bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversity, origin, and evolution of the ESCRT systems
Authors: Makarova Kira S. , Tobiasson Victor , Wolf Yuri I. , Lu Zhongyi , Liu Yang , Zhang Siyu , Krupovic Mart , Li Meng , Koonin Eugene V.
Published: February 2024

Endosomal sorting complexes required for transport (ESCRT) play key roles in protein sorting between membrane-bounded compartments of eukaryotic cells. Homologs of many ESCRT components are identifiable in various groups of archaea, especially in Asgardarchaeota, the archaeal phylum that is currently considered to include the closest relatives of eukaryotes, but not in bacteria. We performed a comprehensive search for ESCRT protein homologs in archaea and reconstructed ESCRT evolution using the phylogenetic tree of Vps4 ATPase (ESCRT IV) as a scaffold and using sensitive protein sequence analysis and comparison of structural models to identify previously unknown ESCRT proteins. Several distinct groups of ESCRT systems in archaea outside of Asgard were identified, including proteins structurally similar to ESCRT-I and ESCRT-II, and several other domains involved in protein sorting in eukaryotes, suggesting an early origin of these components. Additionally, distant homologs of CdvA proteins were identified in Thermoproteales which are likely components of the uncharacterized cell division system in these archaea. We propose an evolutionary scenario for the origin of eukaryotic and Asgard ESCRT complexes from ancestral building blocks, namely, the Vps4 ATPase, ESCRT-III components, wH (winged helix-turn-helix fold) and possibly also coiled-coil, and Vps28-like domains. The last archaeal common ancestor likely encompassed a complex ESCRT system that was involved in protein sorting. Subsequent evolution involved either simplification, as in the TACK superphylum, where ESCRT was co-opted for cell division, or complexification as in Asgardarchaeota. In Asgardarchaeota, the connection between ESCRT and the ubiquitin system that was previously considered a eukaryotic signature was already established.

IMPORTANCE

All eukaryotic cells possess complex intracellular membrane organization. Endosomal sorting complexes required for transport (ESCRT) play a central role in membrane remodeling which is essential for cellular functionality in eukaryotes. Recently, it has been shown that Asgard archaea, the archaeal phylum that includes the closest known relatives of eukaryotes, encode homologs of many components of the ESCRT systems. We employed protein sequence and structure comparisons to reconstruct the evolution of ESCRT systems in archaea and identified several previously unknown homologs of ESCRT subunits, some of which can be predicted to participate in cell division. The results of this reconstruction indicate that the last archaeal common ancestor already encoded a complex ESCRT system that was involved in protein sorting. In Asgard archaea, ESCRT systems evolved toward greater complexity, and in particular, the connection between ESCRT and the ubiquitin system that was previously considered a eukaryotic signature was established.
Uncultivated DPANN archaea are ubiquitous inhabitants of global oxygen-deficient zones with diverse metabolic potential
Authors: Zhang Irene H. , Borer Benedict , Zhao Rui , Wilbert Steven , Newman Dianne K. , Babbin Andrew R.
Published: February 2024

Archaea belonging to the DPANN (Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota, and Nanohaloarchaeota) superphylum have been found in an expanding number of environments and perform a variety of biogeochemical roles, including contributing to carbon, sulfur, and nitrogen cycling. Generally characterized by ultrasmall cell sizes and reduced genomes, DPANN archaea may form mutualistic, commensal, or parasitic interactions with various archaeal and bacterial hosts, influencing the ecology and functioning of microbial communities. While DPANN archaea reportedly comprise a sizeable fraction of the archaeal community within marine oxygen-deficient zone (ODZ) water columns, little is known about their metabolic capabilities in these ecosystems. We report 33 novel metagenome-assembled genomes (MAGs) belonging to the DPANN phyla Nanoarchaeota, Pacearchaeota, Woesearchaeota, Undinarchaeota, Iainarchaeota, and SpSt-1190 from pelagic ODZs in the Eastern Tropical North Pacific and the Arabian Sea. We find these archaea to be permanent, stable residents of all three major ODZs only within anoxic depths, comprising up to 1% of the total microbial community and up to 25%–50% of archaea as estimated from read mapping to MAGs. ODZ DPANN appear to be capable of diverse metabolic functions, including fermentation, organic carbon scavenging, and the cycling of sulfur, hydrogen, and methane. Within a majority of ODZ DPANN, we identify a gene homologous to nitrous oxide reductase. Modeling analyses indicate the feasibility of a nitrous oxide reduction metabolism for host-attached symbionts, and the small genome sizes and reduced metabolic capabilities of most DPANN MAGs suggest host-associated lifestyles within ODZs.

IMPORTANCE

Archaea from the DPANN (Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota, and Nanohaloarchaeota) superphylum have diverse metabolic capabilities and participate in multiple biogeochemical cycles. While metagenomics and enrichments have revealed that many DPANN are characterized by ultrasmall genomes, few biosynthetic genes, and episymbiotic lifestyles, much remains unknown about their biology. We report 33 new DPANN metagenome-assembled genomes originating from the three global marine oxygen-deficient zones (ODZs), the first from these regions. We survey DPANN abundance and distribution within the ODZ water column, investigate their biosynthetic capabilities, and report potential roles in the cycling of organic carbon, methane, and nitrogen. We test the hypothesis that nitrous oxide reductases found within several ODZ DPANN genomes may enable ultrasmall episymbionts to serve as nitrous oxide consumers when attached to a host nitrous oxide producer. Our results indicate DPANN archaea as ubiquitous residents within the anoxic core of ODZs with the potential to produce or consume key compounds.
Two
Toxoplasma gondii
putative pore-forming proteins, GRA47 and GRA72, influence small molecule permeability of the parasitophorous vacuole
Authors: Bitew Mebratu A. , Gaete Pablo S. , Swale Christopher , Maru Parag , Contreras Jorge E. , Saeij Jeroen P. J.
Published: February 2024

Toxoplasma gondii
, a medically important intracellular parasite, uses GRA proteins secreted from dense granule organelles to mediate nutrient flux across the parasitophorous vacuole membrane (PVM). GRA17 and GRA23 are known pore-forming proteins on the PVM involved in this process, but the roles of additional proteins have remained largely uncharacterized. We recently identified
GRA72
as synthetically lethal with
GRA17
. Deleting
GRA72
produced similar phenotypes to Δ
gra17
parasites, and computational predictions suggested it forms a pore. To understand how GRA72 functions, we performed immunoprecipitation experiments and identified GRA47 as an interactor of GRA72. Deletion of
GRA47
resulted in an aberrant “bubble vacuole” morphology with reduced small molecule permeability, mirroring the phenotype observed in
GRA17
and
GRA72
knockouts. Structural predictions indicated that GRA47 and GRA72 form heptameric and hexameric pores, respectively, with conserved histidine residues lining the pore. Mutational analysis highlighted the critical role of these histidines for protein functionality. Validation through electrophysiology confirmed alterations in membrane conductance, corroborating their pore-forming capabilities. Furthermore, Δ
gra47
parasites and parasites expressing GRA47 with a histidine mutation had reduced
in vitro
proliferation and attenuated virulence in mice. Our findings show the important roles of GRA47 and GRA72 in regulating PVM permeability, thereby expanding the repertoire of potential therapeutic targets against
Toxoplasma
infections.

IMPORTANCE

Toxoplasma gondii
is a parasite that poses significant health risks to those with impaired immunity. It replicates inside host cells shielded by the PVM, which controls nutrient and waste exchange with the host. GRA72, previously identified as essential in the absence of the GRA17 nutrient channel, is implicated in forming an alternative nutrient channel. Here we found that GRA47 associates with GRA72 and is also important for the PVM's permeability to small molecules. Removal of GRA47 leads to distorted vacuoles and impairs small molecule transport across the PVM, resembling the effects of GRA17 and GRA72 deletions. Structural models suggest GRA47 and GRA72 form distinct pore structures, with a pore-lining histidine critical to their function.
Toxoplasma
strains lacking GRA47 or those with a histidine mutation have impaired growth and reduced virulence in mice, highlighting these proteins as potential targets for new treatments against toxoplasmosis.
A novel
Bartonella
-like bacterium forms an interdependent mutualistic symbiosis with its host, the stored-product mite
Tyrophagus putrescentiae
Authors: Xiong Qing , Sopko Bruno , Klimov Pavel B. , Hubert Jan
Published: February 2024

A novel
Bartonella
-like symbiont (BLS) of
Tyrophagus putrescentiae
was characterized. BLS formed a separate cluster from the
Bartonella
clade together with an ant symbiont. BLS was present in mite bodies (103 16S DNA copies/mite) and feces but was absent in eggs. This indicated the presence of the BLS in mite guts. The BLS showed a reduction in genome size (1.6 Mb) and indicates gene loss compared to
Bartonella apis
. The BLS can be interacted with its host by using host metabolic pathways (e.g., the histidine and arginine metabolic pathways) as well as by providing its own metabolic pathways (pantothenate and lipoic acid) to the host, suggesting the existence of a mutualistic association. Our experimental data further confirmed these potential mutualistic nutritional associations, as cultures of
T. putrescentiae
with low BLS abundance showed the strongest response after the addition of vitamins. Despite developing an arguably tight dependency on its host, the BLS has probably retained flagellar mobility, as evidenced by the 32 proteins enriched in KEGG pathways associated with flagellar assembly or chemotaxis (e.g., fliC, flgE, and flgK, as highly expressed genes). Some of these proteins probably also facilitate adhesion to host gut cells. The microcin C transporter was identified in the BLS, suggesting that microcin C may be used in competition with other gut bacteria. The 16S DNA sequence comparison indicated a mite clade of BLSs with a broad host range, including house dust and stored-product mites. Our phylogenomic analyses identified a unique lineage of arachnid specific BLSs in mites and scorpions.

IMPORTANCE

A
Bartonella
-like symbiont was found in an astigmatid mite of allergenic importance. We assembled the genome of the bacterium from metagenomes of different stored-product mite (
T. putrescentiae
) cultures. The bacterium provides pantothenate and lipoic acid to the mite host. The vitamin supply explains the changes in the relative abundance of BLSs in
T. putrescentiae
as the microbiome response to nutritional or pesticide stress, as observed previously. The phylogenomic analyses of available 16S DNA sequences originating from mite, scorpion, and insect samples identified a unique lineage of arachnid specific forming large
Bartonella
clade. BLSs associated with mites and a scorpion. The
Bartonella
clade included the previously described
Ca
. Tokpelaia symbionts of ants.
Carboniferous bimodal volcanic sequences along the Northeastern Pamir: Evidence for back-arc extension due to northward subduction of the Paleo-Tethys
Authors: Song Zhi-Hao , Zhang Chuan-Lin , Sargazi Masumeh , Hussain Zahid , Liu Xiao-Qiang , Ye Xian-Tao , Wang Hong-Ran
Published: February 2024

The Pamir plateau lies at the western end of the Tethys domain recording the entire evolution from the opening of the Proto-Tethys to the final closure of the Neo-Tethys. During this long-term evolution, the details of the initial subduction of the Paleo-Tethys and the final amalgamation of the main terranes in the Pamir are still controversial. The Carboniferous bimodal volcanic sequences along the Northern Pamir may supply the key evidence to reveal the subduction process of the Paleo-Tethys Ocean. This study presents the detailed stratigraphic architecture, petrography, geochronological and geochemical data of the Carboniferous–Permian volcanic rocks along the Northern Pamir in western China bordering Tajikistan. Zircons from two plagioclase phenocryst-rich basalts, and an andesite, volcanic agglomerate, and granitic sill emplaced in the basalts yield concordant ages of 319.5 ± 2 Ma, 322.7 ± 1.6 Ma, 288.7 ± 2.5 Ma, 301.6 ± 4.2 Ma, and 300.4 ± 1.5 Ma, respectively. The basalts show mid-oceanic-ridge basalt–like geochemical features with flat to depleted light rare earth element trends [(La/Yb)N = 0.68–1.82], depleted whole-rock εNd(t) (6.44–7.85), and zircon εHf(t) (6.3–10.1) values, suggesting they are primitive magmas derived from a depleted mantle source metasomatized by earlier subduction in line with their low Nb/La ratios (0.30–0.64). As for the intermediate-acid volcanic rocks (andesite and dacite), they show enrichment of large ionic lithophile elements (e.g., Rb, Ba, and Sr) and depletion of high field strength elements (e.g., Nb, Ta, and Ti) as well as negative εNd(t) values ranging from −0.97 to −0.75, demonstrating that they are primitive magmas derived from partial melting of the metasomatized lithospheric mantle source, followed by crystal fraction of hornblende, plagioclase, and minor quartz. Taking together the stratigraphic features, rock associations, and geochemical signatures, the Carboniferous basalts share most features with the Okinawa and the Mariana back-arc basalts. Integrating the new data with the previous studies, we construct a detailed evolution process of the Paleo-Tethys Ocean at the Pamir, i.e., extension of the filled residual Proto-Tethys Ocean between the Tarim and the Northern Pamir induced by the northward Paleo-Tethys subduction in the early Carboniferous, gradually waning of the back-arc basin from the late Carboniferous to the Early Permian, and finally, the closure of the Paleo-Tethys Ocean led to the amalgamation of the Northern, the Central, and the Southern Pamir, resulting in the initial architecture of the Pamir.
Geophysical constraints on continental rejuvenation in central China: Implications for outward growth of the Tibetan Plateau
Authors: Zhang Yi-Peng , Zhang Pei-Zhen , Lease Richard O. , Li Min-Juan , Zhou Renjie , Xu Bin-Bin , Cheng Si-Yuan , Shen Xu-Zhang , Zheng Wen-Jun , He Xiao-Hui , Wang Wei-Tao , Wang Yue-Jun
Published: February 2024

Continental rejuvenation results from the tectonic reactivation of crustal structures and lithospheric reworking by mantle flow. Geochemical observations and field mapping have traditionally provided the primary evidence for the secular evolution of crustal composition and tectonic processes during continental rejuvenation. Nonetheless, the impact of continental rejuvenation on the observed present-day strain rate and orogenic-scale lithospheric structure has not been well constrained. The pre-existing E-W–trending Central China Orogenic Belt has been overprinted by the N-S–trending Central Longitudinal Seismic Belt and constitutes the intracontinental West Qinling Syntaxis in central China, where the tectonic setting changes eastward from contraction to extension. Combining updated global positioning system data and high-resolution crustal seismic tomography, we reveal a modern continental rejuvenation process within the West Qinling Syntaxis in central China. The northward extrusion of the Tibetan Plateau's weak lithospheric layer (middle-lower crust and lithospheric mantle) of southwestern China relative to the rigid Sichuan Basin/Ordos Block of the eastern West Qinling Syntaxis results in regional dextral shearing that shapes the Central Longitudinal Seismic Belt and defines the eastern Tibetan Plateau margin. The pre-existing E-W–trending Central China Orogenic Belt has been preserved above the brittle-ductile transition zone, and the northward movement of the deep lithospheric layer drives the deformation of the upper crust in the West Qinling Syntaxis. Our results, along with previous studies, suggest the presence of an intracontinental lithospheric interchange structure in central China. The continental rejuvenation of the West Qinling Syntaxis results from a combination of fault reactivation in the upper crust (Stage I, Eocene–Oligocene) and reworking of the deep lithosphere (Stage II, middle–late Miocene) related to the plateau-wide shift in stress accommodation ultimately driven by the redistribution of mass outward from the central Tibetan Plateau. At present, the transition zone between the high- and low-velocity anomalies along the Central Longitudinal Seismic Belt not only shapes the landscape boundary but controls the size and recurrence interval of earthquakes within the West Qinling Syntaxis in central China.
Eocene crustal thickening in the Tethyan Himalaya: Insights from Barrovian metamorphism and granite geochemistry from the Ramba area
Authors: Shi Shuai , Jiang Yingde , Weinberg Roberto F. , Zhang Zhi , Wang Qiang
Published: February 2024

Magmatism, structures, and metamorphism in the Ramba dome of the Tethyan Himalaya were investigated to shed light on orogenic processes during the early stages of the India-Asia collision. Deformed granite dikes in the dome envelope yield zircon U-Pb ages of ca. 45 Ma. These Eocene granites have adakitic, Na-rich compositions (K2O/Na2O = 0.20–0.61), weak to no Eu anomaly, enrichment in Sr, depletion in heavy rare earth elements and Y, and low MgO and Mg# contents. These characteristics contrast with the Miocene potassic granites in the core of the dome and suggest that the Eocene adakites were derived from the high-pressure melting of crustal amphibolites in a thick crust. The mica schists of the dome envelope have an early foliation (S1) that is overprinted by upright folds (F2). Phase-equilibria modeling of garnet and staurolite mica schists suggests a Barrovian-type, prograde P-T evolution in association with S1, with peak conditions of 6.7–7.2 kbar/590–605 °C and 7.3–7.8 kbar/650–670 °C, respectively, which are typical of crustal thickening metamorphism. Monazites from S1-dominated staurolite mica schists yield metamorphic ages of ca. 51–49 Ma, while those from the late foliation (S2) that transposed S1 give younger ages of ca. 10 Ma. The integration of geochemical, structural, metamorphic, and geochronological data suggests that peak Barrovian D1 metamorphism and adakitic magmatism occurred in the Eocene in response to crustal thickening. The results provide critical constraints for addressing the crustal shortening deficit of the region.
Tracking cycles of Phanerozoic opening and closing of ocean basins using detrital rutile and zircon geochronology and geochemistry
Authors: Odlum Margaret L. , Capaldi Tomas N. , Thomson Kelly D. , Stockli Daniel F.
Published: February 2024

Sedimentary basins provide a deep time archive of tectonic and Earth-surface processes that can be leveraged by detrital mineral U-Pb dating and geochemistry to track paleogeography, magmatism, and crustal evolution. Zircon preserves the long-term (billions of years) record of supercontinent cycles; however, it is biased toward preserving felsic crustal records. Detrital rutile complements the detrital zircon record by providing constraints on the time and temperature of rifting and mafic magmatism, metamorphism, exhumation of the middle and lower crust, subduction, and amagmatic orogenesis. We use detrital zircon U-Pb and detrital rutile U-Pb geochronology and trace element analysis of Permian to Eocene siliciclastic rocks in the southern Pyrenees to capture supercontinent cycles of ocean basins opening and closing. Detrital rutile age spectra show peaks at ca. 100 Ma associated with rifting and hyperextension in the Pyrenean realm, 200 Ma associated with the Central Atlantic Magmatic Province, and 330 Ma, 375 Ma, and 400 Ma associated with subduction and Rheic Ocean crust formation. Zr-in-rutile thermometry and rutile Cr-Nb systematics provide further insight into metamorphic facies (peak metamorphic temperatures) and source rock lithology (mafic versus felsic affinity). Detrital zircon age spectra have peaks at ca. 300 Ma, 450 Ma, and 600 Ma associated with major orogenic events and felsic magmatism, and Th/U ratios provide information on relative zircon formation temperatures. Comparison of these independent records shows that detrital rutile reflects rifting, magma-poor orogenesis, and oceanic lithospheric processes, while detrital zircon detects continental lithospheric processes. Integrated detrital zircon and rutile data sets archive past geological events across multiple Wilson cycles.
Supplemental Material: Spatiotemporal distribution of giant magnetofossils holds clues to their biological origin
Authors: Xue Pengfei , Chang L. (Liao)
Published: February 2024

Supplemental text, Figures S1–S10, and Table S1.  
Changing contexts of child health: an assessment of unmet physical, psychological and social needs of children with common chronic childhood illness
Authors: Lingam Raghu , Hu Nan , Cecil Elizabeth , Forman Julia , Newham James , Satherley Rose-Marie , Bori Marina Soley , Cousens Simon , Fox-Rushby Julia , Wolfe Ingrid
Published: February 2024

Background

We assessed the biopsychosocial needs and key health drivers among children living with a common chronic illness, as baseline for a cluster randomised controlled trial of a child health system strengthening intervention.

Methods

Cross-sectional data were analysed from a large population sample of children from South London with asthma, eczema or constipation, as exemplar tracer conditions of a new integrated care service. Descriptive and regression analyses, accounting for sociodemographic factors, investigated social needs, psychosocial outcomes and quality of life associated with poor symptom control.

Results

Among 7779 children, 4371 children (56%) had at least one uncontrolled physical health condition. Across the three domains of physical health, mental health and social needs, 77.5% of children (n=4304 of 5554) aged 4–15 years had at least one unmet need, while 16.3% of children had three unmet needs. Children from the most socioeconomically disadvantaged quintile had a 20% increased risk of at least one poorly controlled physical condition (risk ratio (RR)=1.20, 95% CI: 1.11 to 1.31, p<0.001) compared with those from the least disadvantaged quintile. There was an 85% increased risk of clinically important mental health needs among children with uncontrolled asthma (RR=1.85, 95% CI: 1.65 to 2.07, p<0.001), 57% for active constipation (RR=1.57, 95% CI: 1.12 to 2.20, p<0.01) and 39% for uncontrolled eczema (RR=1.39, 95% CI: 1.24 to 1.56, p<0.001). Health-related quality of life was associated with poor symptom control.

Conclusions

There is a large burden of unmet biopsychosocial needs among children with chronic illness, signalling an urgent need for prevention, early intervention and integrated biopsychosocial care.
Internet-based behavioural activation therapy versus online psychoeducation for self-reported suicidal ideation in individuals with depression in Indonesia: a secondary analysis of an RCT
Authors: Heuschen Caroline B B C M , Bolhuis Koen , Zantvoord Jasper B , Arjadi Retha , Denys Damiaan A J P , Nauta Maaike H , Lok Anja , Bockting Claudi L
Published: February 2024

Background

Southeast Asia has the highest suicide mortality worldwide. To improve our knowledge on the effectiveness of interventions for suicidal ideation (SI) in individuals with depression in Indonesia, we conducted a secondary analysis of a randomised controlled trial.

Objective

We explored whether an internet-based behavioural activation (BA) intervention (‘Guided Act and Feel Indonesia’ (GAF-ID)) was superior in targeting SI compared with online-delivered psychoeducation (PE).

Methods

In total, 313 participants were randomised between treatment allocation. The SI item of the Patient Health Questionnaire-9 was the primary outcome measure. Mediation analyses were conducted to identify if BA at week 10 mediated the relationship between intervention and SI at week 24.

Findings

The GAF-ID intervention was not superior in reducing SI compared with online minimal PE at week 10 (OR 0.61, 95% CI (0.37 to 1.01)), nor at week 24 (OR 0.84, 95% CI (0.47 to 1.52)). SI at week 24 was not mediated by BA at week 10 (b=−0.03, 95% CI (−0.05 to 0.00), p=0.07).

Conclusions

In individuals with depression in Indonesia, the GAF-ID intervention was not superior in reducing self-reported SI compared with PE. Also, the association between treatment condition and SI at week 24 was not mediated via BA at week 10.

Clinical implications

This study supports the need for further research on the efficacy of psychological treatments targeting SI in the Southeast Asia context.
Remote pulmonary rehabilitation for interstitial lung disease: developing the model using experience-based codesign
Authors: Brighton Lisa Jane , Spain Nannette , Gonzalez-Nieto Jose , Ingram Karen A , Harvey Jennifer , Man William D-C , Nolan Claire M
Published: February 2024

Background

Remote delivery may improve access to pulmonary rehabilitation (PR). Existing studies are largely limited to individuals with COPD, and the interventions have lacked codesign elements to reflect the needs and experiences of people with chronic respiratory disease, their carers/families and healthcare professionals. The aim of this study was, using experience-based codesign (EBCD), to collaborate with people with interstitial lung disease (ILD), their carers/families and healthcare professionals, to codesign a remote PR programme ready for testing in a future study.

Methods

EBCD comprises interviews, stakeholder workshops and codesign meetings. One-to-one videorecorded interviews with purposively selected people with ILD with experience of PR, their carers/families and healthcare professionals, were edited into a 20 min film. The film was shown at three audiorecorded stakeholder feedback events to identify key themes and touchpoints, and short-list key programme components. The programme was finalised at two further codesign workshops.

Results

Ten people with ILD, four carers/families and seven healthcare professionals were interviewed. Participants in the codesign workshops included service-user group: n=14 and healthcare professional group: n=11; joint event: n=21. Final refinements were made with small codesign teams, one comprising three people with ILD and one carer/family member, one with five healthcare professionals. The final codesigned model is a group based, supervised programme delivered by videoconference. Key elements of programme specific to ILD include recommendations to ensure participant safety in the context of desaturation risk, dedicated time for peer support and adaption of the education programme for ILD needs, including signposting to palliative care.

Conclusion

In this EBCD project, a remote PR programme for people with ILD was codesigned by service-users, their carers/families and multidisciplinary healthcare professionals. Future research should explore the feasibility and acceptability of this intervention.
Effectiveness of the KC@H programme compared with clinic-based rehabilitation in patients recovering from ACL reconstruction: a study protocol for a single-centre, two-arm, single-blinded, randomised controlled superiority trial
Authors: Alegrete Joana , Batalha Nuno , Fernandes Orlando , Parraca Jose Alberto , Rodrigues Ana Maria , Londral Ana Rita , Sousa João Paulo
Published: February 2024

Patients who cannot fully comply with conventional clinic-based rehabilitation (CR) sessions after ACL reconstruction (ACLR) may find additional internet-based sessions beneficial. These remote sessions include therapeutic exercises that can be done at home, potentially extending the reach of rehabilitation services to underserved areas, prolonging the duration of care and providing improved supervision. The study’s main purpose is to determine if the Knee Care at Home (KC@H) programme is more effective than conventional CR alone in improving patient-reported, clinician-reported and physical functional performance outcome measures after ACLR. Additionally, the trial assesses the significance of changes in outcome measures for clinical practice.

This protocol outlines a randomised controlled trial for postoperative recovery following ACLR. Adult participants of both sexes who meet specific criteria will be randomly assigned to either the CR group or the KC@H group. Only the latter group will receive internet-based sessions of therapeutic exercises at home and CR sessions. A follow-up evaluation will be conducted for both groups 12 weeks after the intervention ends.

The trial protocol was approved by the Ethics Committee of the Universidade de Évora and complies with the Code of Ethics of the World Medical Association. All recordings will be stored on a secure server with limited access and deleted as soon as they are no longer needed.

The KC@H programme is expected to be superior to conventional CR for patients recovering from ACLR across multiple outcome measures. Also, the programme has the potential to promote superior recovery and extend the reach and duration of care.

Trial registration number:NCT05828355.
Age-related differences in long-term potentiation-like plasticity and short-latency afferent inhibition and their association with cognitive function
Authors: Lu Qian , Huang Sisi , Zhang Tianjiao , Song Jie , Dong Manyu , Qian Yilun , Teng Jing , Wang Tong , He Chuan , Shen Ying
Published: February 2024

Background

The neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood.

Aims

To reveal the differences in long-term potentiation (LTP)-like plasticity and short-latency afferent inhibition (SAI) between older and younger individuals, alongside their correlation with cognitive function using transcranial magnetic stimulation (TMS).

Methods

The cross-sectional study involved 31 younger adults aged 18–30 and 46 older adults aged 60–80. All participants underwent comprehensive cognitive assessments and a neurophysiological evaluation based on TMS. Cognitive function assessments included evaluations of global cognitive function, language, memory and executive function. The neurophysiological assessment included LTP-like plasticity and SAI.

Results

The findings of this study revealed a decline in LTP among the older adults compared with the younger adults (wald χ2=3.98, p=0.046). Subgroup analysis further demonstrated a significant reduction in SAI level among individuals aged 70–80 years in comparison to both the younger adults (SAI(N20): (t=−3.37, p=0.018); SAI(N20+4): (t=−3.13, p=0.038)) and those aged 60–70 (SAI(N20): (t=−3.26, p=0.025); SAI(N20+4): (t=−3.69, p=0.006)). Conversely, there was no notable difference in SAI level between those aged 60–70 years and the younger group. Furthermore, after employing the Bonferroni correction, the correlation analysis revealed that only the positive correlation between LTP-like plasticity and language function (r=0.61, p<0.001) in the younger group remained statistically significant.

Conclusions

During the normal ageing process, a decline in synaptic plasticity may precede cholinergic system dysfunction. In individuals over 60 years of age, there is a reduction in LTP-like plasticity, while a decline in cholinergic system function is observed in those over 70. Thus, the cholinergic system may play a vital role in preventing cognitive decline during normal ageing. In younger individuals, LTP-like plasticity might represent a potential neurophysiological marker for language function.
Increased PI3K pathway activity is associated with recurrent breast cancer in patients with low and intermediate 21-gene recurrence score
Authors: Lin Lawrence Hsu , Wesseling-Rozendaal Yvonne , Vasudevaraja Varshini , Shen Guomiao , Black Margaret , van Strijp Dianne , Neerken Sigi , van de Wiel Paul A , Jour George , Cotzia Paolo , Darvishian Farbod , Snuderl Matija
Published: February 2024

Aims

We investigated key signalling pathways’ activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence.

Methods

This is a retrospective case–control study of 18 patients with recurrent breast carcinoma with low and intermediate 21-gene RS (<25) and control group of 15 non-recurrent breast cancer patients. DNA and mRNA were extracted from tumour tissue. mRNA expression of genes involved in oestrogen receptor (ER), androgen receptor (AR), PI3K and MAPK signalling pathways was measured by real-time quantitative reverse transcription-qPCR (OncoSIGNal G4 test, InnoSIGN). Tumour mutational landscape was assessed by targeted DNA sequencing (Oncomine Precision Assay).

Results

There were no statistical differences between the groups’ demographic and clinicopathological characteristics. PI3K pathway showed significantly higher activity in cases compared with controls (p=0.0014). Receiver operating characteristic curve analysis showed an area under the curve of 0.79 for PI3K pathway activity in the prediction of recurrent disease in low and intermediate 21-gene RS breast cancer. There was no difference in ER, AR and MAPK pathway activity.PIK3CAalterations were the most common driver mutations, but no difference was found between the groups (p=0.46) and no association with PI3K pathway activity (p=0.86). HigherKi67gene expression was associated with recurrences (p=0.042)

Conclusion

Increased PI3K pathway activity, independent ofPIK3CAmutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.
Modeling chronic disease risk across equity factors using a population-based prediction model: the Chronic Disease Population Risk Tool (CDPoRT)
Authors: Chen Kitty , Kornas Kathy , Rosella Laura C
Published: February 2024

Background

Predicting chronic disease incidence at a population level can help inform overall future chronic disease burden and opportunities for prevention. This study aimed to estimate the future burden of chronic disease in Ontario, Canada, using a population-level risk prediction algorithm and model interventions for equity-deserving groups who experience barriers to services and resources due to disadvantages and discrimination.

Methods

The validated Chronic Disease Population Risk Tool (CDPoRT) estimates the 10-year risk and incidence of major chronic diseases. CDPoRT was applied to data from the 2017/2018 Canadian Community Health Survey to predict baseline 10-year chronic disease estimates to 2027/2028 in the adult population of Ontario, Canada, and among equity-deserving groups. CDPoRT was used to model prevention scenarios of 2% and 5% risk reductions over 10 years targeting high-risk equity-deserving groups.

Results

Baseline chronic disease risk was highest among those with less than secondary school education (37.5%), severe food insecurity (19.5%), low income (21.2%) and extreme workplace stress (15.0%). CDPoRT predicted 1.42 million new chronic disease cases in Ontario from 2017/2018 to 2027/2028. Reducing chronic disease risk by 5% prevented 1500 cases among those with less than secondary school education, prevented 14 900 cases among those with low household income and prevented 2800 cases among food-insecure populations. Large reductions of 57 100 cases were found by applying a 5% risk reduction in individuals with quite a bit workplace stress.

Conclusion

Considerable reduction in chronic disease cases was predicted across equity-defined scenarios, suggesting the need for prevention strategies that consider upstream determinants affecting chronic disease risk.
Mitochondrial replacement techniques for treating infertility
Authors: Braun Esther
Published: February 2024

Mitochondrial replacement techniques (MRTs) usually aim to prevent the genetic transmission of maternally inherited mitochondrial diseases. Until now, only the UK and Australia have implemented specific legal regulations of MRTs. In both countries, clinical trials on these techniques are only permissible for cases with a high risk of severe mitochondrial disease in the offspring. However, these techniques can also be applied to treat infertility, especially for older women with impaired oocyte quality. In some countries without legal regulation of these techniques, MRTs are already offered for this purpose. Yet, this application of MRTs has received insufficient attention in the bioethical literature so far.

In this paper, I examine whether there are ethical reasons to prohibit trials on MRTs in the context of infertility when they are permitted for preventing mitochondrial disease. Allowing MRTs in one context but not the other might be justified either because their application in the context of mitochondrial disease (1) is supported by a more convincing evidence base, (2) has a higher potential benefit or (3) has a lower risk. I compare both applications of MRTs with respect to these three factors. I conclude that there is no convincing reason to prohibit clinical trials on MRTs for infertility when they are permitted in the context of mitochondrial disease.
Differences in reproductive health discussions in an urban Hispanic population with SLE: lessons from the field
Authors: Delgado Martha , Rodman Jack , Xepoleas Meredith , Weisman Michael , Wise Leanna Marderian
Published: February 2024

Objective

Management of reproductive health-related issues is crucial for patients with SLE, given this is a disease that primarily affects women of childbearing age. Little is known as to how the 2020 American College of Rheumatology (ACR) Reproductive Health in Rheumatic Disease Guideline is experienced by an underserved, primarily Hispanic population and their physicians as it relates to pregnancy planning and contraception conversations. Given this population experiences high rates of unplanned pregnancies and worse SLE outcomes compared with the non-Hispanic white population, it is crucial to understand how reproductive health is discussed in this setting.

Methods

A survey based on the 2020 ACR Reproductive Health Guideline was created and distributed in English and Spanish in the outpatient setting to 151 patients with SLE to determine patients’ beliefs, experiences and limitations with reproductive health discussions. Associations between categorical variables were evaluated using Pearson’s χ2or Fisher’s exact test, as appropriate, and differences in continuous variables were assessed using Wilcoxon rank-sum test.

Results

English language survey respondents were significantly more likely to report having conversations regarding contraception, pregnancy planning and peripartum medication use than the Spanish survey respondents. Two-thirds of all respondents relied on the rheumatologist as a top source of reproductive health information.

Conclusion

Disparities exist regarding reproductive health conversations on multiple topics between English-speaking and Spanish-speaking populations with SLE. Further understanding is needed to clarify why reproductive health conversations occur at lower frequencies in Spanish-speaking SLE populations.
Patient-reported outcomes and radiographic progression in patients with rheumatoid arthritis in sustained remission versus low disease activity
Authors: Snoeck Henkemans Selinde V J , Vis Marijn , Looijen Agnes E M , van der Helm-van Mil Annette H M , de Jong Pascal H P
Published: February 2024

Objective

To compare clinical and patient-reported outcomes (PROs) over 5 years between patients with rheumatoid arthritis (RA) in sustained remission (sREM), sustained low disease activity (sLDA) or active disease (AD) in the first year after diagnosis.

Methods

All patients with RA from the treatment in the Rotterdam Early Arthritis CoHort trial, a multicentre, stratified, single-blinded trial with a treat-to-target approach, aiming for LDA (Disease Activity Score (DAS) ≤2.4), were studied. Patients were categorised into: (1) sREM (mean DAS from 6 to 12 months <1.6) (n=173); (2) sLDA (mean DAS from 6 to 12 months 1.6–2.4) (n=142); and (3) AD (mean DAS from 6 to 12 months >2.4) (n=59). Pain, fatigue, functional impairment, health-related quality of life (HRQoL), health status and productivity loss during 5 years were compared between groups. Radiographic progression (modified Total Sharp Score (mTSS)) was compared over 2 years.

Results

Patients in sLDA in the first year had worse PROs during follow-up, compared with patients in sREM: pain (0–10 Likert) was 0.90 units higher (95% CI 0.52 to 1.27), fatigue (Visual Analogue Scale) was 12.10 units higher (95% CI 7.27 to 16.92), functional impairment (Health Assessment Questionnaire—Disability Index) was 0.28 units higher (95% CI 0.17 to 0.39), physical HRQoL (36-item Short Form Health Survey (SF-36) Physical Component Summary score) was 4.42 units lower (95% CI −6.39 to –2.45), mental HRQoL (SF-36 Mental Component Summary score (MCS)) was 2.95 units lower (95% CI −4.83 to –1.07), health status (European Quality of life 5-Dimensions 3-Levels (EQ-5D-3L)) was 0.06 units lower (95% CI −0.09 to –0.03) and productivity loss (0%–100%) was 7.76% higher (95% CI 2.76 to 12.75). Differences between the AD and sREM group were even larger, except for the SF-36 MCS and EQ-5D-3L. No differences in mTSS were found between groups.

Conclusion

Patients with RA who reach sREM in the first year have better HRQoL and function, and less pain, fatigue and productivity loss in the years thereafter, compared with patients with RA who are in sLDA or AD in the first year.
Rheumatoid arthritis, disease-modifying antirheumatic drugs and risk of major osteoporotic fracture: prospective data from the HUNT Study, Norway
Authors: Tronstad Ingebjørg , Hoff Mari , Horn Julie , Vikjord Sigrid Anna Aalberg , Videm Vibeke , Johansson Jonas , Nilsen Tom Ivar Lund , Langhammer Arnulf
Published: February 2024

Objectives

Rheumatoid arthritis has been associated with increased fracture risk. New treatments have improved the course of the disease substantially, but it is not clear if this influences fracture risk. We examined if rheumatoid arthritis, overall and according to disease-modifying antirheumatic drugs (DMARDs), is associated with a risk of major osteoporotic fractures.

Methods

Overall, 92 285 participants in the population-based Nord-Trndelag Health Study (HUNT), Norway were included and linked with hospital records for a validated rheumatoid arthritis diagnosis (n=605), type of DMARD treatment and fracture diagnosis. Participants were followed up until the first major osteoporotic fracture, death, emigration or end of follow-up. Cox regression was used to estimate HRs for fractures among individuals with rheumatoid arthritis, overall and by DMARD treatment, compared with participants without rheumatoid arthritis.

Results

A total of 9670 fractures were observed during follow-up, of which 88 were among those with rheumatoid arthritis. Compared with the reference group of participants without rheumatoid arthritis, those with the disease had an HR of fracture of 1.41 (95% CI 1.13 to 1.74). The association was largely similar for users of csDMARDs (HR 1.44; 95% CI 1.15 to 1.81), whereas the association for bDMARD users was weaker and less precise (HR 1.19; 95% CI 0.64 to 2.21).

Conclusion

Participants with rheumatoid arthritis had a 40% higher risk of fracture than participants without the disease. A similar fracture risk was observed for conventional synthetic DMARD use, whereas there was weak evidence that the use of biological DMARDs may be associated with a somewhat lower fracture risk.
Public support for tobacco endgame policies in South Korea: Findings from the 2020 International Tobacco Control Korea Survey
Authors: Kang Heewon , Yoon Wonjeong , Seo Hong Gwan , Lee Sungkyu , Lim Sujin , Kim Gil-yong , Kim Su Young , Xu Steve S , Yan Mi , Quah Anne C K , Chung-Hall Janet , Craig Lorraine V , Gartner Coral E , Fong Geoffrey T , Cho Sung-il
Published: February 2024

Background

Strong public support can increase the likelihood of adopting tobacco control policies. We assessed support for six commercial tobacco endgame policies in South Korea: limiting the nicotine in cigarettes, banning all additives in cigarettes, restricting the number of places where cigarettes are sold, and banning the manufacture and sales of cigarettes (unconditionally, with the provision of cessation support and with alternative tobacco products available).

Methods

Data were obtained from 4740 adults who completed the 2020 International Tobacco Control Korea Survey. Participants were categorised based on their nicotine use: (1) did not use any products, (2) vaped and/or used heated tobacco products (HTPs) but did not smoke cigarettes, (3) smoked cigarettes only and (4) smoked cigarettes and vaped and/or used HTPs. Attitudes towards the policies were classified as supportive, undecided or opposed. Weighted multinomial logistic regression models assessed support levels according to nicotine use.

Results

Support was highest for limiting the nicotine content in cigarettes (68.4%; 95% CI 64.6% to 72.3%) and restricting the number of retailers (68.1%; 95% CI 64.5% to 71.7%), and lowest for banning cigarette sales if alternative products are made available (45.0%; 95% CI 40.9% to 49.1%). People who did not use any products were most likely to support endgame policies, except for banning cigarette sales with alternatives available. The proportion of undecided participants exceeded 10% (range 13%–25%) for all policies.

Conclusion

There is a strong public support for tobacco endgame policies in South Korea. Further research should prioritise the development of strategies to ensure the effective implementation of highly supported policies.