDNA gene sequence analysis. An
in vitro
antagonistic study showed that Sh420’s lipopeptide (LP) extract exhibited strong antifungal properties and effectively combated
F. graminearum
. Meanwhile, lipopeptides have the ability to decrease ergosterol content, which has an impact on the overall structure and stability of the plasma membrane. The PCR-based screening revealed the presence of antifungal LP biosynthetic genes in this strain’s genomic DNA. In the crude LP extract of Sh420, we were able to discover several LPs such as bacillomycin, iturins, fengycin, and surfactins using ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry. Microscopic investigations (fluorescent/transmission electron microscopy) revealed deformities and alterations in the morphology of the phytopathogen upon interaction with LPs. Sh420 LPs have been shown in grape tests to be effective against
F. graminearum
infection and to stimulate antioxidant activity in fruits by avoiding rust and gray lesions. The overall findings of this study highlight the potential of Sh420 lipopeptides as an effective biological control agent against
F. graminearum
infestations.

IMPORTANCE

This study addresses the potential of lipopeptide (LP) extracts obtained from the strain identified as
Bacillus siamensis
Sh420. This Sh420 isolate acts as a crucial player in providing a sustainable and environmentally friendly alternative to chemical fungicides for suppressing
Fusarium graminearum
phytopathogen. Moreover, these LPs can reduce ergosterol content in the phytopathogen influencing the overall structure and stability of its plasma membrane. PCR screening provided confirmation regarding the existence of genes responsible for biosynthesizing antifungal LPs in the genomic DNA of Sh420. Several antibiotic lipopeptide compounds were identified from this bacterial crude extract using ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry. Microscopic investigations revealed deformities and alterations in the morphology of
F. graminearum
upon interaction with LPs. Furthermore, studies on fruit demonstrated the efficacy of Sh420 LPs in mitigating
F. graminearum
infection and stimulating antioxidant activity in fruits, preventing rust and gray lesions.
Performance evaluation of the SMG HHV-6 Q Real-Time PCR Kit for quantitative detection and differentiation of human herpesvirus 6A and 6B
Authors: Kim Tae Yeul , Park Min-Seung , Yun Sun Ae , Kang Minhee , Kim Doo Ri , Shin Areum , Kim Hyun-Young , Jang Mi-Ae , Jang Ja-Hyun , Kwon Min-Jung , Huh Hee Jae , Kim Yae-Jean , Lee Nam Yong
Published: March 2024

The aim of this study was to compare the performance of the newly developed SMG HHV-6 Q Real-Time PCR Kit (SMG assay) with the RealStar HHV-6 PCR Kit (RealStar assay). The analytical sensitivity and specificity, linearity, and precision of the SMG assay were evaluated. The clinical performance of the SMG assay was assessed and compared with that of the RealStar assay using 207 clinical specimens (HHV-6A positive,
n
= 51; HHV-6B positive,
n
= 64; HHV-6A/B negative,
n
= 92). The limit of detection of the SMG assay was 2.92 log
10
copies/mL for HHV-6A DNA and 2.88 log
10
copies/mL for HHV-6B DNA. The linear range was determined to be 3.40–9.00 log
10
copies/mL for both viruses. Intra- and inter-assay variability were below 5% at concentrations ranging from 4 to 9 log
10
copies/mL. No cross-reactivity was observed with the 25 microorganisms included in the specificity panel. The clinical sensitivity and specificity of the SMG and RealStar assays compared to in-house polymerase chain reaction and sequencing were as follows: SMG assay, 98.0% and 100% for HHV-6A DNA, respectively, and 96.9% and 100% for HHV-6B DNA, respectively; RealStar assay, 98.0% and 100% for HHV-6A DNA, respectively, and 90.6% and 100% for HHV-6B DNA, respectively. The correlation coefficients between viral loads measured by the two assays were 0.948 and 0.975, with mean differences of 0.62 and 0.32 log
10
copies/mL for HHV-6A and HHV-6B DNA, respectively. These results demonstrate that the SMG assay is a sensitive and reliable tool for the quantitative detection and differentiation of HHV-6A and HHV-6B DNA.

IMPORTANCE

Quantitative real-time PCR (qPCR) that can distinguish between HHV-6A and HHV-6B DNA is recommended for diagnosis of active infection. The SMG HHV-6 Q Real-Time PCR Kit (SMG assay) is a newly developed qPCR assay that can differentiate between HHV-6A and HHV-6B DNA; however, little is known about its performance. In this study, we assessed the performance of the SMG assay and compared it with that of a commercially available qPCR assay, the RealStar HHV-6 PCR Kit (RealStar assay). The SMG assay demonstrated excellent analytical sensitivity and specificity, precision, and linearity. Furthermore, the viral loads measured by the SMG assay were highly correlated with those measured by the RealStar assay. Our results suggest that the SMG assay is a useful diagnostic tool for quantitative detection and differentiation of HHV-6A and HHV-6B DNA.
Solitary pleural fibroma causing IGF-2-mediated hypoglycaemia in a non-diabetic patient
Authors: Lachmann Emily , Bennett Benjamin , Ramli Rozana , Sharma Sonal
Published: March 2024

A patient without a diagnosis of diabetes mellitus presented to the hospital due to a fall and hypoglycaemia on admission. The patient was found to have recurrent nocturnal fasting hypoglycaemia. CT revealed a large lung mass consistent with a solitary pleural fibroma, a rare tumour associated with insulin-like growth factor 2 (IGF-2) production. This case is an important reminder that potential causes of hypoglycaemia should be considered in non-diabetic patients.
Atrial fibrillation-induced cardiomyopathy presenting with bilateral intermittent claudication associated with intracardiac thrombi
Authors: Inoue Ryoichi , Watanabe Hirotoshi , Horie Takahiro , Ono Koh
Published: March 2024

Systemic thromboembolism associated with atrial fibrillation (AF) is usually caused by thrombi in the left atrial appendage and acute onset. We experienced an unusual case of a woman in her 60s who presented to the outpatient district having bilateral intermittent claudication for more than 1 month, which turned out to be multiple thromboembolism from asymptomatic AF with tachycardia. She was also complicated with non-ischaemic dilated cardiomyopathy with reduced ejection fraction, consistent with arrhythmia-induced cardiomyopathy (AiCM), along with left atrial and left ventricular thrombi and thromboembolism in multiple organs. Rate control with beta-blockers was not effective. With the administration of amiodarone after adequate anticoagulation therapy, she returned to sinus rhythm, and the ejection fraction was restored. This case is instructive in that AiCM with AF can cause thrombosis in the left ventricle, and the patient may present with worsening intermittent claudication as a result of systemic embolism.
Severe skeletal dysplasia caused by a novel FLNB gene mutation
Authors: Madan Ichchha , Jackson Frank , Sahni Simran , Figueroa Reinaldo
Published: March 2024

A late adolescent primigravida was found to have a fetus with a cystic hygroma and significant shortening of the limbs on first-trimester ultrasound. She underwent chorionic villus sampling with normal microarray result. In the early second trimester, the fetus was found to have the absence of all four limbs and a thorough skeletal dysplasia workup was pursued, identifying a variant in the FLNB gene (c.62C>G). The patient underwent termination of pregnancy. The care of this patient was expedited by first-trimester sonographic evidence of limb abnormalities enabling timely clinical management.
Tracheal compression by brachiocephalic arterial trunk: a rare cause of failed endotracheal intubation
Authors: Noversa Rafaela , Gouveia Isabel , Pinto Carla
Published: March 2024

Encountering and managing an unanticipated difficult airway are among the many challenges faced by anaesthesiologists. Due to the intimate anatomical relationship between the thoracic vasculature and the trachea, an anatomical variation could potentially lead to airway compression. This clinical case report documents a failed intubation in an adult patient caused by undiagnosed extrinsic tracheal compression from the brachiocephalic arterial trunk, a rare condition. After a thorough investigation and diagnostic clarification, a safe anaesthetic plan following the predictable difficult airway guidelines was established to enable surgery. Anaesthesiologists should consider rare vascular causes as potential contributors to difficult airway scenarios, thereby enhancing their expertise.
Colonic epithelial hypoxia remains constant during the progression of diabetes in male UC Davis type 2 diabetes mellitus rats
Authors: Piccolo Brian D , Graham James L , Tabor-Simecka Leslie , Randolph Christopher E , Moody Becky , Robeson Michael S , Kang Ping , Fox Renee , Lan Renny , Pack Lindsay , Woford Noah , Yeruva Laxmi , LeRoith Tanya , Stanhope Kimber L , Havel Peter J
Published: March 2024

Introduction

Colonocyte oxidation of bacterial-derived butyrate has been reported to maintain synergistic obligate anaerobe populations by reducing colonocyte oxygen levels; however, it is not known whether this process is disrupted during the progression of type 2 diabetes. Our aim was to determine whether diabetes influences colonocyte oxygen levels in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model.

Research design and methods

Age-matched male UCD-T2DM rats (174±4 days) prior to the onset of diabetes (PD, n=15), within 1 month post-onset (RD, n=12), and 3 months post-onset (D3M, n=12) were included in this study. Rats were administered an intraperitoneal injection of pimonidazole (60 mg/kg body weight) 1 hour prior to euthanasia and tissue collection to estimate colonic oxygen levels. Colon tissue was fixed in 10% formalin, embedded in paraffin, and processed for immunohistochemical detection of pimonidazole. The colonic microbiome was assessed by 16S gene rRNA amplicon sequencing and content of short-chain fatty acids was measured by liquid chromatography-mass spectrometry.

Results

HbA1c % increased linearly across the PD (5.9±0.1), RD (7.6±0.4), and D3M (11.5±0.6) groups, confirming the progression of diabetes in this cohort. D3M rats had a 2.5% increase in known facultative anaerobes,Escherichia–Shigella, andStreptococcus(false discovery rate <0.05) genera in colon contents. The intensity of pimonidazole staining of colonic epithelia did not differ across groups (p=0.37). Colon content concentrations of acetate and propionate also did not differ across UCD-T2DM groups; however, colonic butyric acid levels were higher in D3M rats relative to PD rats (p<0.01).

Conclusions

The advancement of diabetes in UCD-T2DM rats was associated with an increase in facultative anaerobes; however, this was not explained by changes in colonocyte oxygen levels. The mechanisms underlying shifts in gut microbe populations associated with the progression of diabetes in the UCD-T2DM rat model remain to be identified.
Prevalence and population characteristics associated with frailty in a rural low socioeconomic area in Denmark: the Lolland-Falster Health Study
Authors: Christensen Mathilde Glud , Jacobsen Katja Kemp , Nilsson Charlotte , Jepsen Randi , Thygesen Lau , Suetta Charlotte , Holm Ellen Astrid
Published: March 2024

Background

Frailty is a major geriatric syndrome that predicts increased vulnerability to minor stressor events and adverse outcomes such as falls, fractures, disability and death. The prevalence of frailty among individuals above the age of 65 varies widely with an overall weighted prevalence of 10.7%.

Objectives

The purpose of this study was to examine the prevalence of prefrailty and frailty in community-dwelling older adults from the regions of Lolland-Falster, which is one of the most socioeconomically disadvantaged areas of Denmark with lower income and lower life expectancy compared with the general Danish population. Moreover, the objective was to find selected individual characteristics associated with frailty.

Design

An observational, cross-sectional registry-based population study with data from the regions of Lolland-Falster collected between February 2016 and February 2020.

Results

The study included 19 000 individuals. There were 10 154 above the age of 50 included for analysis. Prevalence of frailty in the age group of 50–64 years was 4.7% and 8.7% in the age group of 65 years and above.

The study demonstrates associations between frailty and high age, female gender, low education level, low income, smoking, living alone, frequency of seeing one’s children and getting help when needed. These associations are comparable with findings from other studies.

Conclusion

The syndrome of frailty consists of not only physiological and medical issues but also education, life conditions such as living alone and living in poverty and how you evaluate your own health.
Prevalence and determinants of not testing for HIV among young adult women in Papua New Guinea: findings from the Demographic and Health Survey, 2016–2018
Authors: Maviso McKenzie , Kalembo Fatch Welcome
Published: March 2024

Objective

The aim of this study was to assess the prevalence of not testing for HIV and its determinants among young adult women aged 15–29 years in Papua New Guinea (PNG).

Design and setting

The study used secondary data from the 2016 to 2018 PNG Demographic and Health Survey (PNGDHS), a nationally representative cross-sectional survey that used a two-stage stratified sampling.

Participants

A total weighed sample of 5164 young adult women aged 15–29 years were included in the analysis.

Primary outcome measure

Ever been tested for HIV was the primary outcome of the study. All analyses were adjusted using survey weights to account for unequal sampling probabilities.

Results

The prevalence of not testing for HIV was 58.8% (95% CI: 57.4% to 60.1%). The mean age was 21.65 years (SD = 4.23). Of the women who were not tested for HIV, the majority were never married (79.4%), without formal education (63%), not working (60.2%), and from rural areas (62.9%). In the multivariable analysis, those who were never married (adjusted OR (AOR) 4.9, 95% CI 3.6 to 6.6), had poor wealth index (AOR 1.8, 95% CI 1.3 to 2.5), were from rural areas (AOR 2.0, 95% CI 1.5 to 2.6), were from the Momase region (AOR 1.3, 95% CI 1.0 to 1.7), did not read newspapers or magazines (AOR 1.7, 95% CI 1.3 to 2.1), did not listen to the radio (AOR 1.5, 95% CI 1.1 to 2.0), experienced early sexual debut (AOR 1.5, 95% CI 1.1 to 1.9), had one sexual partner (AOR 1.5, 95% CI 1.2 to 2.0) and reported no sexually transmitted infection (STI) in the past 12 months (AOR 1.8, 95% CI 1.1 to 3.1) had higher odds of not testing for HIV.

Conclusions

Our study found a very high unmet need for HIV testing among young adult women in PNG. Health promotion programmes should be designed to increase HIV knowledge and access to testing services, particularly targeting young women who are disadvantaged and from rural areas.
Effectiveness, cost-effectiveness and return on investment of individual placement and support compared with traditional vocational rehabilitation for individuals with severe mental illness in the Netherlands: a nationwide implementation study
Authors: Vukadin Miljana , Zwinkels Wim , Schaafsma Frederieke , Spijkerman Marcel , de Graaf-Zijl Marloes , Delespaul Philippe , van Weeghel Jaap , van Dongen Johanna Maria , Anema Johannes
Published: March 2024

Objectives

To assess the effectiveness, cost-effectiveness and return on investment of individual placement and support (IPS) implemented through a reimbursement strategy on a nationwide scale compared with traditional vocational rehabilitation (TVR) regarding sustainable participation in competitive employment in individuals with severe mental illness receiving sickness or disability benefits.

Methods

An observational study was conducted using administrative data regarding all Dutch individuals receiving sickness or disability benefits in the period 2012–2019. Exact matching and difference-in-difference fixed-effect estimations were performed to handle the non-randomised nature of the data. The matched sample consisted of 863 IPS and 16 466 TVR participants. The primary effect measure was the proportion of individuals having worked for at least 48 hours per month in competitive employment (ie, for 12 hours or more per week); the proportion of individuals having worked in competitive employment for at least 1 hour per month was also evaluated. Cost-effectiveness and return on investment were assessed from the societal perspective (intervention, sickness/disability benefit and healthcare costs) and payer perspective (sickness/disability benefit costs).

Results

IPS led to a statistically significant higher probability of being competitively employed for at least 12 hours per week of 3.7% points (95% CI 0.8% to 6.7%) to 7.5% points (95% CI 3.8% to 11.3%) and of being competitively employed for at least 1 hour per month of 4.7% points (95% CI 1.6% to 7.7%) to 8.9% points (95% CI 5.2 to 12.6%) from 6 to 36 months after starting the intervention. From the societal and payer perspective, IPS was—on average—less costly and more effective than TVR and return-on-investment estimates showed that IPS was—on average—cost saving (eg, societal perspective: ∆C: −364 (95% CI −3977 to 3249); ∆E: 0.104 (95% CI 0.046 to 0.164); benefit–cost ratio: 2.1 (95% CI −14.8 to 19.1)), but the uncertainty surrounding these estimates was large.

Conclusions

IPS implemented through a reimbursement strategy on a nationwide scale is more effective and potentially cost-effective than TVR in people with severe mental illness receiving sickness or disability benefits. Based on these results, the implementation of IPS by a wide scale reimbursement strategy could be promoted to enhance sustainable participation in competitive employment in these individuals. Future economic evaluations should strive for a more robust sample size and a long follow-up period.
Management of severe ME/CFS in children and young people in the UK: a British Paediatric Surveillance Unit study
Authors: Royston Alexander Peter , Burge Sarah , Idini Ilaria , Brigden Amberly , Pike Katharine Claire
Published: March 2024

Objective

Severe myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) in children and young people (CYP) is a little-understood condition which significantly impacts education, development and quality of life. We used data from a population-wide surveillance study to explore the screening investigation, referral and management of suspected cases of paediatric severe ME/CFS.

Methods

A British Paediatric Surveillance Unit (BPSU) study reported cases of CYP with suspected severe ME/CFS between February 2018 and February 2019. Paediatricians reporting cases to BPSU and allied healthcare professionals in two large specialist paediatric ME/CFS centres were invited to complete questionnaires for CYP meeting the surveillance case definition. The study focused primarily on CYP with confirmed severe ME/CFS and the extent to which their care met NICE (The National Institute for Health and Care Excellence) recommendations but also considered separately those with probable or possible severe ME/CFS.

Results

This study includes a total of 92 CYP with suspected severe ME/CFS; 33 meeting criteria for severe ME/CFS and an additional 59 classified as probable or possible severe ME/CFS. For 16 possible cases, incomplete investigation to exclude alternative diagnoses prevented confirmation of a severe ME/CFS diagnosis. Only 21 of 33 (64%) confirmed severe ME/CFS cases had been referred to specialist services. The management provided varied considerably between patients and four received nothing at all. Of the management provided, the most frequent approaches were medication (67%), activity management (61%) and physiotherapy (61%). Domiciliary assessments and support, and social services referrals were received by 12% and 6% of confirmed severe cases. Similar proportions of management approaches were seen in probable/possible severe ME/CFS.

Conclusion

Full investigation is frequently incomplete in CYP with suspected severe ME/CFS and recommendations for referral and management are poorly implemented, in particular the needs of CYP who are unable to leave their home might be poorly met.
Timing of CHolecystectomy In Severe PAncreatitis (CHISPA): study protocol for a randomized controlled trial
Authors: Ramírez-Giraldo Camilo , Conde Monroy Danny , Daza Vergara José Alejandro , Isaza-Restrepo Andrés , Van-Londoño Isabella , Trujillo-Guerrero Luisa
Published: March 2024

Acute pancreatitis is the recurrent reason for gastrointestinal admission in a clinical urgent setting, it happens secondary to a wide array of pathologies out of which biliary disease stands as one of the most frequent causes for its presentation. Approximately 20% of pancreatitis are of moderate or severe severity. Currently, there is not a clear recommendation on timing for cholecystectomy, either early or delayed.

CHISPA is a randomized controlled, parallel-group, superior clinical trial. An intention-to-treat analysis will be performed. It seeks to evaluate differences between patients taken to early cholecystectomy during hospital admission (72 hours after randomization) versus delayed cholecystectomy (30±5 days after randomization). The primary endpoint is major complications associated with laparoscopic cholecystectomy defined as a Clavien-Dindo score of over III/V during the first 90 days after the procedure. Secondary endpoints include recurrence of biliary disease, minor complications (Clavien-Dindo score below III/V), days of postoperative hospital stay, and length of stay in an intensive therapy unit postoperatively (if it applies).

The CHISPA trial has been designed to demonstrate that delayed laparoscopic cholecystectomy reduces the rate of complications associated to an episode of severe biliary pancreatitis compared to early laparoscopic cholecystectomy.Trial registration number:NCT06113419.
Patient-perceived progression in multiple system atrophy: natural history of quality of life
Authors: Saulnier Tiphaine , Fabbri Margherita , Le Goff Mélanie , Helmer Catherine , Pavy-Le Traon Anne , Meissner Wassilios G. , Rascol Olivier , Proust-Lima Cecile , Foubert-Samier Alexandra
Published: March 2024

Background

Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy.

Methods

We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. A four-step strategy (1) determined the subdimensions of Hr-QoL, (2) modelled the subdimension trajectories over time, (3) mapped item impairments with disease stages and (4) identified most informative items.

Results

Four dimensions were identified. In addition to the original motor, non-motor and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the non-motor and emotional aspects were already impaired at cohort entry and deteriorated slowly over the disease course. Impairments were associated with sex, diagnosis subtype and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items.

Conclusion

The multidimensional Hr-QoL deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL over time using the four-step strategy can provide perspectives on neurodegenerative diseases’ management to ultimately deliver better support focused on the patient’s perspective.
Hepatic encephalopathy: a neurologist’s perspective
Authors: Needham Edward , Webb Gwilym
Published: March 2024

Liver disease is increasingly common, estimated to affect over 25% of the world’s population. Failure of the liver to maintain a normal metabolic milieu leads to impaired brain function (hepatic encephalopathy), and conditions that cause liver disease can themselves predispose to neurological disease. As neurologists’ involvement with the acute take increases, it is important that we are familiar with the neurological complications of liver disease, their investigation and management, and to know which other neurological diseases occur in this patient population. In this article, we review the causes, presentation and treatment of hepatic encephalopathy, and discuss important differential diagnoses in patients with liver disease who present with neurological disturbance.
Dopa-responsive dystonia and paroxysmal dystonic attacks associated withATP1A3gene variant
Authors: Soares Míriam Carvalho , Parmera Jacy Bezerra , Bezerra Marcos Eugênio Ramalho , Cury Rubens Gisbert
Published: March 2024

An 18-year-old man had episodes of severe generalised dystonia, from aged 7 months and becoming progressively more frequent. He also had gradually developed interictal limb dystonia. He was initially diagnosed with paroxysmal kinesigenic dyskinesia but he did not improve with several medications. A levodopa trial led to levodopa-induced dyskinetic movements. However, a lower titration of 25 mg of levodopa two times per day substantially improved his motor features and quality of life. Laboratory investigations and MR scans of the brain were unremarkable. Whole-exome sequencing identified a pathogenic variant in theATP1A3gene. TheATP1A3-spectrum disorders include non-classical phenotypes such as paroxysmal dystonic attacks. A response to dopamine response is unusual in these disorders. This case highlights the importance of levodopa trials in early-onset dystonia cases.
Deprescribing in older patients with advanced cancer referred to palliative care
Authors: Fernández-Fradejas Jorge , Martínez-Barros Hilario , Rexach-Cano Lourdes , Álvarez-Díaz Ana María , Delgado-Silveira Eva
Published: March 2024

Objectives

This study aimed to explore the prevalence of potentially inappropriate medications (PIMs) in a cohort of older adults with advanced cancer referred to palliative care. Secondary objectives were to describe the categories of identified PIMs and assess risk factors associated with their presence in this population.

Methods

This retrospective, observational study evaluated patients with advanced cancer admitted to a tertiary university hospital in Madrid, Spain and referred to palliative care between 1 January 2020 and 30 June 2020. Demographic, clinical, and pharmacotherapeutic data were obtained from the electronic medical records and regional databases. PIMs were assessed using the Screening Tool of Older Persons Prescriptions in Frail adults (STOPPFrail) criteria, V1.

Results

Among 123 patients (median age 80 years (IQR 73.5–87), 64.2% male), 74% presented at least one PIM according to the STOPPFrail criteria. The most common categories of inappropriate medications were lipid-lowering therapies, proton pump inhibitors, calcium supplements, and oral antidiabetics. The number of chronic comedications was significantly associated with PIM presence.

Conclusions

Our study found a high prevalence of PIM among a cohort of older adults with advanced cancer and short life expectancy. This underlines the need for a comprehensive medication review to optimise pharmacotherapy in this population.
Analytical solution to non-isothermal pore-pressure evolution in hydrating minefill
Authors: Lu Gongda , Selvadurai A.P.S. , Meguid Mohamed A.
Published: March 2024

Anomalous rises in minefill pressure during deposition shutdown have been increasingly reported in recent field investigations, raising growing concerns over contemporary underground tailings disposal. While constrained backfill expansion during hydration-heat release has been invoked to rationalize such perplexing observations, a benchmark for understanding the complex minefill response to thermal loading is still lacking. A novel analytical procedure is thus proposed in this study to characterize the non-isothermal evolution of pore pressure in cemented backfill hydrating in undrained adiabatic settings. By constructing a suitable variable system and selecting a proper auxiliary parameter for calculation, the proposed strategy based on canonical thermo-poroelasticity could enable straightforward implementation and has shown excellent compliance with computational and experimental results. The analytical results suggest that because higher temperature could stimulate cement hydration while enhancing simultaneously fluid expansivity, the pore pressure would decline initially with the rising curing temperature and then revert to increase after a critical threshold. Moreover, our investigation has shown that increasing binder usage is not always conducive to pore-pressure dissipation, as the payoff can be also hinged strongly upon the initial thermal condition. These findings could better elucidate the intriguing control of coupled multiphysics processes on backfill behaviour, and can also serve benchmarking purposes for sophisticated computational procedures.
What is habitat sensitivity? A quantitative definition relating resistance, resilience, and recoverability to environmental impacts
Authors: Dey Cody J. , Tuononen Erik I. , Hodgson Emma E. , Drake D. Andrew R. , Koops Marten A. , Chu Cindy
Published: March 2024

Habitat sensitivity is a consideration for decision-making under environmental laws in many jurisdictions. However, habitat sensitivity has been variously defined and there is no consistent approach to its quantification, which limits our understanding of how habitat sensitivity varies among systems and in response to different pressures. We review various definitions offered in the scientific literature and policy documents before suggesting a universal framework for habitat sensitivity as (i) a habitat trait that defines the ecological impacts from a given pressure, (ii) which is composed of three components (habitat resistance, resilience, and recoverability), and (iii) which is quantified by measuring the change and recovery in the state of key habitat attributes in response to pressures. In addition, we provide guidance toward a consistent approach to assessing habitat sensitivity, which includes the use of pressure benchmarks and standardized metrics of change in key habitat attributes to create a common scale for comparison among habitat attributes and pressures. Our framework and recommendations should help to standardize the way in which habitat sensitivity is defined and assessed, and could be integrated into decision-making processes to improve ecosystem management in different jurisdictions.