bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrocytes in functional recovery following central nervous system injuries
Authors: Alhadidi Qasim M. , Bahader Ghaith A. , Arvola Oiva , Kitchen Philip , Shah Zahoor A. , Salman Mootaz M.
Published: September 2023

Astrocytes are increasingly recognised as partaking in complex homeostatic mechanisms critical for regulating neuronal plasticity following central nervous system (CNS) insults. Ischaemic stroke and traumatic brain injury are associated with high rates of disability and mortality. Depending on the context and type of injury, reactive astrocytes respond with diverse morphological, proliferative and functional changes collectively known as astrogliosis, which results in both pathogenic and protective effects. There is a large body of research on the negative consequences of astrogliosis following brain injuries. There is also growing interest in how astrogliosis might in some contexts be protective and help to limit the spread of the injury. However, little is known about how astrocytes contribute to the chronic functional recovery phase following traumatic and ischaemic brain insults. In this review, we explore the protective functions of astrocytes in various aspects of secondary brain injury such as oedema, inflammation and blood–brain barrier dysfunction. We also discuss the current knowledge on astrocyte contribution to tissue regeneration, including angiogenesis, neurogenesis, synaptogenesis, dendrogenesis and axogenesis. Finally, we discuss diverse astrocyte‐related factors that, if selectively targeted, could form the basis of astrocyte‐targeted therapeutic strategies to better address currently untreatable CNS disorders.

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Fluid–Thermal–Structural Analysis of Partial Admission Axial Impulse Turbines With Liquid Jet Impingement Cooling
Authors: Wang Hanwei , Luo Kai , Zhi Ruoyang , Qin Kan
Published: September 2023

Increasing turbine inlet temperature is beneficial to enhance turbine performance. However, this also results in stringent cooling requirements. Unlike turbines in air cycle machines, the partial admission axial impulse turbines for underwater vehicles can utilize the abundant seawater as the cooling medium. In addition, the short blades cannot accommodate the complex cooling channels used in aero-engines, and the alternative way is jet impingement liquid cooling. This paper proposes a fluid–thermal–structural coupling method to investigate the performance of partial admission axial impulse turbines with water-cooling on the rotating wheel front surface. The volume of fluid multiphase model is employed to study the transient gas–liquid interaction, while the Lee model is chosen to model the heat and mass transfer during phase change. Also, a two-way weakly coupling method among fluid, thermal, and structure is utilized to account for fluid–structure interaction. The results show that the temperature distribution at the turbine wheel drops significantly with the jet impingement liquid cooling. The turbine efficiency is also reduced by 3.38% due to the mixing of cooling medium and gas. From stress analysis, the use of water-cooling can minimize turbine damage and ensure stable turbine operation. This study provides insight into the cooling method for partial admission axial impulse turbines for the underwater vehicle.
CO Laser Absorption Measurements During Syngas Combustion at High Pressure
Authors: Cooper Sean P. , Nativel Damien , Mathieu Olivier , Fikri Mustapha , Petersen Eric L. , Schulz Christof
Published: September 2023

Syngas is a desirable fuel for combustion in the Allam-Fetvedt cycle, which involves combustion under supercritical-CO2 conditions. While some work has been conducted in collecting ignition delay times (IDT) at the extreme pressures required by these systems, significant model deficiencies remain. Additionally, considerable barriers in terms of nonideal gas dynamic effects have been shown for these experiments in shock tubes. Further investigation into the fundamental combustion kinetics of H2/CO/CO2 mixtures is required. Time-resolved speciation measurements for target species have been shown to better aid in improving the understanding of underlying chemical kinetics than global ignition delay time measurements. Therefore, laser absorption measurements of CO were measured behind reflected shock waves during combustion of syngas at 5 and 10 bar and temperatures between 1080 and 2100 K. The mixtures investigated utilized H2-to-CO ratios of 1:1 and 1:4, respectively, each at stoichiometric conditions, allowing for discussions of the effect of initial fuel composition. A ratio of fuel to CO2 of 1:2 was also utilized to represent commercially available syngas. The mixtures were diluted in helium and argon (20% He, 76.5% Ar) to minimize thermal effects and to expedite CO thermal relaxation during the experiment. The resulting CO time histories were then compared to modern chemical kinetics mechanisms, and disagreement is seen for this system, which is assumed to be fairly well known. This study elucidates particular chemistry that needs improvement in moving toward a better understanding of syngas combustion at elevated pressures.
Emergence of the obesity epidemic preceding the presumed obesogenic transformation of the society
Authors: Pedersen Mads Møller , Ekstrøm Claus Thorn , Sørensen Thorkild I.A.
Published: September 2023

The obesity epidemic, evolving in many countries since the 1970s, has been attributed to the widespread contemporary so-called obesogenic transformation of the societies, but what preceded the epidemic? Using quantile regression, we studied the trends by year of birth in the percentile distribution of body mass index (BMI = weight/height
2
) of 320,962 Danish school children, born from 1930 to 1976, and of 205,153 Danish young conscripts, born from 1939 to 1959. The overall trend of the percentiles of the BMI distributions were found to be linear across the years of birth. While the percentiles below the 75th were almost stable, those above showed a steadily steeper rise the more extreme the percentile among both school children and young men is. These changes, indicating the emergence of the obesity epidemic, preceded the presumed obesogenic transformation of the society by several decades and imply that other, so far unknown, factors have been involved.
Wittig/B─H insertion reaction: A unique access to trisubstituted
Z
-alkenes
Authors: Guo Feng-Kai , Lu Yi-Lin , Huang Ming-Yao , Yang Ji-Min , Guo Jia-Lei , Wan Zi-Yi , Zhu Shou-Fei
Published: September 2023

The Wittig reaction, which is one of the most effective methods for synthesizing alkenes from carbonyl compounds, generally gives thermodynamically stable
E
-alkenes, and synthesis of trisubstituted
Z
-alkenes from ketones presents notable challenges. Here, we report what we refer to as Wittig/B─H insertion reactions, which innovatively combine a Wittig reaction with carbene insertion into a B─H bond and constitute a promising method for the synthesis of thermodynamically unstable trisubstituted
Z
-boryl alkenes. Combined with the easy transformations of boryl group, this methodology provides efficient access to a variety of previously unavailable trisubstituted
Z
-alkenes and thus provides a platform for discovery of pharmaceuticals. The unique
Z-
selectivity of the reaction is determined by the maximum overlap of the orbitals between the B─H bond of the borane adduct and the alkylidene carbene intermediate in the transition state.
A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease
Authors: Waddell Scott H. , Yao Yuelin , Olaizola Paula , Walker Alexander , Jarman Edward J. , Gournopanos Konstantinos , Gradinaru Andreea , Christodoulou Ersi , Gautier Philippe , Boerrigter Melissa M. , Cadamuro Massimiliano , Fabris Luca , Drenth Joost PH , Kendall Timothy J. , Banales Jesus M. , Khamseh Ava , Mill Pleasantine , Boulter Luke
Published: September 2023

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia geneWdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor–β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.
Plasmodium falciparum
GCN5 plays a key role in regulating artemisinin resistance-related stress responses
Authors: Lucky Amuza Byaruhanga , Wang Chengqi , Shakri Ahmad Rushdi , Kalamuddin Mohammad , Chim-Ong Anongruk , Li Xiaolian , Miao Jun
Published: September 2023

Plasmodium falciparum
causes the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5’s function in stress responses in
P. falciparum
. The protein level of PfGCN5 was substantially induced under three stress conditions [heat shock, low glucose starvation, and dihydroartemisinin, the active metabolite of artemisinin (ART)]. With a TetR-DOZI conditional knockdown (KD) system, we successfully down-regulated PfGCN5 to ~50% and found that KD parasites became more sensitive to all three stress conditions. Transcriptomic analysis via RNA-seq identified ~1,000 up- and down-regulated genes in the wild-type (WT) and KD parasites under these stress conditions. Importantly, DHA induced transcriptional alteration of many genes involved in many aspects of stress responses, which were heavily shared among the altered genes under heat shock and low glucose conditions, including ART-resistance-related genes such as
K13
and
coronin
. Based on the expression pattern between WT and KD parasites under three stress conditions, ~300–400 genes were identified to be involved in PfGCN5-dependent, general, and stress-condition-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay, we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and ART-resistance-related stress responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention.
Evaluation of the QIAstat-Dx Meningitis/Encephalitis Panel, a multiplex PCR platform for the detection of community-acquired meningoencephalitis
Authors: Sundelin Thomas , Bialas Johanna , de Diego Juana , Hermanowski Markus , Leibhan Hendrik , Ponderand Léa , Juanola-Falgarona Marti , Jones Tara , Rey Melisa , Johnson Sarah , Pareja Josep , Caspar Yvan
Published: September 2023

Rapid identification of the causative pathogens of central nervous system infections is essential for providing appropriate management and improving patient outcomes. The performance of QIAstat-Dx Meningitis/Encephalitis (ME) Panel—a multiplex PCR testing platform—in detecting pathogens implicated in meningitis and/or encephalitis was evaluated using BioFire FilmArray ME Panel as a comparator method. This multicenter study analyzed 585 retrospective residual cerebrospinal fluid specimens and 367 contrived specimens. The QIAstat-Dx ME Panel showed positive percent agreement (PPA) values of 100% for
Neisseria meningitidis
,
Streptococcus agalactiae
,
Escherichia coli
K1,
Listeria monocytogenes
, and
Cryptococcus gattii
/
neoformans
on clinical samples compared to the BioFire FilmArray ME Panel. The PPA values observed for
Haemophilus influenzae
and
Streptococcus pneumoniae
were 80% and 88.24%, respectively. Negative percent agreement (NPA) values were >99.0% for each of the six bacterial targets and one fungal target tested with clinical samples. One viral target, herpes simplex virus 1, exhibited a PPA value of 100.0%, while the remaining viral targets—human parechovirus, herpes simplex virus 2, human herpes virus 6, and varicella zoster virus—were >90.0%, with the exception of enterovirus, which had a PPA value of 77.8%. The QIAstat-Dx ME Panel detected five true-positive and four true-negative cases compared to BioFire FilmArray ME Panel. The NPA values for all viral pathogens were >99.0%. Overall, the QIAstat-Dx ME Panel showed comparable performance to the BioFire FilmArray ME Panel as a rapid diagnostic tool for community-acquired meningitis and encephalitis.
Structural and antigenic characterization of the avian adeno-associated virus capsid
Authors: Hsi Jane , Mietzsch Mario , Chipman Paul , Afione Sandra , Zeher Allison , Huang Rick , Chiorini John , McKenna Robert
Published: September 2023

All adeno-associated virus (AAV) vectors currently used in clinical trials or approved gene therapy biologics are based on human or non-human primate AAVs. A major challenge for AAV gene therapy is the high prevalence of circulating neutralizing antibodies (NAbs) in the general population targeting the virus capsids leading to vector inactivation and a loss of treatment efficacy. A strategy to escape detection by NAbs is the utilization of AAVs that do not disseminate in the primate population and exhibit low or no antigenicity. One such example is avian AAV (AAAV), which was first identified in preparations of the Olson strain of quail bronchitis, an avian adenovirus. AAAV shows very low sequence identities (~54–58%) to the AAV serotypes including to the sequences of the structurally diverse AAV4 and AAV5. In this study, the structure of empty and genome-filled AAAV capsids was determined by cryo-electron microscopy (cryo-EM) at 2.5 and 3.1 Å resolution. Furthermore, AAAV was found to utilize galactose for cell attachment, similar to AAV9 and AAVrh.10. Characterization of AAAV’s antigenic properties revealed that 30% of human sera from healthy individuals were capable of neutralizing transduction. This high rate of antigenicity is caused by conserved epitopes around the fivefold channel of the capsid allowing cross-reactivity of NAbs. This was further confirmed by mapping a cross-reactive human anti-AAV9 monoclonal antibody using cryo-EM. This structure-function characterization will be beneficial to further expand the current repertoire of AAV vectors in human gene therapy applications.

Importance

AAVs are extensively studied as promising therapeutic gene delivery vectors. In order to circumvent pre-existing antibodies targeting primate-based AAV capsids, the AAAV capsid was evaluated as an alternative to primate-based therapeutic vectors. Despite the high sequence diversity, the AAAV capsid was found to bind to a common glycan receptor, terminal galactose, which is also utilized by other AAVs already being utilized in gene therapy trials. However, contrary to the initial hypothesis, AAAV was recognized by approximately 30% of human sera tested. Structural and sequence comparisons point to conserved epitopes in the fivefold region of the capsid as the reason determinant for the observed cross-reactivity.
Identification of hidden N4-like viruses and their interactions with hosts
Authors: Zheng Kaiyang , Liang Yantao , Paez-Espino David , Zou Xiao , Gao Chen , Shao Hongbing , Sung Yeong Yik , Mok Wen Jye , Wong Li Lian , Zhang Yu-Zhong , Tian Jiwei , Chen Feng , Jiao Nianzhi , Suttle Curtis A. , He Jianfeng , McMinn Andrew , Wang Min
Published: September 2023

The N4-like viruses, which were recently assigned to the novel viral family Schitoviridae in 2021, belong to a podoviral-like viral lineage and possess conserved genomic characteristics and a unique replication mechanism. Despite their significance, our understanding of N4-like viruses is primarily based on viral isolates. To address this knowledge gap, this study has established a comprehensive N4-like viral data sets comprising 342 high-quality N4-like viruses/proviruses (144 viral isolates, 158 uncultured viruses, and 40 integrated N4-like proviruses). These viruses were classified into 97 subfamilies (89 of which are newly identified), 148 genera (100 of which are newly identified), and 253 species (177 of which are newly identified). The study reveals that N4-like viruses inhibit the polar region, oligotrophic open oceans, and the human gut, where they infect various bacterial lineages, such as Alpha/Beta/Gamma/Epsilon-proteobacteria in the Proteobacteria phylum. Although N4-like viral endogenization appears to be prevalent in Proteobacteria, it has also been observed in Firmicutes. Additionally, the phylogenetic analysis has identified evolutionary divergence within the hallmark genes of N4-like viruses, indicating a complex origin of the different conserved parts of viral genomes. Moreover, 1,101 putative auxiliary metabolic genes (AMGs) were identified in the N4-like viral pan-proteome, which mainly participate in nucleotide and cofactor/vitamin metabolisms. Of these AMGs, 27 were found to be associated with virulence, suggesting their potential involvement in the spread of bacterial pathogenicity.

Importance

The findings of this study are significant, as N4-like viruses represent a unique viral lineage with a distinct replication mechanism and a conserved core genome. This work has resulted in a comprehensive global map of the entire N4-like viral lineage, including information on their distribution in different biomes, evolutionary divergence, genomic diversity, and the potential for viral-mediated host metabolic reprogramming. As such, this work significantly contributes to our understanding of the ecological function and viral-host interactions of bacteriophages.
Exploring novel alkane-degradation pathways in uncultured bacteria from the North Atlantic Ocean
Authors: Vázquez Rosas Landa Mirna , De Anda Valerie , Rohwer Robin R. , Angelova Angelina , Waldram Georgia , Gutierrez Tony , Baker Brett J.
Published: September 2023

Microbes play a significant role in the degradation of petroleum hydrocarbons in the oceans, yet little is known about the native bacteria that metabolize hydrocarbons before an oil spill. The Faroe-Shetland Channel (FSC) is a deepwater subarctic region of the North Atlantic with prominent oil production and a diverse microbial community associated with the degradation of petroleum. Here, we combine DNA-based stable-isotope probing (DNA-SIP) with metagenomics to elucidate the metabolic underpinnings of native alkane-degrading bacteria from the FSC. From two
13
C
n
-hexadecane SIP experiments using seawater from 5 and 700 m depths in the FSC, we obtained 42 metagenome-assembled genomes (MAGs) belonging to 19 genera, including two previously overlooked hydrocarbon-degrading bacteria,
Lentibacter
(Alphaproteobacteria) and
Dokdonia
(Bacteroidetes). Diversity surveys indicated
Lentibacter
were dominant members of the FSC, constituting up to 17% of these communities. Many of the SIP-enriched MAGs (20/42) encoded a complete alkane oxidation pathway, including alkane monooxygenase (AlkB), rubredoxin reductase (AlkT), and rubredoxin-2 (AlkG). Fourteen Aphaproteobacteria MAGs lacked AlkG for electron transfer. Instead, they encoded novel disulfide isomerases with iron-binding cysteine motifs conserved across rubredoxins.
Dokdonia
lacked AlkT and AlkG, however, their central alkane-degradation catabolic pathways were complete. We describe previously unrecognized bacteria capable of hydrocarbon degradation, including the dominant genera
Lentibacter
, which may continuously purge hydrocarbons released from oil exploration activities in the FSC. This advances the understanding of the diversity and physiologies of alkane degradation in the North Atlantic and provides evidence of new mechanisms used to metabolize alkanes.

IMPORTANCE

Petroleum pollution in the ocean has increased because of rapid population growth and modernization, requiring urgent remediation. Our understanding of the metabolic response of native microbial communities to oil spills is not well understood. Here, we explored the baseline hydrocarbon-degrading communities of a subarctic Atlantic region to uncover the metabolic potential of the bacteria that inhabit the surface and subsurface water. We conducted enrichments with a
13
C-labeled hydrocarbon to capture the fraction of the community actively using the hydrocarbon. We then combined this approach with metagenomics to identify the metabolic potential of this hydrocarbon-degrading community. This revealed previously undescribed uncultured bacteria with unique metabolic mechanisms involved in aerobic hydrocarbon degradation, indicating that temperature may be pivotal in structuring hydrocarbon-degrading baseline communities. Our findings highlight gaps in our understanding of the metabolic complexity of hydrocarbon degradation by native marine microbial communities.
Alteration in gut mycobiota of patients with polycystic ovary syndrome
Authors: Chen Ke , Geng Huafeng , Liu Junbao , Ye Cong
Published: September 2023

Polycystic ovary syndrome (PCOS) is a serious disease characterized by high androgen, insulin resistance (IR), hyperglycemia, and obesity, leading to infertility. The gut mycobiota has been reported to evolve in metabolic diseases including obesity, hyperglycemia, and fatty liver. However, little is known about the gut mycobiota and PCOS. In the current study, we recruited 17 PCOS patients and 17 age-matched healthy controls for community structure and functional analysis of the gut mycobiota. The results showed that PCOS patients have reduced diversity and richness of the gut microbiota compared with healthy controls. β-Diversity analysis showed that the community structure of the gut microbiota of patients with PCOS was significantly different from healthy controls. At the phylum level, PCOS patients have reduced
Basidiomycota
and increased
Ascomycota
compared with healthy controls. At the family level, the higher relative abundance of
Saccharomycetaceae
and lower
Trichosporonaceae
and
Ascomycota_unclassified
were detected in PCOS patients than in healthy controls. At the genus level, different microbial compositions were also observed between PCOS patients and healthy controls. In addition, PICRUSt2 showed that patients with PCOS have different microbial functions in the gut compared with healthy controls. LEfSe indicated that
Saccharomyces
and
Lentinula
were enriched in the fecal samples of PCOS patients, while
Aspergillus
was depleted compared with healthy controls. Our finding indicates that PCOS patients have different community structures and functions of the gut mycobiota, which provides new insight into PCOS pathogenesis and intervention.

IMPORTANCE

It was found that intestinal fungi as well as serum metabolites in PCOS patients were significantly different from those in healthy subjects. However, no studies have been done to show exactly which fungus interacts with which bacteria in humans or which fungus acts alone. As fungal research progresses, it will be possible to fill this gap.
Regulatory response to a hybrid ancestral nitrogenase in
Azotobacter vinelandii
Authors: Rivier Alex J. , Myers Kevin S. , Garcia Amanda K. , Sobol Morgan S. , Kaçar Betül
Published: September 2023

Biological nitrogen fixation, the microbial reduction of atmospheric nitrogen to bioavailable ammonia, represents both a major limitation on biological productivity and a highly desirable engineering target for synthetic biology. However, the engineering of nitrogen fixation requires an integrated understanding of how the gene regulatory dynamics of host diazotrophs respond across sequence-function space of its central catalytic metalloenzyme, nitrogenase. Here, we interrogate this relationship by analyzing the transcriptome of
Azotobacter vinelandii
engineered with a phylogenetically inferred ancestral nitrogenase protein variant. The engineered strain exhibits reduced cellular nitrogenase activity but recovers wild-type growth rates following an extended lag period. We find that expression of genes within the immediate nitrogen fixation network is resilient to the introduced nitrogenase sequence-level perturbations. Rather the sustained physiological compatibility with the ancestral nitrogenase variant is accompanied by reduced expression of genes that support trace metal and electron resource allocation to nitrogenase. Our results spotlight gene expression changes in cellular processes adjacent to nitrogen fixation as productive engineering considerations to improve compatibility between remodeled nitrogenase proteins and engineered host diazotrophs.

IMPORTANCE

Azotobacter vinelandii
is a key model bacterium for the study of biological nitrogen fixation, an important metabolic process catalyzed by nitrogenase enzymes. Here, we demonstrate that compatibilities between engineered
A. vinelandii
strains and nitrogenase variants can be modulated at the regulatory level. The engineered strain studied here responds by adjusting the expression of proteins involved in cellular processes adjacent to nitrogen fixation, rather than that of nitrogenase proteins themselves. These insights can inform future strategies to transfer nitrogenase variants to non-native hosts.
Hereditary haemochromatosis discovered after COVID-19 hospitalisation
Authors: Hall Zachary , Manlove Emily
Published: September 2023

COVID-19 infection and hereditary haemochromatosis (HH) have something in common; the disease course can be monitored with ferritin levels. Throughout the pandemic, physicians have looked for markers to help predict disease severity. Ferritin levels are commonly used to predict and monitor disease severity in hospitalised patients with COVID-19. While ferritin is elevated as part of the acute-phase reaction in response to infection, it can also be elevated due to iron overload. We report a case of undiagnosed, asymptomatic HH that was unveiled after COVID-19 infection via monitoring for resolution of ferritin levels that were found to be extremely elevated during a moderate COVID-19 infection. This diagnosis allowed the patient to initiate phlebotomy treatment before symptoms of HH arose.
Unravelling the mystery of a rare infection: a challenging case of pulmonary sequestration with Mycobacterium avium complex and the importance of a thorough microbiological investigation
Authors: Mughrabi Abdallah , Fennelly Jeffrey , Fandreyer Felicitas , Fleisher Jorge
Published: September 2023

Pulmonary sequestration is a rare congenital condition. It is a dysplastic lung tissue with a separate systemic blood supply and without a bronchial tree connection. The emergence of a superimposed infection can lead to its diagnosis, such asStaphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroids and Aspergillus sp. pneumonia. Mycobacterium avium complex (MAC) superimposed disease is exceedingly rare. We report a case of a man in his third decade without known medical disorders presenting with a persistent cough. After an extensive microbiological workup, an MAC infection was diagnosed. An elevated carbohydrate antigen 19-9 (CA 19-9) was also noted. He was treated with antimycobacterial therapy and lobectomy resulting in clinical improvement and CA19-9 normalisation. This case illustrates the value of comprehensive microbiological investigations in patients with chronic respiratory symptoms and imaging findings that are not typical of bacterial pneumonia. Clinical studies remain needed to investigate the utility of CA 19-9 in a scoring system to guide MAC therapy.
Rare cause of persistent hypocalcaemia in infancy due to PTH gene mutation
Authors: Khadse Savita , Takalikar Vrushali Satish , Ghildiyal Radha , Shah Nikhil
Published: September 2023

Hypocalcaemia is a frequently encountered electrolyte abnormality in neonates and it is mostly transient. However, persistent hypocalcaemia can point towards an endocrine abnormality like hypoparathyroidism, which is usually due to genetic disorders like DiGeorge and Kearns Sayre syndrome or due to mutations of genes like GCM2, CaSR and PTH.

Our patient was a female child, who presented with hypocalcaemic convulsions in the neonatal period. On laboratory assessment, serum phosphate levels were noted to be high along with inappropriately low parathyroid hormone (PTH) levels. The child was diagnosed to have hypoparathyroidism and was started on oral calcium and 1,25-dihydroxycholecalciferol supplements to which she responded well. However, the child was lost to follow-up and was readmitted with hypocalcaemic convulsions in infancy. Clinical exome analysis done was diagnostic of homozygous PTH gene mutation. This case demonstrates a rare form of congenital isolated hypoparathyroidism with no other syndromic associations.
Deep learning detection of diabetic retinopathy in Scotland’s diabetic eye screening programme
Authors: Fleming Alan D , Mellor Joseph , McGurnaghan Stuart J , Blackbourn Luke A K , Goatman Keith A , Styles Caroline , Storkey Amos J , McKeigue Paul M , Colhoun Helen M
Published: September 2023

Background/Aims

Support vector machine-based automated grading (known as iGradingM) has been shown to be safe, cost-effective and robust in the diabetic retinopathy (DR) screening (DES) programme in Scotland. It triages screening episodes as gradable with no DR versus manual grading required. The study aim was to develop a deep learning-based autograder using images and gradings from DES and to compare its performance with that of iGradingM.

Methods

Retinal images, quality assurance (QA) data and routine DR grades were obtained from national datasets in 179 944 patients for years 2006–2016. QA grades were available for 744 images. We developed a deep learning-based algorithm to detect whether either eye contained ungradable images or any DR. The sensitivity and specificity were evaluated against consensus QA grades and routine grades.

Results

Images used in QA which were ungradable or with DR were detected by deep learning with better specificity compared with manual graders (p<0.001) and with iGradingM (p<0.001) at the same sensitivities. Any DR according to the DES final grade was detected with 89.19% (270 392/303 154) sensitivity and 77.41% (500 945/647 158) specificity. Observable disease and referable disease were detected with sensitivities of 96.58% (16 613/17 201) and 98.48% (22 600/22 948), respectively. Overall, 43.84% of screening episodes would require manual grading.

Conclusion

A deep learning-based system for DR grading was evaluated in QA data and images from 11 years in 50% of people attending a national DR screening programme. The system could reduce the manual grading workload at the same sensitivity compared with the current automated grading system.
Uncovering heterogeneous cardiometabolic risk profiles in US adults: the role of social and behavioral determinants of health
Authors: Ding Qinglan , Lu Yuan , Herrin Jeph , Zhang Tianyi , Marrero David G
Published: September 2023

Introduction

Social and behavioral determinants of health (SBDH) have been linked to diabetes risk, but their role in explaining variations in cardiometabolic risk across race/ethnicity in US adults is unclear. This study aimed to classify adults into distinct cardiometabolic risk subgroups using SBDH and clinically measured metabolic risk factors, while comparing their associations with undiagnosed diabetes and pre-diabetes by race/ethnicity.

Research design and methods

We analyzed data from 38,476 US adults without prior diabetes diagnosis from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. The k-prototypes clustering algorithm was used to identify subgroups based on 16 SBDH and 13 metabolic risk factors. Each participant was classified as having no diabetes, pre-diabetes or undiagnosed diabetes using contemporaneous laboratory data. Logistic regression was used to assess associations between subgroups and diabetes status, focusing on differences by race/ethnicity.

Results

Three subgroups were identified: cluster 1, primarily middle-aged adults with high rates of smoking, alcohol use, short sleep duration, and low diet quality; cluster 2, mostly young non-white adults with low income, low health insurance coverage, and limited healthcare access; and cluster 3, mostly older males who were the least physically active, but with high insurance coverage and healthcare access. Compared with cluster 2, adjusted ORs (95% CI) for undiagnosed diabetes were 14.9 (10.9, 20.2) in cluster 3 and 3.7 (2.8, 4.8) in cluster 1. Clusters 1 and 3 (vs cluster 2) had high odds of pre-diabetes, with ORs of 1.8 (1.6, 1.9) and 2.1 (1.8, 2.4), respectively. Race/ethnicity was found to modify the relationship between identified subgroups and pre-diabetes risk.

Conclusions

Self-reported SBDH combined with metabolic factors can be used to classify adults into subgroups with distinct cardiometabolic risk profiles. This approach may help identify individuals who would benefit from screening for diabetes and pre-diabetes and potentially suggest effective prevention strategies.
Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial)
Authors: Pang Kai , Yang Yun , Tian Dan , Zeng Na , Cao Shun , Ling Shen , Gao Jiale , Zhao Pengfei , Wang Hao , Kong Yuanyuan , Zhang Jie , Chen Guangyong , Deng Wei , Bai Zhigang , Jin Lan , Wu Guoju , Zhu Danyang , Wang Yue , Zhou Jiaolin , Wu Bin , Lin Guole , Xiao Yi , Gao Zhidong , Ye Yingjiang , Wang Xin , Li Ang , Han Jiagang , Yao Hongwei , Yang Yingchi , Zhang Zhongtao
Published: September 2023

Introduction

Recent preclinical studies have discovered unique synergism between radiotherapy and immune checkpoint inhibitors, which has already brought significant survival benefit in lung cancer. In locally advanced rectal cancer (LARC), neoadjuvant radiotherapy plus immune checkpoint inhibitors have also achieved surprisingly high pathological complete response (pCR) rates even in proficient mismatch-repair patients. As existing researches are all phase 2, single-cohort trials, we aim to conduct a randomised, controlled trial to further clarify the efficacy and safety of this novel combination therapy.

Methods and analysis

Eligible patients with LARC are randomised to three arms (two experiment arms, one control arm). Patients in all arms receive long-course radiotherapy plus concurrent capecitabine as neoadjuvant therapy, as well as radical surgery. Distinguishingly, patients in arm 1 also receive anti-PD-1 (Programmed Death 1) treatment starting at Day 8 of radiation (concurrent plan), and patients in arm 2 receive anti-PD-1 treatment starting 2 weeks after completion of radiation (sequential plan). Tislelizumab (anti-PD-1) is scheduled to be administered at 200 mg each time for three consecutive times, with 3-week intervals. Randomisation is stratified by different participating centres, with a block size of 6. The primary endpoint is pCR rate, and secondary endpoints include neoadjuvant-treatment-related adverse event rate, as well as disease-free and overall survival rates at 2, 3 and 5 years postoperation. Data will be analysed with an intention-to-treat approach.

Ethics and dissemination

This protocol has been approved by the institutional ethical committee of Beijing Friendship Hospital (the primary centre) with an identifying serial number of 2022-P2-050-01. Before publication to peer-reviewed journals, data of this research will be stored in a specially developed clinical trial database.

Trial registration number

NCT05245474.
Efficacy and safety of drug therapy for the prevention and treatment of chemotherapy-induced peripheral neuropathy: a protocol for a systematic review and network meta-analysis
Authors: Sato Miki Takenaka , Hasegawa Takeshi , Noma Hisashi , Sugita Hideki , Ota Erika
Published: September 2023

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of chemotherapeutic drugs. Numerous clinical trials of various targeted drugs for the prevention or treatment of CIPN have been conducted; however, previous systematic reviews with direct comparisons have failed to demonstrate the efficacy of these drugs in the prevention or treatment of CIPN. In addition, no systematic reviews have indirectly compared CIPN prevention and treatment. This article describes a protocol for evaluating the efficacy and safety of drug therapy for the prevention and treatment of CIPN. The results of the proposed systematic review with network meta-analysis (NMA) will provide new insights into the prevention and treatment of CIPN.

Methods and analysis

We will conduct a literature search in MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov to find relevant articles published through January 2023. We will include studies that investigated the efficacy and safety of vitamin B12, goshajinkigan, non-steroidal anti-inflammatory analgesics, opioids, calcium and magnesium, antidepressants and anticonvulsants on CIPN. Two authors will individually screen the retrieved reports and review the full text based on the selection criteria. The primary outcome is the incidence and severity of CIPN. The risk of bias will be assessed using V.2.0 of the Cochrane risk-of-bias tool. We will apply a frequentist random-effects NMA model to pool effect sizes across trials using risk ratios and mean differences with their 95% CIs. Competing interventions will be ranked using the surface under cumulative ranking probabilities. Heterogeneity will be assessed using the heterogeneity variance τ2, Cochran’s Q test and I² statistic.

Ethics and dissemination

This review does not require ethical approval. The research will be published in a peer-reviewed journal.

PROSPERO registration number

CRD42022371829.
Development of practice-based quality indicators for the primary care of older adults: a RAND/UCLA Appropriateness Method study protocol
Authors: Correia Rebecca H , Siu Henry Yu-Hin , Vanstone Meredith , Jones Aaron , Gopaul Aquila , Costa Andrew P
Published: September 2023

Introduction

Older adults have high rates of primary care utilisation, and quality primary care has the potential to address their complex medical needs. Family physicians have different levels of knowledge and skills in caring for older patients, which may influence the quality of care delivery and resulting health outcomes. In this study, we aim to establish consensus on practice-based metrics that characterise quality of care for older primary care patients and can be examined using secondary, administrative data.

Methods and analysis

We describe a two-round RAND/UCLA Appropriateness Method (RAM) study to assess the consensus of a technical expert panel. We will recruit pan-Canadian experts who demonstrate excellence in clinical practice or scholarship related to the primary care of older adults. A literature review will generate a candidate list of practice-based quality indicators. The first round aims to evaluate the appropriateness and importance of candidate indicators through an online questionnaire. We will then develop technical definitions for each endorsed indicator using ICES data holdings. Panellists will offer feedback on the technical definitions in a virtual synchronous meeting and provide ratings on the same criteria in a second questionnaire.

Ethics and dissemination

Our study has been approved by the Hamilton Integrated Research Ethics Board (Project ID #15545). Findings will be disseminated via manuscripts, presentations and the lead author’s thesis.

Trial registration number

ISRCTN17074347
Characteristics of programmes designed to link community-dwelling older adults in high-income countries from community to clinical sectors: a scoping review protocol
Authors: Gofine Miriam , Laynor Gregory , Schoenthaler Antoinette
Published: September 2023

Introduction

Research on effectively navigating older adults into primary care is urgently needed. Community–clinic linkage models (CCLMs) aim to improve population health by linking the health and community sectors in order to improve patients’ access to healthcare and, ultimately, population health. However, research on community-based points of entry linking adults with untreated medical needsintothe healthcare sector is nascent. CCLMs implemented for the general adult population are not necessarily accessible to older adults. Given the recency of the CCLM literature and the seeming rarity of CCLM interventions designed for older adults, it is appropriate to employ scoping review methodology in order to generate a comprehensive review of the available information on this topic. This protocol will inform a scoping review that reviews characteristics of community-based programmes that link older adults with the healthcare sector.

Methods and analysis

The present protocol was developed as per JBI Evidence Synthesis best practice guidance and reporting items for the development of scoping review protocols. The proposed scoping review will follow Levac and colleagues’ update to Arksey and O’Malley’s scoping review methodology. Healthcare access at the system and individual levels will be operationalised in data extraction and analysis in accordance with Levesque and colleagues’ Conceptual Framework of Access to Health. The protocol complies with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. Beginning in August 2023 or later, citation databases (AgeLine (Ebsco); CINAHL Complete; MEDLINE (PubMed); Scopus Advanced (Elsevier); Social Services Abstracts (ProQuest); Web of Science Core Collection (Clarivate)) and grey literature (Google; American Public Health Association Annual Meeting Conference Proceedings; SIREN Evidence & Resource Library) will be searched.

Ethics and dissemination

The authors plan to disseminate their findings in conference proceedings and publication in a peer-reviewed journal and deposit extracted data in the Figshare depository. The study does not require Institutional Review Board approval.

Registration details

Protocol registered in Open Science Framework (DOIhttps://doi.org/10.17605/OSF.IO/2EF9D).
Development and validation of a product acceptability questionnaire for intranasal Q-Griffithsin COVID-19 prophylaxis (SPRAY PAL)
Authors: Cash Elizabeth , Deitz Kailyn , Potts Kevin L , Nabeta Henry W , Zahin Maryam , Rai Shesh N , Dryden Gerald W , Palmer Kenneth E
Published: September 2023

Objectives

Patient experiences are critical when determining the acceptability of novel interventional pharmaceuticals. Here, we report the development and validation of a product acceptability questionnaire (SPRAY PAL) assessing feasibility, acceptability and tolerability of an intranasal Q-Griffithsin (Q-GRFT) drug product designed for COVID-19 prophylaxis.

Design

SPRAY PAL validation was undertaken as part of an ongoing phase 1 clinical trial designed to test the safety, pharmacokinetics and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection.

Setting

The phase 1 clinical trial took place at a University Outpatient Clinical Trials Unit from November 2021 to September 2023.

Participants

The initial SPRAY PAL questionnaire was piloted among healthy volunteers ages 25 to 55 in phase 1a of the clinical trial (N=18) and revised for administration in phase 1b for participants ages 24–59 (N=22).

Results

Spearman correlations tested convergent and discriminant validity. Internal consistency was assessed using Cronbach’s alpha, and test–retest reliability was assessed using intraclass correlation coefficients of responses collected from three repeated questionnaire administrations. The initial version demonstrated excellent internal consistency. The revised version demonstrated very good internal consistency after removal of one item (alpha=0.739). Excellent test–retest reliability (intraclass coefficient=0.927) and adequate convergent (r’s=0.208–0.774) and discriminant (r’s=0.123–0.392) validity were achieved. Subscales adequately distinguished between the constructs of acceptability, feasibility and tolerability.

Conclusions

The SPRAY PAL product acceptability questionnaire is a valid and reliable patient-reported outcomes measure that can be considered a credible tool for assessing patient-reported information about product acceptability, feasibility of use, tolerability of product and side effects and cost of product for novel intranasal drug formulations. The SPRAY PAL is generalisable, and items may be readily adapted to assess other intranasal formulations.

Trial registration numbers

NCT05122260andNCT05437029.
Intravenous versus oral hydration to reduce the risk of postcontrast acute kidney injury after intravenous contrast-enhanced CT in patients with severe chronic kidney disease (ENRICH): a study protocol for a single-centre, parallel-group, open-labelled non-inferiority randomised controlled trial in Denmark
Authors: Ravn Emil Johannes , Hasific Selma , Thomassen Mads , Hjortebjerg Rikke , Bach Laursen Kristian , Diederichsen Axel , Bistrup Claus , Øvrehus Kristian A
Published: September 2023

Introduction

Contrast-enhanced CT (CECT) is widely used for diagnostic purposes. The use of contrast medium carries a risk for postcontrast acute kidney injury (PC-AKI), especially in patients with AKI or chronic kidney disease (CKD). Current guidelines recommend prophylactic intravenous hydration to prevent PC-AKI in high-risk patients. Oral hydration is non-inferior to intravenous hydration in patients with moderate CKD, but it has not been evaluated in high-risk patients.

Methods and analysis

The ENRICH trial will enrol 254 patients with estimated glomerular filtration rate ≤30 mL/min/1.73 m2undergoing intravenous CECT, who are block randomised (2-4-2) with stratification for CKD stage, diabetes status, and indication for referral to prophylactic treatment with oral or intravenous hydration. PC-AKI is defined as an absolute increase in SCr of >0.3 mg/dL or >1.5 from baseline at 2–5 days. Renal function will also be evaluated <90 days, <7 days and 1–3 days before intravenous CECT, and 25–40 days after intravenous CECT. Secondary outcomes include dialysis, renal adverse events, hospitalisation due to hydration-related or contrast-related sequelae, and all-cause mortality ≤30 days postcontrast. Pre- and postcontrast plasma and urinary biomarkers will be evaluated for diagnostic and prognostic accuracy of the primary and secondary outcomes.

Ethics and dissemination

Oral hydration is patient-friendly and less costly compared with intravenous hydration. If oral hydration is non-inferior to intravenous hydration in high-risk patients, it could be implemented as new hydration strategy, which will facilitate the clinical diagnosing of elective patients with severe CKD without unnecessary resource utilisation. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20210126), and the Data Protection Agency (21/66779). The study is conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported in international peer-reviewed journals.

Trial registration number

NCT05283512.