bluuebunny/crossref_metadata_2025 huggingface dataset:
International harm reduction indicators are still not reached: results from a repeated cross-sectional study on drug paraphernalia distribution in Germany, 2021
Authors: Hommes Franziska , Krings Amrei , Dörre Achim , Neumeier Esther , Schäffer Dirk , Zimmermann Ruth
Published: September 2023

Background

To prevent the transmission of blood-borne infections and reach the elimination of viral hepatitis by 2030, the World Health Organization (WHO) has set the goal to distribute 300 sterile needles and syringes each year per person who injects drugs (PWID). We aimed to assess drug paraphernalia distribution in Germany in 2021, including the WHO indicator, and to analyse changes to the distribution measured in 2018.

Methods

We conducted a repeated cross-sectional study of low-threshold drug services in Germany. We assessed type and quantity of distributed drug paraphernalia and the number of supplied PWID in 2021 using an online and paper-based questionnaire. We conducted a descriptive statistical analysis of data from 2021, assessed fulfillment of the WHO indicator and changes in services that participated 2021 and in the previous study 2018.

Results

Five hundred and eighty-nine of 1760 distributed questionnaires were returned in 2021. 204 drug services from 15 out of 16 federal states confirmed drug paraphernalia distribution, covering 20% of Germany’s rural and 51% of urban counties. 108 services had also participated in 2018. The most frequently distributed paraphernalia for injecting drug use in 2021 were syringes (97% of services), needles (96%) and vitamin C (90%). Pre-cut aluminium foil (79% of services) and pipes (28%) for inhaling, and sniff tubes (43%) for nasal use were distributed less frequently. We found a median reduction in distributed syringes by 18% and by 12% for needles compared to 2018. Of 15 states, two reached the 2030 WHO-target for needles and one for syringes.

Conclusions

The current national estimates and changes from 2018 to 2021 for drug paraphernalia distribution seem far from meeting the WHO target. Reasons could include a change in drug consumption behaviour towards less injecting use and more inhaling, and effects of the COVID-19 pandemic (supply difficulties, social distancing, lockdown, reduced opening hours of services). We observed pronounced regional differences in drug paraphernalia distribution. To close existing gaps, Germany should expand its drug paraphernalia distribution programmes and other harm reduction services, such as drug consumption rooms. Further investigation of determinants for adequate distribution is essential to reduce blood-borne infections in this key population.
Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer
Authors: Rocca Carmine , Soda Teresa , De Francesco Ernestina Marianna , Fiorillo Marco , Moccia Francesco , Viglietto Giuseppe , Angelone Tommaso , Amodio Nicola
Published: September 2023

A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.
Structural ultrasound of joints and tendons in healthy children: development of normative data
Authors: Wittoek Ruth , Decock Céline , Dewaele Nele , Arnold Lara , Baeyens Pieter , De Schrijver Ignace , Pardaens Lisa , Raftakis Ioannis , Renson Thomas , Rinkin Charline , Thooft Alexander D. J. , Vanhaverbeke Tine , Verbist Caroline
Published: September 2023

Background

Musculoskeletal ultrasound is a well accessible technique to assess disease activity in children with juvenile idiopathic arthritis. Knowledge of reference values of joint structures is indispensable to differentiate between physiological and pathological finding. The aim of this study was to assess the structural sonographic features of joints and tendons in healthy children from several age groups (0.2–18 year), and develop a set of normative data.

Methods

Greyscale ultrasound was performed in 500 healthy children (age 0.2–18 years) according to a predefined scanning protocol (Additional file 1) including the shoulder, elbow, wrist, second metacarpophalangeal joint, hip, knee, ankle, and first metatarsophalangeal joint). Demographic data and values of cartilage thickness, tendon diameters, and the degree of capsular distention measured by bone-capsular distance (BCD) were collected. Differences according to the sex were assessed by unpaired t-test. Single and multiple regression analyses were performed between the ultrasound outcomes and covariates such as age, height, weight and body mass index. Growth charts and tables were developed with respect to age. Nonparametric quantile regression was applied using the R-packages quantreg and quantregGrowth.

Results

A total of 195 male and 305 female volunteers were included between the age of 0 and 18 years (mean age 8.9; range: 0.2–17.9 years). Cartilage diminished markedly as children aged, and cartilage of the boys was significantly thicker compared to the girls in all joints (p < 0.001). In addition, cartilage became thinner as children’s height and weight increased (beta regression coefficients between − 0.27 and − 0.01, p < 0.0001). Capsular distention (i.e., BCD > 0 mm) was uncommon in the ankle, wrist and MCP2 (resp. in 3, 6, and 3% of cases). It was more common in the suprapatellar and parapatellar knee, MTP1 and posterior recess of the elbow (resp. in 34, 32, 46, and 39% of cases). In the hip, some capsular distention was always present. Age was found to be the best predictor for BCD (beta regression coefficients between 0.05 and 0.13, p < 0.0001). Height was, in addition to age, a good predictor of tendon diameter (beta regression coefficients between 0.03 and 0.14, p < 0.0001). Growth curves and tables for each variable were developed.

Conclusions

Reference values of sonographic cartilage thickness, BCD and diameters of tendons at several joints were established from 500 healthy children, aged between 0.2 and 18 years. Growth charts and tables were developed to distinguish normal findings from pathology in children with complaints suspicious of arthritis.
Transcranial magnetic stimulation and transcranial direct current stimulation affect explicit but not implicit emotion regulation: a meta-analysis
Authors: Qiu Xiufu , He Zhenhong , Cao Xueying , Zhang Dandan
Published: September 2023

Emotion regulation (ER) refers to the process through which people influence the occurrence, experience, and expression of emotions. It can be established in an explicit (voluntary) or implicit (automatic) way, both of which are essential for mental and physical well-being. Recent evidence has highlighted the potential of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) targeting the prefrontal cortex (PFC) to modulate ER. However, previous studies have only evaluated the effects of TMS and tDCS on explicit ER, leaving implicit ER relatively unexplored. In this review and meta-analysis, we systematically evaluated the effects of TMS and tDCS over the PFC on the two forms of ER, using both subjective and physiological response as outcome indicators. Twenty-seven studies were included in our study. Both subjective (Hedges’ g = − 0.20) and physiological (Hedges’ g = − 0.65) results indicated a significant effect of TMS and tDCS targeting PFC on down-regulation of explicit ER, but not implicit ER (Hedges’ g = − 0.04). Moreover, moderation analysis indicated that the effect of TMS and tDCS on the down-regulating of subjective experience was moderated by several factors, including stimulation method, target area, target hemisphere, and stimulation timing. Specifically, our results showed that applying TMS or targeting the right PFC, particularly the right ventrolateral prefrontal cortex, or using offline TMS and tDCS produced a larger stimulation effect on ER. In summary, these findings suggest that TMS and tDCS has a positive effect on explicit, but not implicit ER. The distinct TMS and tDCS effect on the two forms of ER help deepen our understanding of TMS and tDCS use and provide valuable insights for the development of tailored TMS and tDCS protocols for explicit and implicit regulation.
Application of non-invasive prenatal testing to 91,280 spontaneous pregnancies and 3477 pregnancies conceived by in vitro fertilization
Authors: Wei Rong , Li Jingran , Xia Yuanyuan , Wang Chaohong , Lu Xinran , Fang Yuqin , Zhu Jiansheng
Published: September 2023

Background

Many clinical studies based on spontaneous pregnancies (SPs) have demonstrated the superiority of non-invasive prenatal testing (NIPT), and the question of whether this technology is suitable for offspring conceived by assisted reproductive technology has attracted attention. This study aimed to evaluate the application value of NIPT in screening for trisomy (T)21, T18, T13 and sex chromosome aneuploidy (SCA) in pregnant women who conceived by in vitro fertilization (IVF).

Results

In total, there were 804 high-risk cases [0.88% (804/91280), singleton = 795, twin = 9] in the SP group. Among the 558 invasive prenatal diagnosis (IPD) cases (singleton = 556, twin = 2), 343 (singleton = 342, twin = 1) were true positive, including 213 cases of T21, 28 of T18, 5 of T13 and 97 (singleton = 96, twin = 1) of SCA. The positive predictive values (PPVs) of T21, T18, T13, SCA and T21/T18/T13 combined in singleton pregnancy were 89.12% (213/239), 51.85% (28/54), 21.74% (5/23), 40.00% (96/240), and 77.85% (246/316), respectively, and the PPV of SCA in twin pregnancy was 100.00%. In the IVF group, IPD was performed in 19 (singleton = 16, twin = 3) of the 27 high-risk cases [0.78% (27/3477), singleton = 16, twin = 3], of which 9 (singleton = 8, twin = 1) were true positive, including 5 cases (singleton = 4, twin = 1) of T21 and 4 of SCA. The PPVs of singleton T21, SCA and T21/T18/T13 combined were 66.67% (4/6), 50.00% (4/8) and 57.14% (4/7), respectively, and the PPV of twin T21 was 100.00% (1/1). There were no significant differences in PPV among T21, SCA and T21/T18/T13 combined in singletons between the groups (89.12% vs. 66.67%, p = 0.09; 40.00% vs. 50.00%, p = 0.57; 77.85% vs. 57.14%, p = 0.20). The sensitivity and specificity were higher for singleton and twin pregnancies in the two groups. Based on follow-up results, 1 case of false negative T21 was found in the singleton SP group. Additionally, the mean foetal fraction (FF) of the IVF group was lower than that of the SP group (11.23% vs. 10.51%, p < 0.05).

Conclusion

NIPT has high sensitivity and specificity in screening chromosomal aneuploidies in both IVF pregnancy and spontaneous pregnancy, so it is an ideal screening method for IVF pregnancy.
Comparison of Huntington’s disease phenotype progression in male and female heterozygous FDNQ175 mice
Authors: Li Si Han , Colson Tash-Lynn L. , Chen Jingwei , Abd-Elrahman Khaled S. , Ferguson Stephen S. G.
Published: September 2023

Huntington’s Disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment due to the expansion of a polyglutamine (CAG) repeat in the N-terminal region of the huntingtin (Htt) protein. The creation of HD mouse models represents a critical step in the research for HD treatment. Among the currently available HD mouse models, the zQ175 knock-in mouse line is the first to display robust disease phenotype on a heterozygous background. The newer FDNQ175 mouse model is derived from the zQ175 mouse line and presents a more aggressive phenotype. Moreover, increasing evidence has implicated sex as a contributing factor in the progression of HD symptoms. Here, we compared the progression of HD phenotypes in male and female heterozygous FDNQ175 mice. We found that both male and female heterozygous mice showed deficits in forelimb grip strength and cognition as early as 6 months of age. However, female FDNQ175 mice were less vulnerable to HD-associated decline in limb coordination and movement. Neither male nor female FDNQ175 mice exhibited reduced locomotor activity in the open field or exhibit consistent differences in anxiety at 6–12 months of age. Both male and female FDNQ175 mice exhibited increased numbers of huntingtin aggregates with age and 8-month-old female FDNQ175 mice had significantly more aggregates than their male counterparts. Taken together, our results provide further evidence that sex can influence the progression of HD phenotype in preclinical animal models and must be taken into consideration for future HD research.
Bronchiolitis guidelines: what about the Italian situation in a primary care setting?
Authors: Porcaro Federica , Cutrera Renato , Vittucci Anna Chiara , Villani Alberto
Published: September 2023

Acute viral bronchiolitis is the most common cause of hospitalization in children under 12 months of age. The variable clinical presentation and the potential for sudden deterioration of the clinical conditions require a close monitoring by healthcare professionals.

In Italy, first access care for children is provided by primary care physicians (PCPs) who often must face to a heterogeneous disease presentation that, in some cases, make the management of patient with bronchiolitis challenging. Consequently, Italian studies report poor adherence to national and international guidelines processed to guide the clinicians in decision making in acute viral bronchiolitis.

This paper aims to identify the potential factors contributing to the lack of adherence to the suggested guidelines derived by clear and evidence-based recommendations among primary care physicians operating in an outpatient setting, with a specific focus on the context of Italy. Particularly, we focus on the prescription of medications such as β2-agonists, systemic steroids, and antibiotics which are commonly prescribed by PCPs to address conditions that can mimic bronchiolitis.
Protocol for a randomized control trial of the Building Regulation in Dual Generations Program (BRIDGE): preventing the intergenerational transmission of mental illness in at-risk preschool children
Authors: Penner-Goeke Lara , Belows Madeline , Kristjanson Amanda , Andrade Brendan F. , Cameron Emily E. , Giuliano Ryan , Katz Laurence Y. , Kelly Lauren E. , Letourneau Nicole , Mota Natalie , Reynolds Kristin , Zalewski Maureen , Pharazyn Ashley , Roos Leslie E.
Published: September 2023

Background

Since the onset of the COVID-19 pandemic, the worldwide prevalence of maternal depression has risen sharply; it is now estimated that one quarter of mothers experience clinically significant depression symptoms. Exposure to maternal depression during early childhood increases the risk for the development of childhood mental illness (MI) in offspring, with altered parenting practices mediating the association between maternal depression and child outcomes. Dual-generation interventions, which aim to simultaneously treat parent and child mental health, show promise for improving outcomes for mothers with depression and their young children. The Building Regulation in Dual Generations (BRIDGE) program combines Dialectical Behavior Therapy (DBT) and parenting skills training to concurrently treat maternal depression and improve parenting practices. In pilot within-group studies, BRIDGE has led to large reductions in maternal depression and child MI symptoms. The aim of the current study is to evaluate the efficacy of BRIDGE in reducing maternal depression and child MI symptoms (primary outcomes) as well as parenting stress and harsh parenting (secondary outcomes).

Methods

A three-armed randomized control trial with equal group sizes will be conducted to compare the efficacy of (1) BRIDGE (DBT + parenting skills), (2) DBT skills training, and (3) services-as-usual. Participants (n = 180) will be mothers of 3- to 5-year-old children who report elevated depression symptoms. Those randomized to BRIDGE or DBT skills training will complete a 16-week group therapy intervention. Assessments will be administered at pre-intervention(T1) post-intervention (T2), and 6-month follow-up (T3).

Discussion

Dual-generation programs offer an innovative approach to prevent the intergenerational transmission of mental illness. The current study will add to the evidence base for BRIDGE by comparing it to a stand-alone mental health intervention and a services-as-usual group. These comparisons will provide valuable information on the relative efficacy of including parenting support in a mental health intervention for parents. The results will contribute to our understanding of how maternal depression affects children’s development and how intervening at both a mental health and parenting level may affect child and family outcomes.

Trial registration

Name of registry: Clinical Trials Protocol Registration and Results System; trial registration number: NCT05959538; date of registry: July 24, 2023; available: https://classic.clinicaltrials.gov/ct2/show/NCT05959538
Exploring the cellulolytic and hemicellulolytic activities of manganese peroxidase for lignocellulose deconstruction
Authors: Liu Xiaoqing , Ding Sunjia , Gao Fang , Wang Yaru , Taherzadeh Mohammad J. , Wang Yuan , Qin Xing , Wang Xiaolu , Luo Huiying , Yao Bin , Huang Huoqing , Tu Tao
Published: September 2023

Background

A cost-effective pretreatment and saccharification process is a necessary prerequisite for utilizing lignocellulosic biomass (LCB) in biofuel and biomaterials production. Utilizing a multifunctional enzyme with both pretreatment and saccharification functions in a single step for simultaneous biological pretreatment and saccharification process (SPS) will be a green method of low cost and high efficiency. Manganese peroxidase (MnP, EC 1.11.1.13), a well-known lignin-degrading peroxidase, is generally preferred for the biological pretreatment of biomass. However, exploring the role and performance of MnP in LCB conversion will promote the application of MnP for lignocellulose-based biorefineries.

Results

In this study, we explored the ability of an MnP from Moniliophthora roreri, MrMnP, in LCB degradation. With Mn2+ and H2O2, MrMnP decomposed 5.0 g/L carboxymethyl cellulose to 0.14 mM of reducing sugar with a conversion yield of 5.0 mg/g, including 40 μM cellobiose, 70 μM cellotriose, 20 μM cellotetraose, and 10 μM cellohexaose, and degraded 1.0 g/L mannohexaose to 0.33 μM mannose, 4.08 μM mannotriose, and 4.35 μM mannopentaose. Meanwhile, MrMnP decomposed 5.0 g/L lichenan to 0.85 mM of reducing sugar with a conversion yield of 30.6 mg/g, including 10 μM cellotriose, 20 μM cellotetraose, and 80 μM cellohexose independently of Mn2+ and H2O2. Moreover, the versatility of MrMnP in LCB deconstruction was further verified by decomposing locust bean gum and wheat bran into reducing sugars with a conversion yield of 54.4 mg/g and 29.5 mg/g, respectively, including oligosaccharides such as di- and tri-saccharides. The catalytic mechanism underlying MrMnP degraded lignocellulose was proposed as that with H2O2, MrMnP oxidizes Mn2+ to Mn3+. Subsequently, it forms a complex with malonate, facilitating the degradation of CMC and mannohexaose into reducing sugars. Without H2O2, MrMnP directly oxidizes malonate to hydroperoxyl acetic acid radical to form compound I, which then attacks the glucosidic bond of lichenan.

Conclusion

This study identified a new function of MrMnP in the hydrolysis of cellulose and hemicellulose, suggesting that MrMnP exhibits its versatility in the pretreatment and saccharification of LCB. The results will lead to an in-depth understanding of biocatalytic saccharification and contribute to forming new enzymatic systems for using lignocellulose resources to produce sustainable and economically viable products and the long-term development of biorefinery, thereby increasing the productivity of LCB as a green resource.
Urban malaria vector bionomics and human sleeping behavior in three cities in Senegal
Authors: Diop Abdoulaye , Ndiaye Fatou , Sturm-Ramirez Katherine , Konate Lassana , Senghor Massila , Diouf El Hadji , Dia Abdoulaye Kane , Diedhiou Seynabou , Samb Badara , Sene Doudou , Zohdy Sarah , Dotson Ellen , Diouf Mame Birame , Koscelnik Valerie , Gerberg Lilia , Bangoura Abdoulaye , Faye Ousmane , Clark Tiffany , Niang El Hadji Amadou , Chabi Joseph
Published: September 2023

Background

Malaria is endemic in Senegal, with seasonal transmission, and the entire population is at risk. In recent years, high malaria incidence has been reported in urban and peri-urban areas of Senegal. An urban landscape analysis was conducted in three cities to identify the malaria transmission indicators and human behavior that may be driving the increasing malaria incidence occurring in urban environments. Specifically, mosquito vector bionomics and human sleeping behaviors including outdoor sleeping habits were assessed to guide the optimal deployment of targeted vector control interventions.

Methods

Longitudinal entomological monitoring using human landing catches and pyrethrum spray catches was conducted from May to December 2019 in Diourbel, Kaolack, and Touba, the most populous cities in Senegal after the capital Dakar. Additionally, a household survey was conducted in randomly selected houses and residential Koranic schools in the same cities to assess house structures, sleeping spaces, sleeping behavior, and population knowledge about malaria and vector control measures.

Results

Of the 8240Anophelesmosquitoes collected from all the surveyed sites, 99.4% (8,191) wereAn. gambiaes.l., and predominantlyAn. arabiensis(99%). A higher number ofAn. gambiaes.l. were collected in Kaolack (77.7%,n = 6496) than in Diourbel and Touba. The overall mean human biting rate was 14.2 bites per person per night (b/p/n) and was higher outdoors (15.9 b/p/n) than indoors (12.5 b/p/n). The overall mean entomological inoculation rates ranged from 3.7 infectious bites per person per year (ib/p/y) in Diourbel to 40.2 ib/p/y in Kaolack. Low anthropophilic rates were recorded at all sites (average 35.7%). Of the 1202 households surveyed, about 24.3% of household members slept outdoors, except during the short rainy season between July and October, despite understanding how malaria is transmitted and the vector control measures used to prevent it.

Conclusion

Anopheles arabiensiswas the primary malaria vector in the three surveyed cities. The species showed an outdoor biting tendency, which represents a risk for the large proportion of the population sleeping outdoors. As all current vector control measures implemented in the country target endophilic vectors, these data highlight potential gaps in population protection and call for complementary tools and approaches targeting outdoor biting malaria vectors.

Graphical Abstract
Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome
Authors: Sun Jing , Zhao Jianhui , Jiang Fangyuan , Wang Lijuan , Xiao Qian , Han Fengyan , Chen Jie , Yuan Shuai , Wei Jingsun , Larsson Susanna C. , Zhang Honghe , Dunlop Malcolm G , Farrington Susan M , Ding Kefeng , Theodoratou Evropi , Li Xue
Published: September 2023

Background

The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC).

Methods

Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets.

Results

Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC.

Conclusions

This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.
Unveiling difficult-to-treat rheumatoid arthritis: long-term impact of biologic or targeted synthetic DMARDs from the KOBIO registry
Authors: Jung Ju-Yang , Lee Eunyoung , Kim Ji-Won , Suh Chang-Hee , Shin Kichul , Kim Jinhyun , Kim Hyoun-Ah
Published: September 2023

Background

While the availability of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) has improved outcomes for rheumatoid arthritis (RA) patients, there remains a subset of individuals who fail to achieve low disease activity or remission despite multiple cycles of b/tsDMARDs. This state is referred to as 'difficult-to-treat (D2T)' RA.

Methods

Data from the Korean College of Rheumatology Biologics registry were utilized to analyze patients with RA who were treated with b/tsDMARDs.

Results

Among 2,321 RA patients with RA treated with b/tsDMARDs, 271 (11.7%) were diagnosed with D2T RA. Lower age (OR = 0.98, p < 0.001), longer disease duration (OR = 1.06, p < 0.001), lower patient global assessment (OR = 0.89, p = 0.045), higher SDAI (OR = 1.06, p = 0.014) and RAPID3 (OR = 1.06, p = 0.002), lower RF positivity (OR = 0.65, p = 0.04), and lower prior use of methotrexate (OR = 0.44, p = 0.008), sulfasalazine (OR = 0.59, p = 0.003), and leflunomide (OR = 0.67, p = 0.013) were associated with D2T RA. The drug survival rate of b/tsDMARDs did not differ between patients with D2T RA and non-D2T RA (p = 0.35). However, the drug survival of individual b/tsDMARD differed between patients with D2T RA and non-D2T RA after eight years. Patients with D2T RA withdrew from b/tsDMARDs due to inefficacy more frequently than those without D2T RA (p < 0.001).

Conclusions

D2T RA patients experienced higher disease activity despite maintaining b/tsDMARD therapy. Withdrawal rates due to inefficacy were higher in D2T RA. Effective therapeutic strategies are needed to improve disease control and treatment outcomes in this unique patient population.
Dynamic household structure and composition: a manual for longitudinal analysis of living arrangements
Authors: Menashe-Oren Ashira , Compaoré Yacouba , Bocquier Philippe , Ginsburg Carren
Published: September 2023

Objective

This research note introduces a set of tools to conduct analysis of household structure and composition with either limited or comprehensive longitudinal data. The data used here are from Health and Demographic Surveillance Systems in Africa, but the methods can be adapted and applied to other longitudinal micro-data such as register data. A training manual describing the procedures for creating time-varying household measures step-by-step is supplied as supplementary material to this note. Code is provided in STATA but can easily be translated for other statistical software, and the logic for each step remains the same.

Results

The analysis of household structure demonstrates how with limited data (such as a household identifier), it is possible to construct time-varying measures of household membership, including household size or the number of members in specific age and sex groups. The analysis of household composition demonstrates how with expanded data (including links to parents in addition to residence status in the same household), it is possible to construct time-varying measures of household membership of specific kin, i.e. mother, sibling or grandparent. The results illustrated in this research note are a taste of what can be achieved by following the training manual in the supplementary material.
Impact of planting Phallus rubrovolvatus on physicochemical and microbial properties and functional groups of soil
Authors: Gao Xu , Ding Mengjiao , Wu Tao , Deng Xiaohua , Li Qiang
Published: September 2023

Purpose

Soil microbial communities are critically important to agricultural ecosystems. The present study aimed to evaluate the changes in soil microbial community composition and functional groups after planting Phallus rubrovolvatus.

Methods

Illumina platform were adopted to characterize the bacterial and fungal diversity in the soil cropped with P. rubrovolvatus for 0 and 1 year.

Results

The results showed that planting P. rubrovolvatus reduced the bacterial and fungal diversity in the soil, and the dynamics of the soil bacterial diversity changed more drastically. This study also indicated that, as keystone taxa, the dominant bacteria (Actinobacteria, Sphingomonas, Xanthobacteraceae, and Gemmatimonadaceae) and dominant fungi (Mortierellales and Eurotiales) served as a key component in the network of soil microbial communities. Moreover, the bacterial and fungal communities in the soil planted with P. rubrovolvatus formed more similar and weak networks.

Conclusion

Planting P. rubrovolvatus significantly influenced the structure and composition of microbial communities. In the future, we will focus on ways to improve the soil environment after planting P. rubrovolvatus.
Natural language processing for automatic evaluation of free-text answers — a feasibility study based on the European Diploma in Radiology examination
Authors: Stoehr Fabian , Kämpgen Benedikt , Müller Lukas , Zufiría Laura Oleaga , Junquero Vanesa , Merino Cristina , Mildenberger Peter , Kloeckner Roman
Published: September 2023

Background

Written medical examinations consist of multiple-choice questions and/or free-text answers. The latter require manual evaluation and rating, which is time-consuming and potentially error-prone. We tested whether natural language processing (NLP) can be used to automatically analyze free-text answers to support the review process.

Methods

The European Board of Radiology of the European Society of Radiology provided representative datasets comprising sample questions, answer keys, participant answers, and reviewer markings from European Diploma in Radiology examinations. Three free-text questions with the highest number of corresponding answers were selected: Questions 1 and 2 were “unstructured” and required a typical free-text answer whereas question 3 was “structured” and offered a selection of predefined wordings/phrases for participants to use in their free-text answer. The NLP engine was designed using word lists, rule-based synonyms, and decision tree learning based on the answer keys and its performance tested against the gold standard of reviewer markings.

Results

After implementing the NLP approach in Python, F1 scores were calculated as a measure of NLP performance: 0.26 (unstructured question 1, n = 96), 0.33 (unstructured question 2, n = 327), and 0.5 (more structured question, n = 111). The respective precision/recall values were 0.26/0.27, 0.4/0.32, and 0.62/0.55.

Conclusion

This study showed the successful design of an NLP-based approach for automatic evaluation of free-text answers in the EDiR examination. Thus, as a future field of application, NLP could work as a decision-support system for reviewers and support the design of examinations being adjusted to the requirements of an automated, NLP-based review process.

Clinical relevance statement

Natural language processing can be successfully used to automatically evaluate free-text answers, performing better with more structured question-answer formats. Furthermore, this study provides a baseline for further work applying, e.g., more elaborated NLP approaches/large language models.

Key points

• Free-text answers require manual evaluation, which is time-consuming and potentially error-prone.

• We developed a simple NLP-based approach — requiring only minimal effort/modeling — to automatically analyze and mark free-text answers.

• Our NLP engine has the potential to support the manual evaluation process.

• NLP performance is better on a more structured question-answer format.

Graphical Abstract
CDC42-mediated Wnt signaling facilitates odontogenic differentiation of DPCs during tooth root elongation
Authors: Zhou Tao , Chen Guoqing , Xu Yuchan , Zhang Shuning , Tang Huilin , Qiu Tao , Guo Weihua
Published: September 2023

Background

CDC42 is a member of Rho GTPase family, acting as a molecular switch to regulate cytoskeleton organization and junction maturation of epithelium in organ development. Tooth root pattern is a highly complicated and dynamic process that dependens on interaction of epithelium and mesenchyme. However, there is a lack of understanding of the role of CDC42 during tooth root elongation.

Methods

The dynamic expression of CDC42 was traced during tooth development through immunofluorescence staining. Then we constructed a model of lentivirus or inhibitor mediated Cdc42 knockdown in Herwig’s epithelial root sheath (HERS) cells and dental papilla cells (DPCs), respectively. Long-term influence of CDC42 abnormality was assessed via renal capsule transplantation and in situ injection of alveolar socket.

Results

CDC42 displayed a dynamic spatiotemporal pattern, with abundant expression in HERS cells and apical DPCs in developing root. Lentivirus-mediated Cdc42 knockdown in HERS cells didn’t disrupt cell junctions as well as epithelium-mesenchyme transition. However, inhibition of CDC42 in DPCs undermined cell proliferation, migration and odontogenic differentiation. Wnt/β-catenin signaling as the downstream target of CDC42 modulated DPCs’ odontogenic differentiation. The transplantation and in situ injection experiments verified that loss of CDC42 impeded root extension via inhibiting the proliferation and differentiation of DPCs.

Conclusions

We innovatively revealed that CDC42 was responsible for guiding root elongation in a mesenchyme-specific manner. Furthermore, CDC42-mediated canonical Wnt signaling regulated odontogenic differentiation of DPCs during root formation.
Paracrine signalling between keratinocytes and SVF cells results in a new secreted cytokine profile during wound closure
Authors: Balko Stefan , Kerr Evan , Buchel Ed , Logsetty Sarvesh , Raouf Afshin
Published: September 2023

Stromal vascular fraction (SVF) cells, and the adipose-derived mesenchymal stem cells they contain, have shown enhanced wound healing in vitro and in vivo, yet their clinical application has been limited. In this regard, understanding the mechanisms that govern SVF-enhanced wound healing would improve their application in the clinic. Here, we show that the SVF cells and keratinocytes engage in a paracrine crosstalk during wound closure, which results in a new cytokine profile that is distinct from the cytokines regularly secreted by either cell type on their own. We identify 11 cytokines, 5 of which are not regularly secreted by the SVF cells, whose expressions are significantly increased during wound closure by the keratinocytes. This new cytokine profile could be used to accelerate wound closure and initiate re-epithelialization without the need to obtain the SVF cells from the patient.
Application of mesenchymal stem cells for anti-senescence and clinical challenges
Authors: Wang Yaping , Gao Tianyun , Wang Bin
Published: September 2023

Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
Evaluation of safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells in pediatric bronchiolitis obliterans syndrome (BoS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT)
Authors: Mohseni Rashin , Mahdavi Sharif Pouya , Behfar Maryam , Modaresi Mohammad Reza , Shirzadi Rohola , Mardani Mahta , Jafari Leila , Jafari Fahimeh , Nikfetrat Zeynab , Hamidieh Amir Ali
Published: September 2023

Background

Allo-HSCT is a definite approach for the management of a wide variety of lethal and debilitating malignant and non-malignant disorders. However, its two main complications, acute and chronic graft-versus-host disease (GVHD), exert significant morbidities and mortalities. BoS, as a manifestation of chronic lung GVHD, is a gruesome complication of allo-HSCT, and for those with steroid-refractory disease, no approved second-line therapies exist. Mesenchymal stem cells (MSCs) exert anti-inflammatory and growth-promoting effects, and their administration against a wide range of inflammatory and neurologic disorders, as well as GVHD, has been associated with promising outcomes. However, literature on the safety and effectiveness of MSC therapy for BoS and pediatric cGVHD is scarce.

Methods

We designed a single-arm trial to administer adipose tissue (AT)-derived MSCs to pediatric patients with refractory BoS after allo-HSCT. AT-MSCs from obese, otherwise healthy donors were cultured in an ISO class 1 clean room and injected into the antecubital vein of eligible patients with a dose of 1 × 106/kg. The primary endpoints included a complete or partial response to therapy [in terms of increased forced expiratory volume in one second (FEV1) values and steroid dose reduction] and its safety profile.

Results

Four eligible patients with a median age of 6.5 years were enrolled in the study. Steroid-induced osteoporosis and myopathy were present in three cases. A partial response was evident in three cases after a single injection of AT-MSCs. The treatment was safe and tolerable, and no treatment-related adverse events were noted. Two patients developed manageable COVID-19 infections one and 4 months after AT-MSC injection. After a median follow-up duration of 19 months, all cases are still alive and have had no indications for lung transplantation.

Conclusions

AT-MSCs could be safely administered to our pediatric cases with BoS post-allo-HSCT. Considering their advanced stage of disease, their sub-optimal functional capacity due to steroid-induced complications, and COVID-19 infection post-treatment, we believe that AT-MSC therapy can have possible efficacy in the management of pediatric BoS. The conduction of further studies with larger sample sizes and more frequent injections is prudent for further optimization of AT-MSC therapy against BoS.

Trial registration Iranian Registry of Clinical Trials (IRCT), IRCT20201202049568N2. Registered 22 February 2021, https://en.irct.ir/trial/53143.
Integrating synthetic accessibility with AI-based generative drug design
Authors: Parrot Maud , Tajmouati Hamza , da Silva Vinicius Barros Ribeiro , Atwood Brian Ross , Fourcade Robin , Gaston-Mathé Yann , Do Huu Nicolas , Perron Quentin
Published: September 2023

Generative models are frequently used for de novo design in drug discovery projects to propose new molecules. However, the question of whether or not the generated molecules can be synthesized is not systematically taken into account during generation, even though being able to synthesize the generated molecules is a fundamental requirement for such methods to be useful in practice. Methods have been developed to estimate molecule “synthesizability”, but, so far, there is no consensus on whether or not a molecule is synthesizable. In this paper we introduce the Retro-Score (RScore), which computes a synthetic accessibility score of molecules by performing a full retrosynthetic analysis through our data-driven synthetic planning software Spaya, and its dedicated API: Spaya-API (https://spaya.ai). We start by comparing several synthetic accessibility scores to a binary “chemist score” as estimated by chemists on a bench of generated molecules, as a first experimental validation that the RScore is a reliable synthetic accessibility score. We then describe a pipeline to generate molecules that validate a list of targets while still being easy to synthesize. We further this idea by performing experiments comparing molecular generator outputs across a range of constraints and conditions. We show that the RScore can be learned by a Neural Network, which leads to a new score: RSPred. We demonstrate that using the RScore or RSPred as a constraint during molecular generation enables our molecular generators to produce more synthesizable solutions, with higher diversity. The open-source Python code containing all the scores and the experiments can be found on (https://github.com/iktos/generation-under-synthetic-constraint).

Graphic Abstract
School of cheminformatics in Latin America
Authors: Gonzalez-Ponce Karla , Horta Andrade Carolina , Hunter Fiona , Kirchmair Johannes , Martinez-Mayorga Karina , Medina-Franco José L. , Rarey Matthias , Tropsha Alexander , Varnek Alexandre , Zdrazil Barbara
Published: September 2023

We report the major highlights of the School of Cheminformatics in Latin America, Mexico City, November 24–25, 2022. Six lectures, one workshop, and one roundtable with four editors were presented during an online public event with speakers from academia, big pharma, and public research institutions. One thousand one hundred eighty-one students and academics from seventy-nine countries registered for the meeting. As part of the meeting, advances in enumeration and visualization of chemical space, applications in natural product-based drug discovery, drug discovery for neglected diseases, toxicity prediction, and general guidelines for data analysis were discussed. Experts from ChEMBL presented a workshop on how to use the resources of this major compounds database used in cheminformatics. The school also included a round table with editors of cheminformatics journals. The full program of the meeting and the recordings of the sessions are publicly available at https://www.youtube.com/@SchoolChemInfLA/featured.
SPLF/SMFU/SRLF/SFAR/SFCTCV Guidelines for the management of patients with primary spontaneous pneumothorax
Authors: Jouneau Stéphane , Ricard Jean-Damien , Seguin-Givelet Agathe , Bigé Naïke , Contou Damien , Desmettre Thibaut , Hugenschmitt Delphine , Kepka Sabrina , Le Gloan Karinne , Maitre Bernard , Mangiapan Gilles , Marchand-Adam Sylvain , Mariolo Alessio , Marx Tania , Messika Jonathan , Noël-Savina Elise , Oberlin Mathieu , Palmier Ludovic , Perruez Morgan , Pichereau Claire , Roche Nicolas , Garnier Marc , Martinez Mikaël
Published: September 2023

Introduction

Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management.

Methods

Literature review, analysis of the literature according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients and organizers to reach a consensus. Only expert opinions with strong agreement were selected.

Results

A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥ 2 cm at the hilum level on frontal chest X-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described.

Conclusion

These guidelines are a step towards PSP treatment and follow-up strategy optimization in France.