bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing perioperative age and comorbidity: a 16-year cohort study at two University hospital sites in Sweden
Authors: Leigard Ellen , Hertzberg Daniel , Konrad David , Bell Max
Published: March 2024

Background:

Increasing life expectancy affects all aspects of healthcare. During surgery, elderly patients are prone to complications and have a higher risk of death. The authors aimed to investigate if adult patients undergoing surgery at a large Swedish university hospital were getting older and sicker over time and if this potential shift in age and illness severity was associated with higher patient mortality rates.

Materials and methods:

This was a 16-year cohort study on all surgical procedures performed in adult patients 2006–2021 at two sites of Karolinska University Hospital. Study data was obtained from the surgical system, electronic medical records, and cause-of-death register. Information on age, sex, American Society of Anesthesiologists (ASA) classification, date, type, acuity and duration of surgery was collected. ICD codes were used to calculate the Charlson comorbidity index (CCI). Short-term, medium-term and long-term mortality rates were assessed. Logistic regression models were used to evaluate changes over time.

Results:

There were 622 814 surgical procedures 2006–2021. Age, ASA classification, and CCI increased over time (P<0.0001). The proportions of age older than or equal to 60 years increased from 41.8 to 52.8% and of ASA class greater than or equal to 3 from 22.5 to 47.6%. Comparing 2018–2021 with 2006–2009, odds ratios (95% CIs) of 30-day, 90-day and 365-day mortality, adjusted for age, sex, non-elective surgery and ASA classification, decreased significantly to 0.75 (0.71–0.79), 0.72 (0.69–0.76), and 0.76 (0.74–0.79), respectively.

Conclusion:

Although the surgical population got older and sicker during the 16-year study period, short-term, medium-term and long-term mortality rates decreased significantly. These demographic shifts must be taken into account when planning for future healthcare needs to preserve patient safety.
Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis
Authors: Li Wei , Xu Jing-Wen , Chai Jin-Lian , Guo Cong-Cong , Li Guang-Zheng , Gao Mei , Liang Xue-Zhen
Published: March 2024

Purpose:

Previous studies have explored the role of immune cells on osteonecrosis. This Mendelian randomization (MR) study further assessed 731 immunocyte phenotypes on osteonecrosis, whether a causal relationship exists, and provides some evidence of causality.

Methods:

The 731 immunocyte phenotypes and osteonecrosis data used in this study were obtained from their respective genome-wide association studies (GWAS). The authors used inverse variable weighting (IVW) as the primary analysis method. In addition, the authors simultaneously employed multiple analytical methods, including MR-Egger, weighted mode, simple mode, and weighted median, to strengthen the final results. Finally, sensitivity analyses were conducted to verify the stability and feasibility of the data.

Results:

The results of the IVW method of MR analysis showed that 8 immunocyte phenotypes were positively associated with osteonecrosis [P<0.05, odds ratio (OR) > 1]; 18 immunocyte phenotypes were negatively associated with osteonecrosis (P<0.05, OR<1), none of which were heterogeneous or horizontally pleiotropic (P > 0.05) or reverse causality. In addition to this, in reverse MR, osteonecrosis was positively associated with 10 additional immunocyte phenotypes (P<0.05, OR > 1) and negatively associated with 14 immunocyte phenotypes (P<0.05, OR<1). And none of them had heterogeneity and horizontal pleiotropy (P > 0.05) or reverse causality.

Conclusions:

The authors demonstrated a complex causal relationship between multiple immune phenotypes and osteonecrosis through a comprehensive two-way, two-sample MR analysis, highlighting the complex pattern of interactions between the immune system and osteonecrosis.
Association of follow-up neutrophil-to-lymphocyte ratio and systemic inflammation response index with stroke-associated pneumonia and functional outcomes in cerebral hemorrhage patients: a case-controlled study
Authors: Xu Mengmeng , Wang Jingru , Zhan Chenyi , Zhou Ying , Luo Zhixian , Yang Yunjun , Zhu Dongqin
Published: March 2024

Background:

The neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation response index (SIRI) at admission are independent diagnostic biomarkers in stroke-associated pneumonia (SAP). Our study aimed to investigate the association between NLR, SIRI, specifically follow-up NLR and SIRI, and SAP, as well as their relationship with functional outcomes.

Patients and methods:

We retrospectively included 451 consecutive intracerebral hemorrhage patients from May 2017 to May 2019. We conducted univariate and multivariable analyses to identify the factors independently associated with SAP and poor functional outcomes.

Results:

Compared to 127 (28.16%) patients diagnosed with SAP, those without SAP had both lower baseline and follow-up NLR and SIRI values (P<0.001). After adjustments, we found that baseline NLR [OR, 1.039 (95% CI, 1.003–1.077); P=0.036] and follow-up NLR [OR, 1.054 (95% CI, 1.011–1.098); P=0.012] were independently associated with SAP. The follow-up NLR was also associated with a higher mRS [OR, 1.124 (95% CI, 1.025–1.233); P=0.013] and lower ADL-MBI score [OR, 1.167 (95% CI, 1.057–1.289); P=0.002] at discharge. Multivariable analysis indicated that advanced age and nasogastric tube feeding were independently associated with SAP (P<0.05). We constructed a dynamic nomogram to identify SAP risk. Further subgroup analysis revealed that baseline NLR [OR, 1.062 (95% CI, 1.007–1.120); P=0.026] is independently associated with SAP in the nasogastric feeding group, while follow-up NLR [OR, 1.080 (95% CI, 1.024–1.139); P=0.005] was associated with the occurrence of SAP in non-nasogastric feeding patients.

Conclusions:

We found elevated baseline and follow-up NLR values were associated with SAP occurrence, and increasing follow-up NLR indicated poor functional outcomes. Inflammatory markers at different stages may offer individualized guidance for patients receiving various treatments.
Global trends in colorectal cancer and metabolic syndrome research: a bibliometric and visualization analysis
Authors: Wu Peng-Ning , Liu Jia-Li , Fang Mei-Juan , Fu Xiao-Shuo , Wei Jia-Li , Wang Yue , Qian Hai-Hua , Zhang Dan
Published: March 2024

Numerous studies have demonstrated a robust correlation between metabolic syndrome (MetS) and colorectal cancer (CRC). Nonetheless, no systematic analysis or visualization of relevant publications has been conducted via bibliometrics. This research, centred on 616 publications obtainable through the Web of Science Core Collection (WoSCC), employed CiteSpace software and VOSviewer software for correlation analyses of authors, journals, institutions, countries, keywords, and citations. The findings indicate that the Public Library of Science had the highest number of publications, while the United States, China, and South Korea were the most contributory nations. Recent years have seen the mechanisms linking Metabolic Syndrome with Colorectal Cancer, including diet, obesity, insulin resistance, and intestinal flora, remain a burgeoning research area. Furthermore, bariatric surgery appears to be a promising new area of study. This paper presents the initial bibliometric and visualization analysis of research literature concerning CRC and MetS which examines research trends and hotspots.
Iron chelators: as therapeutic agents in diseases
Authors: Salimi Zohreh , Afsharinasab Mehdi , Rostami Mehdi , Eshaghi Milasi Yaser , Mousavi Ezmareh Seyedeh Fatemeh , Sakhaei Fariba , Mohammad-Sadeghipour Maryam , Rasooli Manesh Sayyed Mehdi , Asemi Zatollah
Published: March 2024

The concentration of iron is tightly regulated, making it an essential element. Various cellular processes in the body rely on iron, such as oxygen sensing, oxygen transport, electron transfer, and DNA synthesis. Iron excess can be toxic because it participates in redox reactions that catalyze the production of reactive oxygen species and elevate oxidative stress. Iron chelators are chemically diverse; they can coordinate six ligands in an octagonal sequence. Because of the ability of chelators to trap essential metals, including iron, they may be involved in diseases caused by oxidative stress, such as infectious diseases, cardiovascular diseases, neurodegenerative diseases, and cancer. Iron-chelating agents, by tightly binding to iron, prohibit it from functioning as a catalyst in redox reactions and transfer iron and excrete it from the body. Thus, the use of iron chelators as therapeutic agents has received increasing attention. This review investigates the function of various iron chelators in treating iron overload in different clinical conditions.
Bilateral hearing impairment as an early symptom in a patient with Charcot-Marie-Tooth Type 1: the first case report from Syria
Authors: Hamsho Suaad , Almohamed Ahmad , Haydar Hasan , Alsaffaf Yousef , Sultan Enas , Sukkar Yassen , kazkz Waddah
Published: March 2024

Introduction:

Charcot-Marie-Tooth (CMT) is a group of inherited neuromuscular disorders that vary clinically and genetically. It is characterized by peripheral nerve damage, leading to muscle weakness and sensory loss.

Case presentation:

A 13-year-old male presented to the rheumatology department with bilateral hearing impairment since the age of 3 years, pes cavus, and difficulties walking. Some family members had Achilles tendon lengthening surgery. During physical examination, the patient had a shortened Achilles tendon, there are high arches in the feet, curled toes, loss of touch sensation in the feet, ankles, and legs, atrophy in the foot muscles. An eye examination revealed a discrepancy that needed glasses. Neurological findings included horizontal and vertical nystagmus, proprioception disorder, and demyelinating sensorimotor disorder diagnosed as CMT type 1. The audiogram showed bilateral sensorineural hearing impairment. MRI revealed spinal disc bulges. The treatment plan includes Achilles tendon lengthening surgery and physical therapy.

Clinical discussion:

CMT patients need to receive supportive treatment including physical therapy, hearing aids, and glasses, to help improve their quality of life.

Conclusion:

CMT disease is a genetic disorder that causes difficulties in movement, coordination, and daily activities due to muscle weakness and sensory impairments. In a few cases, patients have been documented to have bilateral hearing impairment as their first symptoms. It affects individuals in Syria and around the world, and requires proper diagnosis and treatment.
Depressive Symptoms, Socioeconomic Position, and Mortality in Older People Living With and Beyond Cancer
Authors: Miller Natalie Ella , Fisher Abigail , Frank Philipp , Lally Phillippa , Steptoe Andrew
Published: March 2024

Objective

Evidence shows that higher depressive symptoms are associated with mortality among people living with and beyond cancer (LWBC). However, prior studies have not accounted for a wider range of potential confounders, and no study has explored whether socioeconomic position (SEP) moderates the association. This study aimed to examine the association between depressive symptoms and mortality among people LWBC, and moderation by SEP.

Methods

Participants from the English Longitudinal Study of Aging, diagnosed with cancer and with a measure of depressive symptoms within 4 years after their diagnosis, were included. Elevated depressive symptoms were indicated by a score of ≥3 on the eight-item Center for Epidemiologic Studies Depression Scale. Cox regression models examined associations with all-cause mortality. Competing risk regression examined associations with cancer mortality.

Results

In 1352 people LWBC (mean age = 69.6 years), elevated depressive symptoms were associated with a 93% increased risk of all-cause mortality (95% confidence interval = 1.52–2.45) within the first 4 years of follow-up and a 48% increased risk within a 4- to 8-year follow-up (95% confidence interval = 1.02–2.13) after multivariable adjustment. Elevated depressive symptoms were associated with a 38% increased risk of cancer mortality, but not after excluding people who died within 1 year after baseline assessments. There were no interactions between depressive symptoms and SEP.

Conclusions

Elevated depressive symptoms are associated with a greater risk of all-cause mortality among people LWBC within an 8-year follow-up period. Associations between depressive symptoms and cancer mortality might be due to reverse causality.
Bullet holes: A novel model to identify the most impactful gaps in the firearm homicide prevention laws of each state
Authors: Laudon Aksel D. , Davis Elizabeth S. , Zhao Xuewei , Kenzik Kelly , Torres Crisanto , Sanchez Sabrina E. , Brahmbhatt Tejal S. , Scantling Dane R.
Published: March 2024

BACKGROUND

Firearm homicides (FH) are a major cause of mortality in the United States. Firearm law implementation is variable across states, and legislative gaps may represent opportunities for FH prevention. For each state, we sought to identify which firearm law category would have been most effective if implemented and how effective it would have been.

METHODS

We conducted a retrospective cohort study examining the effects of firearm laws on FH rates in the 48 contiguous US states 2010 to 2019. Data were obtained from the CDC WONDER and FBI UCR databases, State Firearm Law Database, and US Census. Firearm laws were grouped into 14 categories. We assessed the association between the presence of each law category and FH rate as an incidence rate ratio (IRR) using a Poisson regression accounting for state population characteristics and laws of surrounding states. We estimated the IRR for each state that did not have a given law category present and determined which of these missing law categories would have been associated with the greatest reduction in FH rate.

RESULTS

FH rates varied widely across states and increased from a mean of 3.2 (SD = 1.7) to 4.2 (SD = 2.9) FH per 100,000. All law categories were significantly associated with decreased FH rate (p < 0.05), with IRR ranging from 0.25 to 0.85. The most effective missing law category differed between states but was most commonly child access prevention (34.09% of states), assault weapons and large-capacity magazines (15.91%), preemption (15.91%), and concealed carry permitting (13.64%). In total across 2010 to 2019, we estimated that 129,599 fewer FH would have occurred with enactment of the most effective missing law category in each state.

CONCLUSION

Modeling firearm law prevention of FH with regard to state legislative and population characteristics can identify the highest impact missing law categories in each state. These results can be used to inform efforts to reduce FH.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Clinical characteristics of patients with myelin oligodendrocyte glycoprotein antibodies
Authors: Maillart Elisabeth , Deiva Kumaran , Marignier Romain
Published: March 2024

Purpose of review

The clinical landscape associated to myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) has undergone a remarkable transformation over the past two decades, primarily driven by advancements in antibody detection techniques that have enhanced both the specificity and sensitivity of assays, enabling the identification of novel clinical phenotypes.

Recent findings

Recent pivotal research publications, comprehensive reviews from established research groups, and most notably the first proposed international criteria for MOG-Ab associated disease (MOGAD) have substantially enriched our understanding of the clinical features associated with MOG-Ab. This review presents a comprehensive overview of the clinical characteristics of patients with MOG-Ab, systematically examining each core clinical syndrome defined by the proposed international MOGAD criteria. We incorporated recent insights and discussed potential challenges in applying these criteria across diverse clinical scenarios.

The proposed international MOGAD criteria provide a comprehensive, homogeneous, and specific framework for characterizing the clinical features of patients with MOG-Ab, encompassing both paediatric and adult populations. In the future, the widespread adoption of specific and reliable assays for MOG-Ab detection, complemented by the development of surrogate fluid and imaging markers, holds promise for better characterizing atypical presentations, only-cerebrospinal fluid positivity and the MOGAD “seronegative” situations.
Robotics vs Laparoscopy in Foregut Surgery: Systematic Review and Meta-Analysis Analyzing Hiatal Hernia Repair and Heller Myotomy
Authors: Awshah Sabrina , Mhaskar Rahul , Diab Abdul-Rahman Fadi , Read Meagan , Coughlin Emily , Ganam Samer , Saad Adham R , Sujka Joseph , DuCoin Christopher
Published: March 2024

BACKGROUND:

Laparoscopic surgery remains the mainstay of treating foregut pathologies. Several studies have shown improved outcomes with the robotic approach. A systematic review and meta-analysis comparing outcomes of robotic and laparoscopic hiatal hernia repairs (HHR) and Heller myotomy (HM) repairs is needed.

STUDY DESIGN:

PubMed, EMBASE, and SCOPUS databases were searched for studies published between January 2010 and November 2022. The risk of bias was assessed using the Cochrane Risk of Bias in Non-Randomized Studies of Interventions tool. Assessed outcomes included intra- and postoperative outcomes. We pooled the dichotomous data using the Mantel-Haenszel random-effects model to report odds ratio (OR) and 95% CIs and continuous data to report mean difference and 95% CIs.

RESULTS:

Twenty-two comparative studies enrolling 196,339 patients were included. Thirteen (13,426 robotic and 168,335 laparoscopic patients) studies assessed HHR outcomes, whereas 9 (2,384 robotic and 12,225 laparoscopic patients) assessed HM outcomes. Robotic HHR had a nonsignificantly shorter length of hospital stay (LOS) (mean difference −0.41, 95% CI −0.87 to −0.05), fewer conversions to open (OR 0.22, 95% CI 0.03 to 1.49), and lower morbidity rates (OR 0.76, 95% CI 0.47 to 1.23). Robotic HM led to significantly fewer esophageal perforations (OR 0.36, 95% CI 0.15 to 0.83), reinterventions (OR 0.18, 95% CI 0.07 to 0.47) a nonsignificantly shorter LOS (mean difference −0.31, 95% CI −0.62 to 0.00). Both robotic HM and HHR had significantly longer operative times.

CONCLUSIONS:

Laparoscopic and robotic HHR and HM repairs have similar safety profiles and perioperative outcomes. Randomized controlled trials are warranted to compare the 2 methods, given the low-to-moderate quality of included studies.
Microbiota-derived acetylcholine can promote gut motility in
Drosophila melanogaster
Authors: Fujita Yuka , Kosakamoto Hina , Obata Fumiaki
Published: March 2024

The gut microbiota is crucial for intestinal health, including gastrointestinal (GI) motility. How commensal bacterial species influence GI motility has not been fully elucidated. A major factor of GI motility is the gut contraction promoting the propulsive movement of orally ingested materials. Here, we developed a method to monitor and quantify gut contractions in living
Drosophila melanogaster
larvae. We found that the culture medium of an isolated strain
Lactiplantibacillus plantarum
Lsi promoted gut contraction
in vivo
, which was not observed in
Leuconostoc
sp. Leui nor
Acetobacter persici
Ai culture medium. To identify bacteria-derived metabolites, we performed metabolome analysis of the culture media by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Of the 66 metabolites detected, we found that some metabolites changed in a species-specific manner. Among them, acetylcholine was specifically produced by
L. plantarum.
Feeding exogenous acetylcholine increased the frequency of gut contractions, which was blocked by D-tubocurarine, an inhibitor of nicotinic acetylcholine receptors. In this study, we propose a mechanism by which the gut microbiota influences
Drosophila
gut motility.

This article is part of the theme issue ‘Sculpting the microbiome: how host factors determine and respond to microbial colonization’.
More than a colour; how pigment influences colourblind microbes
Authors: Wessel Gary M. , Xing Lili , Oulhen Nathalie
Published: March 2024

Many animals have pigments when they themselves cannot see colour. Perhaps those pigments enable the animal to avoid predators, or to attract mates. Maybe even those pigmented surfaces are hosts for microbes, even when the microbes do not see colour. Do some pigments then serve as a chemical signal for a good or bad microbial substrate? Maybe pigments attract or repel various microbe types? Echinoderms serve as an important model to test the mechanisms of pigment-based microbial interactions. Echinoderms are marine benthic organisms, ranging from intertidal habitats to depths of thousands of metres and are exposed to large varieties of microbes. They are also highly pigmented, with a diverse variety of colours between and even within species. Here we focus on one type of pigment (naphthoquinones) made by polyketide synthase, modified by flavin-dependent monoxygenases, and on one type of function, microbial interaction. Recent successes in targeted gene inactivation by CRISPR/Cas9 in sea urchins supports the contention that colour is more than it seems. Here we dissect the players, and their interactions to better understand how such host factors influence a microbial colonization.

This article is part of the theme issue ‘Sculpting the microbiome: how host factors determine and respond to microbial colonization’.
Integrated Analysis Reveals Immunogenic Cell Death in Sepsis-induced Cardiomyopathy
Authors: wang qinxue , huang haobin
Published: March 2024

Background

Sepsis-induced cardiomyopathy (SIC) poses a significant challenge in critical care, necessitating comprehensive understanding and innovative diagnostic approaches. This study explores the immune-related molecular intricacies underlying SIC, employing bioinformatics analyses and machine learning techniques.

Methods

RNA-seq and scRNA-seq datasets (GSE79962 and GSE190856) were obtained from the Gene Expression Omnibus (GEO). After initial quality control and preprocessing, scRNA-seq data (GSE190856) were analyzed using the Seurat package, including cell clustering and annotation. The CellChat package was then used to analyze immune cell interactions. Unsupervised clustering of SIC patients was performed based on differentially expressed ICD-related genes (GSE79962). Immune cell infiltration and gene set variation analysis were conducted, and weighted gene co-expression network analysis identified co-expression modules. A predictive signature for SIC was constructed through machine learning methods.

Results

Trough analyzing the GSE190856 scRNA-seq dataset, the communication between macrophages/monocytes and lymphocytes was found to be enhanced in mouse myocardial tissue during the early onset of SIC. Meanwhile, the expression level of ICD-related genes was upregulated in the monocytes infiltrating to the heart. These results suggestted that ICD may play a crucial role in the pathogenesis of SIC, which had been verified by the upregulated expression of ICD-related genes in the hearts of SIC patients in the GSE79962 dataset. The SIC patients were classified to 2 clusters, with cluster 1 exhibited an upregulation of the renin-angiotensin system, while cluster 2 displayed heightened activity in the RIG-I-like receptor signaling pathway. After comparing four machine learning models, the support vector machine (SVM) model exhibited better discrimination for SIC patients. By correlating the expression levels of the five crucial genes contained in this model with the clinical features of SIC patients, we found that JARID2 was negatively related to the Left Ventricular Ejection Fractions, while TNIP2 was negatively related to the variety of inotropes and vasopressors used in the SIC patients.

Conclusion

This research unveils the correlation between ICD and SIC, offering insights into immune activity in the hearts during sepsis. The constructed SVM model with selected genes provides a promising molecular strategy for SIC diagnosis.
Economic Evaluation: Costing participatory learning and action cycles with women’s groups to improve feeding, care and dental hygiene for South Asian infants in London
Authors: Zhang Yeqing , Patil Priyanka , Lakhanpaul Monica , Heys Michelle , Chakraborty Subarna , Dwardzweska Joanna , Llewellyn Clare H. , Webb-Martin Kelley , Irish Carol , Archibong Mfon , Gilmour Jenny , Kalungi Phoebe , Skordis Prof Jolene , Manikam Logan , Batura Neha
Published: March 2024

Background

The Nurture Early for Optimal Nutrition (NEON) programme was designed to promote equitable early childhood development by educating mothers of South Asian origin in east London on optimal feeding, care, and dental hygiene practices. This study conducts a cost analysis of the NEON programme and evaluates its financial sustainability.

Methods

We conducted an economic costing from the provider perspective and followed a stepdown procedure to identify all costs incurred from December 2019, the initiation of the trial, to May 2023, the completion of final evaluation and dissemination. Costs associated with start-up, implementation, and monitoring and evaluation activities are differentiated. Affordability analysis was conducted with respect to the budget of the local authorities.

Results

The total cost of NEON design and delivery in Newham and Towe Hamlets was £75,992 ($INT 114,445), with 45% for staff salaries, 50% for material, and 5% for capital investment. The start-up stage cost 57% while the implementation stage cost 43%. The average cost per mother participating in the programme was £409($INT 615). The total cost of trial delivery in Newham accounted for around 0.053% of the borough’s annual child development expenditure, while the total trial cost in Tower Hamlets was equivalent to 0.003% of its’ spending on children’s development.

Conclusion

The delivery of NEON is largely within local authorities’ budget for childhood development. The unit cost is expected to decrease when sharing costs are spread across more participants and implementing systems are validated and well developed.
Interventions to reduce opioid use for patients with chronic non-cancer pain in primary care settings: a systematic review and meta-analysis
Authors: Cai Qian , Grigoroglou Christos , Allen Thomas , Chen Teng-Chou , Chen Li-Chia , Kontopantelis Evangelos
Published: March 2024

Objective

This systematic review and meta-analysis aimed to assess interventions to reduce opioid use for patients with chronic non-cancer pain (CNCP) versus usual care or active controls in primary care settings.

Methods

In this registered study (PROSPERO: CRD42022338458), we searched MEDLINE, Embase PsycInfo, CINAHL, and Cochrane Library from inception to December 28th2021, and updated on Dec 14th2023 for randomized controlled trials (RCTs) and cohort studies with no restrictions. Methodological quality was assessed using the Cochrane Risk of Bias tool for RCTs and Newcastle Ottawa Scale for cohort studies. Primary outcomes included mean reduction in morphine equivalent daily dose (reported as mean differences [MDs] mg/day; 95% confidence intervals [95%CIs]) and/or opioid cessation proportion. Secondary outcomes were mean changes in pain severity (reported as standardized mean difference [SMDs]; 95%CIs) and (serious) adverse events. Meta-analyses were performed using random-effects models.

Results

We identified 3,826 records, of which five RCTs (953 participants) and six cohort studies (967 participants) were included. Overall, opioid dosage was significantly reduced in intervention groups compared to controls (MD: -24.88 mg/day, 95%CI: -36.40 to -13.36; I2=59.41%; nine studies). Subgroup analyses revealed significant opioid dose reductions with mindfulness (MD: -29.36 mg/day 95%CI: - 40.55 to -18.17; I2=0.0%; two trials) and CBT-based multimodalities (MD: -41.68 mg/day; 95%CI: -58.47 to -24.89; I2=0.0%; two cohort studies), respectively, compared to usual care. No significant differences were observed in opioid cessation (Odds ratio: 1.55, 95%CI: 0.3 to 2.81, I2=50.79%; three studies) or pain severity (SMD: -0.13, 95%CI: -0.37 to 0.11; I2=33.51%; three trials). Adverse events were infrequently examined, with withdrawal symptoms commonly reported.

Conclusions

The studied interventions were effective in reducing opioid dosage for people with CNCP in primary care. They highlighted the importance of multidisciplinary collaboration. Large-scale RCTs measuring the long-term effects and cost of these interventions are needed before their implementation.
Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq
Authors: Gaynor-Gillett Sophia C. , Cheng Lijun , Shi Manman , Liu Jason , Wang Gaoyuan , Spector Megan , Flaherty Mary , Wall Martha , Hwang Ahyeon , Gu Mengting , Chen Zhanlin , Chen Yuhang ,   PsychENCODE Consortium, Moran Jennifer R. , Zhang Jing , Lee Donghoon , Gerstein Mark , Geschwind Daniel , White Kevin P.
Published: March 2024

Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.
Chloroplastic ascorbate acts as a regulatory hub in plant metabolism regardless of oxidative stress
Authors: Tóth Dávid , Tengölics Roland , Aarabi Fayezeh , Karlsson Anna , Vidal-Meireles André , Kovács László , Kuntam Soujanya , Körmöczi Tímea , Fernie Alisdair R. , Hudson Elton P. , Papp Balázs , Tóth Szilvia Z.
Published: March 2024

Ascorbate is a major plant metabolite that plays crucial roles in various processes, from reactive oxygen scavenging to epigenetic regulation. However, to what extent and how ascorbate modulates metabolism is largely unknown. To address this, we investigated the consequences of chloroplastic and total cellular ascorbate-deficiencies by studying chloroplastic ascorbate-transporterpht4;4mutant lines, and the ascorbate-deficientvtc2-4mutant ofArabidopsis thaliana. Under regular growth conditions, both ascorbate-deficiencies caused minor alterations in photosynthesis, with no apparent signs of oxidative damage. In contrast, metabolomics analysis revealed a global and largely overlapping metabolome rewiring in both ascorbate-deficiencies, suggesting that chloroplastic ascorbate modulates plant metabolism. We observed significant alterations in amino acid metabolism, particularly in arginine metabolism, activation of nucleotide salvage pathways, and changes in secondary metabolism. In addition, proteome-wide analysis of thermostability revealed that ascorbate may interact with enzymes involved in arginine metabolism, the Calvin-Benson cycle, and several photosynthetic electron transport components. Overall, our results suggest that, independently of oxidative stress, chloroplastic ascorbate interconnects and coordinates diverse metabolic pathways in vascular plants and thus acts as a regulatory hub.
Empowering future scientists: Mentors employ various strategies to engage students in professional science disciplinary literacy practices
Authors: Minocha Trisha , Bhagatwala Tanya , Mirzoyan Gwendolyn , McDowell Gary S , Fankhauser Sarah C
Published: March 2024

Peer-review and publication are important parts of the scientific enterprise, and research has shown that engaging students in such scholarly practices helps build their sense of belonging and scientific identity. Yet, these disciplinary literacy skills and professional practices are often part of the hidden curriculum of science research, thus excluding students and others from fully understanding ways in which scientific knowledge is constructed, refined, and disseminated even though students are participating in such activities. Secondary students are increasingly involved in scientific research projects that include authentic disciplinary literacy components such as research proposals, posters, videos, and scientific research papers. More and more, students are also engaging in professional practice of publishing their scientific research papers through dedicated secondary science journals. How teachers and other mentors support the development of professional disciplinary literacies in students is critical to understand as part of supporting more student participation in research. To this end, we used a mixed- methods study of interviews and surveys to examine the experience and conceptions of the mentors (teachers and professional scientists) who guided pre-college students through the writing and publication of their scientific research projects. Analyzing our data from a lens of cognitive apprenticeship, we find that mentors encourage independence by primarily employing the method of “exploration”. We also find that mentors have divergent views on the value of publication within science, versus for student scientists specifically. Our findings suggest that mentors could work to explicitly reveal their own thinking within science writing to provide more sequenced support for student scientists.
Estimation of spatial demographic maps from polymorphism data using a neural network
Authors: Smith Chris C. R. , Patterson Gilia , Ralph Peter L. , Kern Andrew D.
Published: March 2024

A fundamental goal in population genetics is to understand how variation is arrayed over natural landscapes. From first principles we know that common features such as heterogeneous population densities and barriers to dispersal should shape genetic variation over space, however there are few tools currently available that can deal with these ubiquitous complexities. Geographically referenced single nucleotide polymorphism (SNP) data are increasingly accessible, presenting an opportunity to study genetic variation across geographic space in myriad species. We present a new inference method that uses geo-referenced SNPs and a deep neural network to estimate spatially heterogeneous maps of population density and dispersal rate. Our neural network trains on simulated input and output pairings, where the input consists of genotypes and sampling locations generated from a continuous space population genetic simulator, and the output is a map of the true demographic parameters. We benchmark our tool against existing methods and discuss qualitative differences between the different approaches; in particular, our program is unique because it infers the magnitude of both dispersal and density as well as their variation over the landscape, and it does so using SNP data. Similar methods are constrained to estimating relative migration rates, or require identity by descent blocks as input. We applied our tool to empirical data from North American grey wolves, for which it estimated mostly reasonable demographic parameters, but was affected by incomplete spatial sampling. Genetic based methods like ours complement other, direct methods for estimating past and present demography, and we believe will serve as valuable tools for applications in conservation, ecology, and evolutionary biology. An open source software package implementing our method is available fromhttps://github.com/kr-colab/mapNN.
Neural dynamics of semantic control underlying generative storytelling
Authors: Rastelli Clara , Greco Antonino , Finocchiaro Chiara , Penazzi Gabriele , Braun Christoph , De Pisapia Nicola
Published: March 2024

Storytelling has been pivotal for the transmission of knowledge and cultural norms across human history. A crucial process underlying the generation of narratives is the exertion of cognitive control on the semantic representations stored in memory, a phenomenon referred as semantic control. Despite the extensive literature investigating the neural mechanisms of semantic control in generative language tasks, little effort has been done towards storytelling under naturalistic conditions. Here, we probed human participants to generate stories in response to a set of instructions which triggered a narrative that was either appropriate (ordinary), novel (random), or balanced (creative), while recording functional magnetic resonance imaging (fMRI) signal. By leveraging deep language models, we demonstrated how participants ideally balanced the level of semantic control during story generation. At the neural level, creative stories were differentiated by a multivariate pattern of neural activity in frontal cortices compared to ordinary ones and in fronto- temporo-parietal cortices with respect to randomly generated stories. Crucially, similar brain regions were also encoding the features that distinguished the stories behaviourally. Moreover, we decomposed the neural dynamics into connectome harmonic modes and found specific spatial frequency patterns underlying the modulation of semantic control during story generation. Finally, we found different functional coupling within and between the default mode, salience and control networks when contrasting creative stories with their controls. Together, our findings highlight the neural mechanisms underlying the regulation of semantic exploration during narrative ideation and contribute to a deeper understanding of the neural dynamics underpinning the role of semantic control in generative storytelling.
An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration
Authors: Leventhal Matthew J , Zanella Camila A , Kang Byunguk , Peng Jiajie , Gritsch David , Liao Zhixiang , Bukhari Hassan , Wang Tao , Pao Ping-Chieh , Danquah Serwah , Benetatos Joseph , Nehme Ralda , Farhi Samouil , Tsai Li-Huei , Dong Xianjun , Scherzer Clemens R , Feany Mel B , Fraenkel Ernest
Published: March 2024

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer’s disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration inDrosophilawith human andDrosophilaAlzheimer’s disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics inDrosophilamodels of Alzheimer’s disease and identified Alzheimer’s disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimer’s disease multi-omic data. We computationally predicted and experimentally demonstrated howHNRNPA2B1andMEPCEenhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hitsCSNK2A1andNOTCH1regulate DNA damage inDrosophilaand human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer’s disease.
Mutational analysis of the F plasmid partitioning protein ParA reveals novel residues required for oligomerisation and plasmid maintenance
Authors: Mitra Nivedita , Mishra Dipika , Puthethu Irene Aniyan , Srinivasan Ramanujam
Published: March 2024

Mobile genetic elements such as plasmids play a crucial role in the emergence of antimicrobial resistance. Hence, plasmid maintenance proteins like ParA of the Walker A type cytoskeletal ATPases/ ParA superfamily are potential targets for novel antibiotics. Plasmid partitioning by ParA relies upon ATP-dependent dimerisation and formation of chemophoretic gradients of ParA-ATP on bacterial nucleoids. Though polymerisation of ParA has been reported in many instances, the need for polymerisation in plasmid maintenance remains unclear. In this study, we provide novel insights into the polymerisation of ParA and the effect of polymerisation on plasmid maintenance. We first characterise two mutations, Q351H and W362E, in ParA from F plasmid (ParAF) that form cytoplasmic filaments independent of the ParBSFpartitioning complex. Both mutants fail to partition plasmids, do not bind non-specific DNA and act as super-repressors to suppress transcription from the ParA promoter. Further, we show that the polymerisation of ParAFrequires the conformational switch to the ParA-ATP* state. We identify two mutations, R320A in the C-terminal helix-14 and E375A helix-16 of ParAF,that abolish filament assembly and affect plasmid partitioning. Our results thus suggest a role for higher-order structures or polymerisation of ParA in plasmid maintenance.
A deep profile of gene expression across 18 human cancers
Authors: Qiu Wei , Dincer Ayse B. , Janizek Joseph D. , Celik Safiye , Pittet Mikael , Naxerova Kamila , Lee Su-In
Published: March 2024

Clinically and biologically valuable information may reside untapped in large cancer gene expression data sets. Deep unsupervised learning has the potential to extract this information with unprecedented efficacy but has thus far been hampered by a lack of biological interpretability and robustness. Here, we present DeepProfile, a comprehensive framework that addresses current challenges in applying unsupervised deep learning to gene expression profiles. We use DeepProfile to learn low-dimensional latent spaces for 18 human cancers from 50,211 transcriptomes. DeepProfile outperforms existing dimensionality reduction methods with respect to biological interpretability. Using DeepProfile interpretability methods, we show that genes that are universally important in defining the latent spaces across all cancer types control immune cell activation, while cancer type-specific genes and pathways define molecular disease subtypes. By linking DeepProfile latent variables to secondary tumor characteristics, we discover that tumor mutation burden is closely associated with the expression of cell cycle-related genes. DNA mismatch repair and MHC class II antigen presentation pathway expression, on the other hand, are consistently associated with patient survival. We validate these results through Kaplan-Meier analyses and nominate tumor-associated macrophages as an important source of survival-correlated MHC class II transcripts. Our results illustrate the power of unsupervised deep learning for discovery of cancer biology from existing gene expression data.
A progeria-associated BAF-1 mutation modulates gene expression and accelerates aging inC. elegans
Authors: Romero-Bueno Raquel , Fragoso-Luna Adrian , Ayuso Cristina , Mellmann Nina , Kavsek Alan , Riedel Christian G. , Ward Jordan D , Askjaer Peter
Published: March 2024

Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. These include both tissue specific and systemic diseases. A single amino acid substitution in human barrier to autointegration factor (BAF) at position 12 (A12T) causes Nestor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition affects a variety of tissues, leading to growth retardation and severe skeletal defects, including scoliosis. Taking advantage of the conservation between human andC. elegansBAF proteins, we have modified thebaf-1locus inC. elegansto mimic the human NGPS mutation (baf-1(G12T)). In this work, we characterized the phenotypes caused by the G12T mutation at molecular, cellular, and organismal scale. We found that the mutation induced multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging inbaf-1(G12T), relative to wild-type animals, coinciding with an important hallmark of cells from progeria patients. Nuclear envelope accumulation of lamin and emerin was reduced whereas localization of BAF-1(G12T) was similar to wild-type BAF-1. We determined the chromatin binding profiles for wild-type and mutant BAF-1 and performed transcriptome analyses through tissue-specific DamID. Although the global profiles for wild-type and G12T BAF-1 resembled one another, we also identified many discrete regions with altered BAF-1(G12T) association. Most genes deregulated by thebaf-1(G12T)mutation were characterized by a change in BAF-1 association, suggesting a direct relation between association of a gene to BAF-1 and its expression. We conclude thatC. elegansis a relevant model to understand how a mutation in an essential protein expressed throughout development triggers the appearance of symptoms in early childhood.
Discovery of active mouse, plant and fungal cytochrome P450s in endogenous proteomes and upon expressionin planta
Authors: Farre Maria Font , Brown Daniel , Toth Reka , Mahadevan Chidambareswaren , Brazier-Hicks Melissa , Morimoto Kyoko , Kaschani Farnusch , Sinclair John , Dale Richard , Hall Samantha , Morris Melloney , Kaiser Markus , Wright Aaron T. , Burton Jonathan , van der Hoorn Renier A. L.
Published: March 2024

Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogenZymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.