bluuebunny/crossref_metadata_2025 huggingface dataset:
Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway
Authors: Liu Peng , Zu Fuqiang , Chen Hui , Yin Xiaoli , Tan Xiaodong
Published: October 2022

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with invasive and metastatic characteristics and poor prognosis. Intracellular protein homeostasis is associated with invasion and metastasis of pancreatic cancer, but the specific molecular mechanism remains unclear. Our previous studies have revealed that DNAJB11, a key protein in protein homeostasis, is secreted by exosomes in the supernatant of dissociated pancreatic cancer cells with high metastasis. The results from transcriptome sequencing and co-immunoprecipitation (Co-IP)-based liquid chromatography with tandem mass spectrometry (LC–MS/MS) showed that depletion of DNAJB11 levels could increase HSPA5 expression and induce endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase signaling pathway in pancreatic cancer cells. Furthermore, exosomal DNAJB11 promoted cell development of PC cells in vitro and in vivo. In addition, exosomal DNAJB11 could regulate the expression of EGFR and activate the downstream MAPK signaling pathway. Clinical blood samples were collected to evaluate the potential of exosome DNAJB11 as a diagnostic biomarker and therapeutic target for the treatment of pancreatic cancer. This study could provide a new theoretical basis and potential molecular targets for the treatment of pancreatic cancer.
Experiences and consequences of phasing out substances of concern in a multinational healthcare company
Authors: Ujaczki Éva , Stark-Rogel Véronique , Olbrich Martin , Fuetsch Michaela , Backmann Jan
Published: October 2022

Background

In 2015, one of the largest healthcare companies in the world committed to phasing out from all its products and processes worldwide any substances declared by the European Chemicals Agency to be of very high concern. Since then, extended practical experience was gained in the phasing out of substances of concern.

Results

We report in detail on a company-wide programme to phase out substances of concern, the challenges of and the approaches to the phase-out. The paper provides concrete ideas of how to address the legitimate urge to remove substances of concern from economic activities in a holistic way, taking into account the broad diversity of aspects of sustainability. The present paper also reviews the regulatory and societal environment in which substances of concern are being phased out. The paper attempts to contribute to the ongoing discussion of how to improve the chemicals policy in Europe and beyond.

Conclusions

Phasing out substances of concern, substance selection for new products and processes, and the avoidance of regrettable substitutions while maintaining the pace of genuine innovation will stay a major challenge for our industry in the years ahead whereby not only toxicological and ecotoxicological hazards have to be considered in the selection and deselection of substances, but also other sustainability criteria characterising the entire life cycle will play an increasingly important role. Legislators and industry need to pay more attention to how this is implemented while avoiding slowing down innovation, making essential products unnecessarily more expensive, and further pushing material production out of highly regulated countries.
Characterization of sepsis inflammatory endotypes using circulatory proteins in patients with severe infection: a prospective cohort study
Authors: Ricaño-Ponce Isis , Riza Anca-Lelia , de Nooijer Aline H. , Pirvu Andrei , Dorobantu Stefania , Dragos Adina , Streata Ioana , Roskanovic Mihaela , Grondman Inge , Dumitrescu Florentina , Kumar Vinod , Netea Mihai G. , Ioana Mihai
Published: October 2022

Background

Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene expression data, different inflammatory profiles have been identified. However, it remains unknown whether these endotypes mirror inflammatory proteome profiling, which would be more feasible to assess in clinical practice. We aim to identify different inflammatory endotypes based on circulating proteins in a cohort of moderately ill patients with severe infection (Sepsis-2 criteria).

Methods

In this prospective study, 92 inflammatory plasma markers were profiled using a targeted proteome platform and compared between patients with severe infection (Sepsis-2 criteria) and healthy controls. To identify endotypes with different inflammatory profiles, we performed hierarchical clustering of patients based on the differentially expressed proteins, followed by clinical and demographic characterization of the observed endotypes.

Results

In a cohort of 167 patients with severe infection and 192 healthy individuals, we found 62 differentially expressed proteins. Inflammatory proteins such as TNFSF14, OSM, CCL23, IL-6, and HGF were upregulated, while TRANCE, DNER and SCF were downregulated in patients. Unsupervised clustering identified two different inflammatory profiles. One endotype showed significantly higher inflammatory protein abundance, and patients with this endotype were older and showed lower lymphocyte counts compared to the low inflammatory endotype.

Conclusions

By identifying endotypes based on inflammatory proteins in moderately ill patients with severe infection, our study suggests that inflammatory proteome profiling can be useful for patient stratification.
Risk and severity of SARS-CoV-2 reinfection among patients with multiple sclerosis vs. the general population: a population-based study
Authors: Barzegar Mahdi , Manteghinejad Amirreza , Bagherieh Sara , Sindarreh Setayesh , Mirmosayyeb Omid , Javanmard Shaghayegh Haghjooy , Shaygannejad Vahid , Nasirian Maryam
Published: October 2022

Background

We conducted this study to compare the risk of reinfection between multiple sclerosis (MS) patients and a control group without MS.

Method

In this retrospective study, data of all SARS-CoV-2 tests (n = 793,301) and almost all MS patients (n = 10,639) in Isfahan province were collected from January 01, 2020 to August 22, 2021. Of the 2196 MS patients and 793,301 persons from the general population who had been tested at least once, 3 control for each MS patient were identified, leaving 1560 MS patients and 4680 controls without MS. We compared the risk of reinfection after 90 days of a primary infection between those with and without a previous positive COVID-19 test.

Results

736 (47.2%) MS patients and 2013 (43.0%) control individuals had at least one positive test. A total of 17 (2.3%) and 22 (1.1%) possible reinfections in MS and control groups were observed. The estimated protection against reinfection in all MS patients, MS patients on rituximab, MS patients on DMTs rather than rituximab, and controls were 68.2% (46.2, 81.2%), 57.4% (− 0.1, 83.1%), 71.5% (45.5, 85.2%), and 82.1% (72.1, 88.5%), respectively. We found no statistically significant difference in estimated protection (p = 0.123) and odd of reinfection (adjusted OR: 2.01 [0.98, 4.08]) between all MS patients and control group. Two patients were hospitalized at first infection but none required hospitalization at reinfection event.

Conclusions

MS patients on rituximab may be at a greater risk of reinfection. Further studies are required to assess the risk of the second reinfection among the MS population.
Effects of endovascular treatment and prognostic factors for recovery of oculomotor nerve palsy caused by posterior communicating artery aneurysms: a multi-center retrospective analysis
Authors: Wang Bin , Liu Sheng , Na Shi-Jie , Peng Ya , Ding Wen-Bin , Zhao Lin-Bo , Jia Zhen-Yu , Shi Hai-Bin , Feng Qing
Published: October 2022

Background

Oculomotor nerve palsy (ONP) may result from posterior communicating artery (PcomA) aneurysms. We aimed to evaluate the resolution of ONP after endovascular treatment with the intention of clarifying predictors of nerve recovery in a relatively large series.

Methods

A total of 211 patients with ONP caused by PcomA aneurysms underwent endovascular coiling between May 2010 and December 2020 in four tertiary hospitals. We evaluated the demographics, clinical characteristics, aneurysm morphology parameters and ONP resolution to analyze the predictors of ONP recovery using univariate and multivariate analyses.

Results

At the last available clinical follow-up, ONP resolution was complete in 126 (59.7%) patients, partial in 73 (34.6%) patients, and no recovery in 12 (5.7%) patients. The median resolution time after endovascular treatment was 55 days (interquartile range: 40–90 days). In multivariate analysis, degree of ONP (incomplete palsy) on admission (OR 5.396; 95% CI 2.836–10.266;P < 0.001), duration of ONP (≤ 14 days) before treatment (OR 5.940; 95% CI 2.724–12.954;P < 0.001) were statistically significant predictors of complete recovery of ONP. In the subgroup analysis of patients with unruptured aneurysms, aspirin showed a higher complete recovery rate in univariate analysis (OR 2.652; 95% CI 1.057–6.656;P = 0.038).

Conclusion

Initial incomplete ONP and early management might predict better recovery of ONP after endovascular treatment.
A randomized phase 2 clinical trial of phentolamine mesylate eye drops in patients with severe night vision disturbances
Authors: Pepose Jay , Brigell Mitchell , Lazar Eliot , Heisel Curtis , Yousif Jonah , Rahmani Kavon , Kolli Ajay , Hwang Min , Mitrano Cara , Lazar Audrey , Charizanis Konstantinos , Sooch Mina , McDonald Marguerite
Published: October 2022

Purpose

Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD.

Methods

In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed.

Results

Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly − 1.3 mm (0 to − 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia.

Conclusion

PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD.

Trial registration

The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.
Molecular epidemiology of human adenoviruses in children with and without respiratory symptoms: Preliminary findings from a case-control study
Authors: Zadheidar Sevrin , Yavarian Jila , Heydarifard Zahra , Nejati Ahmad , Sadeghi Kaveh , Ghavami Nastaran , Abbasi Simin , Shatizadeh Malekshahi Somayeh , Mokhtari-Azad Talat , Shafiei-Jandaghi Nazanin-Zahra
Published: October 2022

Background

Human adenovirus (HAdV) is an important viral agent in children which can lead to severe acute respiratory infection (SARI). Reports on molecular epidemiology of HAdVs in Iran are limited. This case-control study is conducted to compare the HAdV infection rate and molecular epidemiology among two groups of children with and without respiratory symptoms in Tehran, Iran during 2018–2019.

Methods

Nested PCR was performed on 120 oropharyngeal swabs taken from children aged five and younger with SARI who were hospitalized as the case group, and 120 oropharyngeal swabs were collected from children of the same age without respiratory symptoms as the control group. For positive samples Sanger sequencing was done and a phylogenetic tree was drawn afterward.

Results

Out of 120 cases, 8 (6.6%) tested positive for eachHAdV types including 6 (75%) HAdV-B7, 1 (12.5%) HAdV-C2, and 1 (12.5%) HAdV-C6. Among the control group, out of 120 samples, 8 (6.6%) were positive comprising 5 (62.5%) HAdV-C5, 2 (25%) HAdV-F41, and 1 (12.5%) HAdV-C6.

Conclusion

The present study indicated a different viewpoint of HAdV molecular epidemiology in which the genotypes were compared in children with and without respiratory symptoms. HAdV prevalence was equally common in cases and controls but different genotypes were detected in these two groups. HAdV-B7 was the main type among children with SARI, dissimilar to children with no respiratory symptoms where HAdV-C5 was the predominant type. Detecting HAdV-F in oropharyngeal swabs was a rare finding, which requires further investigation.
Prevalence and determinants of overweight/obesity among under-five children in sub-Saharan Africa: a multilevel analysis
Authors: Ayele Belete Achamyelew , Tiruneh Sofonyas Abebaw , Ayele Asnakew Achaw , Zemene Melkamu Aderajew , Chanie Ermias Sisay , Hailemeskel Habtamu Shimels
Published: October 2022

Introduction

Childhood obesity has become a major public health problem for both developed and developing nations. It is uncommon to find under-nutrition in many low and middle-income countries; as well, obesity is a double burden in these settings. This study aimed to investigate the pooled prevalence of overweight /obesity among under-five (under-5) children in sub-Saharan Africa (SSA).

Methods

Data were accessed from the recent nationally representative demographic and health survey datasets from 33 SSA Countries. A total of 192,132 under-five children were recruited for this study. The pooled prevalence of overweight /obesity among under-5 was done using random-effects meta-analysis command. Multivariable multi-level mixed-effects logistic regression analysis was used to identify determinants for the prevalence of under-5 overweight and/or obesity. A P-value less than 0.05 was used to declare statistical significance.

Results

The pooled prevalence of overweight /obesity among under-5 was 5.10% (9% CI: 4.45 – 5.76) in SSA. South Africa region (8.80%, 95% CI: 4.18 – 13.42) had a higher prevalence of under-5 overweight and/or obesity followed by the East Africa region. Male under-5 children (adjusted odds ratio (AOR) = 1.09, 95 confidence interval (CI): 1.02 – 1.25), Larger birth weight under-5 children (AOR = 1.39, 95% CI: 1.26 – 1.54), under-5 children aged older two to three years (AOR = 0.85, 95% CI: 0.76 – 0.94), under-5 children born from educated mothers (secondary and above) (AOR = 1.12, 95% CI: 1.01 – 1.25), and under-5 children living in the West Africa (AOR = 0.67, 95% CI: 0.56 – 0.81) and South Africa (AOR = 1.87, 95% CI: 1.09 – 3.21) were significant determinants for under-5 overweight and/or obesity.

Conclusion

Childhood obesity is becoming a great challenge and double burden in developing nations. In SSA Africa 1 in 20 under 5 children were overweight and/or obese. Male under-5 children, older aged, under-5 children born from educated mothers, and under-5 children living in the South Africa region were at higher risk for developing overweight and/or obesity. Thus, SSA countries should implement early to pause these consequences preventing the double burden of undernutrition.
Design of an RCT on cost-effectiveness of group schema therapy versus individual schema therapy for patients with Cluster-C personality disorder: the QUEST-CLC study protocol
Authors: Groot Iuno Z. , Venhuizen Anne-Sophie S. M. , Bachrach Nathan , Walhout Simone , de Moor Bregje , Nikkels Kasper , Dalmeijer Susanne , Maarschalkerweerd Myrte , van Aalderen Joël R. , de Lange Hinde , Wichers Renske , Hollander Agatha Ph. , Evers Silvia M. A. A. , Grasman Raoul P. P. P. , Arntz Arnoud
Published: October 2022

Background

Given the high prevalence of Cluster-C Personality Disorders (PDs) in clinical populations, disease burden, high societal costs and poor prognosis of comorbid disorders, a major gain in health care can be achieved if Cluster-C PDs are adequately treated. The only controlled cost-effectiveness study published so far found Individual Schema Therapy (IST) to be superior to Treatment as Usual (TAU). Group ST (GST) might improve cost-effectiveness as larger numbers can be treated in (>50%) less time compared to IST. However, to date there is no RCT supporting its (cost-) effectiveness. The overall aim of this study is to assess the evidence for GST for Cluster-C PDs and to improve treatment allocation for individual patients. Three main questions are addressed: 1) Is GST for Cluster-C PDs (cost-)effective compared to TAU? 2) Is GST for Cluster-C PDs (cost-) effective compared to IST? 3) Which patient-characteristics predict better response to GST, IST, or TAU?

Methods

In a multicenter RCT, the treatment conditions GST, IST, and TAU are compared in 378 Cluster-C PD patients within 10 sites. GST and IST follow treatment protocols and are completed within 1 year. TAU is the optimal alternative treatment available at the site according to regular procedures. Severity of the Cluster-C PD is the primary outcome, assessed with clinical interviews by independent raters blind for treatment. Functioning and wellbeing are important secondary outcomes. Assessments take place at week 0 (baseline), 17 (mid-GST), 34 (post-GST), 51 (post-booster sessions of GST), and 2 years (FU). Patient characteristics predicting better response to a specific treatment are studied, e.g., childhood trauma, autistic features, and introversion. A tool supporting patients and clinicians in matching treatment to patient will be developed. An economic evaluation investigates the cost-effectiveness and cost-utility from a societal perspective. A process evaluation by qualitative methods explores experiences of participants, loved ones and therapists regarding recovery, quality of life, and improving treatment.

Discussion

This study will determine the (cost-)effectiveness of treatments for Cluster-C PDs regarding treatment type as well as optimal matching of patient to treatment and deliver insight into which aspects help Cluster-C-PD patients recover and create a fulfilling life.

Trial registration

Dutch Trial Register: NL9209. Registered on 28-01-2021,
Decreased inflammatory gene expression accompanies the improvement of liver enzyme and lipid profile following aerobic training and vitamin D supplementation in T2DM patients
Authors: Hoseini Rastegar , Rahim Hiwa Ahmed , Ahmed Jalal Khdhr
Published: October 2022

Background

Type 2 Diabetes Mellitus (T2DM) is one of the health issues causing untoward low-grade systemic inflammation. Aerobic Training (AT) and Vitamin D (Vit D) supplementation are among the approaches that improve lipid profile and liver enzymes in T2DM. However, the mechanisms responsible for these improvements are not fully elucidated.

Objectives

This study aimed to evaluate the effects of AT and Vit D supplementation on lipid profile, liver enzymes, Interleukin-6 (IL-6), Interleukin-10 (IL-10), Cluster of differentiation 27 (CD27), Chemokine (C-X-C motif) Ligand 13 (CXCL13), Interferon-Gamma (IFN-γ) and Transforming Growth Factor-Beta 1 (TGF-β1) gene expressions in patients with T2DM.

Methods

In this study, 40 male T2DM patients aged 35–50 years were randomly selected and assigned into four groups (n = 10 for each); AT+vitamin D supplementation (AT+Vit D), AT+placebo (AT), Vit D supplementation (Vit D), and control+placebo (C). The intervention consisted of 8 weeks of 20–40 minutes AT protocol at 60–75% HRmax 3 sessions/week and taking 50,000 IU of Vit D supplement once a week. Serum levels of lipid profile and liver enzymes and gene expression of IL-6, IL-10, CD27, CXCL13, IFN-γ, and TGF-β1 in Peripheral Blood Mononuclear Cells (PBMCs) were measured. One-way analysis of variance (ANOVA), Tukey’s post hoc, and paired sample t-test at P-values less than 0.05 were used to analyze the data using SPSS software.

Results

AT+Vit D, AT, and Vit D significantly decreased TC, TG, LDL, AST, ALT, and GGT while increased HDL after 8 weeks in favor of AT+Vit D. Also, gene expressions of IL-6, IL-10, CD27, CXCL13, IFN-γ, and TGF-β1 were downregulated significantly in AT+Vit D, AT, and Vit D, while upregulated in C. Furthermore, compared to individual AT or Vit D, AT+Vit D significantly downregulated IL-6 (P = 0.013; P = 0.025), IL-10 (P = 0.012; P = 0.026), CD27 (P = 0.023; P = 0.041), CXCL13 (P = 0.014; P = 0.025), IFN-γ (P = 0.017; P = 0.026), and TGF-β1 (P = 0.001; P = 0.028).

Conclusion

In comparison to individual AT or Vit D, AT+Vit D may enhance lipid profile, and liver enzymes and drive the balance to favor inhibition of inflammation by downregulating gene expression of inflammation-related factors. As a result, AT+Vit D may be considered appropriate therapy for managing T2DM.
Deletion patterns, genetic variability and protein structure of pfhrp2 and pfhrp3: implications for malaria rapid diagnostic test in Amhara region, Ethiopia
Authors: Molina - de la Fuente Irene , Yimar Mulat , García Luz , González Vicenta , Amor Arancha , Anegagrie Melaku , Benito Agustín , Martínez Javier , Moreno Marta , Berzosa Pedro
Published: October 2022

Background

Although rapid diagnostic tests (RDTs) play a key role in malaria-control strategies, their efficacy has been threatened by deletion and genetic variability of the genes pfhrp2/3. This study aims to characterize the deletion, genetic patterns and diversity of these genes and their implication for malaria RDT effectiveness, as well as their genetic evolution in the Amhara region of Ethiopia.

Methods

The study included 354 isolates from symptomatic patients from the Amhara region of Ethiopia who tested positive by microscopy. Exon 1–2 and exon 2 of genes pfhrp2 and -3 were amplified, and exon 2 was sequenced to analyse the genetic diversity, phylogenetic relationship and epitope availability.

Results

The deletion frequency in exon 1–2 and exon 2 was 22 and 4.6% for pfhrp2, and 68 and 18% for pfhrp3, respectively. Double deletion frequency for pfhrp2 and pfhrp3 was 1.4%. High genetic diversity, lack of clustering by phylogenetic analysis and evidence of positive selection suggested a diversifying selection for both genes. The amino-acid sequences, classified into different haplotypes, varied widely in terms of frequency of repeats, with novel amino-acid changes. Aminoacidic repetition type 2 and type 7 were the most frequent in all the sequences. The most frequent epitopes among protein sequences were those recognized by MAbs 3A4 and C1-13.

Conclusion

Deletions and high amino acidic variation in pfhrp2 and pfhrp3 suggest their possible impact on RDT use in the Amhara region, and the high genetic diversity of these genes could be associated with a diversifying selection in Ethiopia. Surveillance of these genes is, therefore, essential to ensure the effectiveness of public health interventions in this region.

Graphical Abstract
Composition of the infiltrating immune cells in the brain of healthy individuals: effect of aging
Authors: Nevalainen Tapio , Autio Arttu , Hurme Mikko
Published: October 2022

Immune cells infiltrating the central nervous system (CNS) are involved in the defense against invading microbes as well as in the pathogenesis of neuroinflammatory diseases. In these conditions, the presence of several types of immune and inflammatory cells have been demonstrated. However, some studies have also reported low amounts of immune cells that have been detected in the CNS of healthy individuals, but the cell types present have not been systematically analyzed. To do this, we now used brain samples from The Genotype- Tissue Expression (GTEx) project to analyze the relative abundance of 22 infiltrating leukocyte types using a digital cytometry tool (CIBERSORTx). To characterize cell proportions in different parts of the CNS, samples from 13 different anatomic brain regions were used. The data obtained demonstrated that several leukocyte types were present in the CNS. Six leukocyte types (CD4 memory resting T cells, M0 macrophages, plasma cells, CD8 T cells, CD4 memory activated T cells, and monocytes) were present with a proportion higher than 0.05, i.e. 5%. These six cell types were present in most brain regions with only insignificant variation. A consistent association with age was seen with monocytes, CD8 T cells, and follicular helper T cells. Taken together, these data show that several infiltrating immune cell types are present in the non-diseased CNS tissue and that the proportions of infiltrating cells are affected by age in a manner that is consistent with literature on immunosenecence and inflammaging.
The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor
Authors: Franz Colin K. , Murthy Nikhil K. , Malik George R. , Kwak Jean W. , D’Andrea Dom , Wolfe Alexis R. , Farr Ellen , Stearns Melanie A. , Deshmukh Swati , Tavee Jinny O. , Sun Fang , Swong Kevin N. , Rydberg Leslie , Cotton R. James , Wolfe Lisa F. , Walter James M. , Coleman John M. , Rogers John A.
Published: October 2022

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.
Platelet-rich plasma use in meniscus repair treatment: a systematic review and meta-analysis of clinical studies
Authors: Li Ziquan , Weng Xisheng
Published: October 2022

Background

There is conflicting clinical evidence whether platelet-rich plasma (PRP) therapies could translate to an increased meniscus healing rate and improved functional outcomes. The objective of this systematic review and meta-analysis was to compare the failure rate and patient-reported functional outcomes in meniscus repair augmented with and without PRP.

Methods

We comprehensively searched the PubMed, Web of Science, Medline, Embase, and Cochrane Library databases to identify studies that compared the clinical efficacy of meniscus repair performed with PRP versus without PRP. The primary outcome was the meniscus repair failure rate, while the secondary outcomes were knee-specific patient-reported outcomes, including the International Knee Documentation Committee (IKDC) score, Lysholm knee scale, visual analog scale, Tegner activity level score, Western Ontario and McMaster Universities Osteoarthritis Index score, Single Assessment Numeric Evaluation score, and Knee injury and Osteoarthritis Outcome Score. Furthermore, subgroup analyses were performed by stratifying the studies according to the PRP preparation technique to investigate the potential sources of heterogeneity among studies.

Results

Our meta-analysis included nine studies (two RCTs and seven non-RCTs) with 1164 participants. The failure rate in the PRP group was significantly lower than that in the non-PRP group [odds ratio: 0.64, 95% confidence interval (CI) (0.42, 0.96), P = 0.03]. Furthermore, the PRP group was associated with a statistically significant improvement in the visual analog scale for pain [Mean difference (MD): − 0.76, 95% CI (− 1.32, − 0.21), P = 0.007] and Knee injury and Osteoarthritis Outcome Score-symptom [MD: 8.02, 95% CI (2.99, 13.05), P = 0.002] compared with the non-PRP group. However, neither the IKDC score nor the Lysholm knee scale showed any differences between the two groups. In addition, the results of subgroup analyses favored PRP over platelet-rich fibrin matrix (PRFM) regarding the IKDC score.

Conclusions

Although meniscus repairs augmented with PRP led to significantly lower failure rates and better postoperative pain control compared with those of the non-PRP group, there is insufficient RCT evidence to support PRP augmentation of meniscus repair improving functional outcomes. Moreover, PRP could be recommended in meniscus repair augmentation compared with PRFM. PRFM was shown to have no benefit in improving functional outcomes.
Effectiveness of photofunctionalized titanium alloy on osseointegration in rats with type 2 diabetes
Authors: Jin Shengdao , Yamamoto Yuji , Harada Yoshifumi , Kaneko Sho , Oishi Kazuki , Ishibashi Yasuyuki
Published: October 2022

Background

Ultraviolet (UV) light-mediated photofunctionalization improves the osseointegration of pure titanium and titanium alloy (Ti6Al4V). However, little is known about the effect of UV irradiation on Ti6Al4V, used frequently in orthopedic surgery, in diabetic patients. We examined the effect of UV irradiation on Ti6Al4V in rats with type 2 diabetes.

Methods

Cylinder Ti6Al4V implants were used. Half the animals were Sprague Dawley rats (the control group), and the other half were Spontaneously Diabetic Torii fatty rats (the diabetes mellitus model). For radiological analysis, bone density was observed and calculated using 3D microcomputed tomography. Histological analysis was performed to calculate the bone–implant contact (BIC) ratio. We used Pearson correlation to analyze the correlation between average blood glucose level and BIC ratio, and between average blood glucose level and bone volume (BV) ratio.

Results

In the UV light-treated group, the BIC ratios of the normal and diabetic rats increased significantly compared with those in the untreated group at 2 weeks; at 4 weeks, the BIC ratio of the diabetic rats increased significantly, but there was no significant increase in the control animals. In both the control and diabetic groups, there was no significant difference in the BV ratios between the UV-treated and untreated implants at 2 or 4 weeks. The average blood glucose level in the 4-week group negatively correlated with the BIC and BV ratios. The average blood glucose level in the UV-treated group negatively correlated with the BIC ratio.

Conclusion

Photofunctionalization of Ti6Al4V implants may promote osseointegration in the early stages in rats with type 2 diabetes.
Distal aortic replacement followed by endovascular repair for the management of severe intra-pleural adhesions accidentally detected during open surgery for chronic type B aortic dissection: a report of two cases
Authors: Daimon Masahiro , Shimada Ryo , Motohashi Yoshikazu , Uchida Hiroaki , Ozawa Hideki , Katsumata Takahiro
Published: October 2022

Background

Open repair is the most promising curative treatment option for patients with chronic type B aortic dissection. However, based on our experience, following the accidental detection of intra-pleural adhesions during open surgery for chronic type B aortic dissection, complete replacement of the diseased aorta cannot be accomplished. To overcome this problem, we switched the procedure to create a distal landing zone for subsequent endovascular repair by replacing the distal aorta with a vascular graft.

Case presentation

We report two cases in which open repair was attempted; however, the proximal descending thoracic aorta could not be exposed due to the presence of severe adhesion in the pleural cavity. In these patients, we accessed the lower descending thoracic aorta or thoracoabdominal aorta and created a distal landing zone for subsequent endovascular repair by replacing the aorta with a vascular graft. Thereafter, endovascular repair was performed with good outcomes.

Conclusions

Replacement of the distal aorta, which is typically easy to access despite the presence of intra-pleural adhesions, with a vascular graft serves as a reliable distal landing zone for subsequent endovascular repair. This method may be a viable option for the management of severe adhesions accidentally detected in the pleural cavity during open repair for chronic type B aortic dissection.
China’s terrestrial ecosystem carbon balance during the 20th century: an analysis with a process-based biogeochemistry model
Authors: Lu Yanyu , Huang Yao , Zhuang Qianlai , Sun Wei , Chen Shutao , Lu Jun
Published: October 2022

Background

China’s terrestrial ecosystems play a pronounced role in the global carbon cycle. Here we combine spatially-explicit information on vegetation, soil, topography, climate and land use change with a process-based biogeochemistry model to quantify the responses of terrestrial carbon cycle in China during the 20th century.

Results

At a century scale, China’s terrestrial ecosystems have acted as a carbon sink averaging at 96 Tg C yr− 1, with large inter-annual and decadal variabilities. The regional sink has been enhanced due to the rising temperature and CO2 concentration, with a slight increase trend in carbon sink strength along with the enhanced net primary production in the century. The areas characterized by C source are simulated to extend in the west and north of the Hu Huanyong line, while the eastern and southern regions increase their area and intensity of C sink, particularly in the late 20th century. Forest ecosystems dominate the C sink in China and are responsible for about 64% of the total sink. On the century scale, the increase in carbon sinks in China’s terrestrial ecosystems is mainly contributed by rising CO2. Afforestation and reforestation promote an increase in terrestrial carbon uptake in China from 1950s. Although climate change has generally contributed to the increase of carbon sinks in terrestrial ecosystems in China, the positive effect of climate change has been diminishing in the last decades of the 20th century.

Conclusion

This study focuses on the impacts of climate, CO2 and land use change on the carbon cycle, and presents the potential trends of terrestrial ecosystem carbon balance in China at a century scale. While a slight increase in carbon sink strength benefits from the enhanced vegetation carbon uptake in China’s terrestrial ecosystems during the 20th century, the increase trend may diminish or even change to a decrease trend under future climate change.
Rare disease curative care expenditure-financing scheme-health provider–beneficiary group analysis: an empirical study in Sichuan Province, China
Authors: Li Jia , Yang Lian , Zhang Yitong , Liao Hailun , Ma Yuan , Sun Qun
Published: October 2022

Background

Rare diseases impose a heavy economic burden on patients’ families and society worldwide. This study used the samples from Sichuan Province in China to estimate the curative care expenditure (CCE) of ten rare diseases, for supporting the prioritization of rare disease health policies.

Methods

Multi-stage cluster sampling method was adopted to investigate 9714 rare disease patients from 1556 medical institutions in Sichuan Province. Based on the System of Health Accounts 2011, this study estimated the total CCE of 10 rare diseases, financing schemes, and their allocation among different medical institutions and groups of people.

Results

In 2018, the total CCE of the ten rare diseases was $19.00 million, the three costliest rare diseases were Hemophilia ($4.38 million), Young-onset Parkinson’s disease ($2.96 million), and Systemic Sclerosis ($2.45 million). Household out-of-pocket expenditure (86.00% for outpatients, 41.60% for inpatients) and social health insurance (7.85% for outpatients; 39.58% for inpatients) were the main sources of financing CCE. The out-of-pocket expenditures for patients with Young-onset Parkinson’s disease, Congenital Scoliosis, and Autoimmune Encephalitis accounted for more than 60% of the total CCE. More than 80% of the rare disease CCE was incurred in general hospitals. The 40–59 age group accounted for the highest CCE (38.70%) while men spent slightly more (55.37%) than women (44.64%).

Conclusions

As rare disease treatment is costly and household out-of-pocket expenditure is high, we suggest taking steps to include rare disease drugs in the National Reimbursement Drug List and scientifically re-design insurance coverage. It is also necessary to explore a multi-tiered healthcare security system to pay for the CCE of rare diseases and reduce the economic burden on patients.
Historical and projected public spending on drugs for rare diseases in Canada between 2010 and 2025
Authors: Lech Richard , Chow Gideon , Mann Kamalpreet , Mott Patrick , Malmberg Christine , Forte Lindy
Published: October 2022

Objective

Rare diseases are life-threatening, debilitating, or serious chronic conditions that affect < 50/100,000 people. Canadians can only access approximately 60% of drugs for rare diseases (DRDs), which is partially related to high per-patient costs and payers’ affordability concerns. However, limiting access to DRDs can reduce survival and quality of life among patients and caregivers. Therefore, we projected Canadian non-oncology DRD spending relative to total public drug spending to provide perspective for decision makers.

Methods

Candidate historical (2010–2020) and pipeline (2021–2025) Canadian-marketed non-oncology DRDs were identified using definitions from the European Medicines Agency and the US Food and Drug Administration databases. Inclusion and exclusion criteria were applied to identify eligible DRDs. Public payer claims data, prevalence rates, regulatory, and health technology assessment factors were used to project DRD spending in relation to total Canadian public drug spending.

Results

We included 42 historical DRDs and 122 pipeline DRDs. Public spending on DRDs grew from $14.8 million in 2010 (11 DRDs) to $380.9 million in 2020, then a projected $527.6 million in 2021 (59 potential DRDs) and $1.6 billion in 2025 (164 potential DRDs). Projected DRD spending increased from 3.2% of $16.5 billion public drug spending in 2021 to 8.3% of $19.4 billion in 2025. These projections do not include confidential manufacturer discounts, health outcome-related offsets, or additional safety-related costs.

Conclusions

Projected DRD spending shows robust growth but remains a fraction of total public drug spending. Limiting DRD access because of this growth is not aligned with Canadian patient or societal values. Given the renewed interest in a Canadian DRD framework, our results may help guide discussions that aim to balance control of public drug spending with the well-being of patients with rare diseases.
A systematic review of telehealth screening, assessment, and diagnosis of autism spectrum disorder
Authors: Liu Meimei , Ma Zenghui
Published: October 2022

There is a significant delay between parents having concerns and receiving a formal assessment and Autism Spectrum Disorder (ASD) diagnosis. Telemedicine could be an effective alternative that shortens the waiting time for parents and primary health providers in ASD screening and diagnosis. We conducted a systematic review examining the uses of telemedicine technology for ASD screening, assessment, or diagnostic purposes and to what extent sample characteristics and psychometric properties were reported. This study searched four databases from 2000 to 2022 and obtained 26 studies that met the inclusion criteria. The 17 applications used in these 26 studies were divided into three categories based on their purpose: screening, diagnostic, and assessment. The results described the data extracted, including study characteristics, applied methods, indicators seen, and psychometric properties. Among the 15 applications with psychometric properties reported, the sensitivity ranged from 0.70 to 1, and the specificity ranged from 0.38 to 1. The present study highlights the strengths and weaknesses of current telemedicine approaches and provides a basis for future research. More rigorous empirical studies with larger sample sizes are needed to understand the feasibility, strengths, and limitations of telehealth technologies for screening, assessing, and diagnosing ASD.
Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021
Authors: Wu Qing , Qian Wei , Sun Xiaoli , Jiang Shaojie
Published: October 2022

The United States Food and Drug Administration (US FDA) has always been a forerunner in drug evaluation and supervision. Over the past 31 years, 1050 drugs (excluding vaccines, cell-based therapies, and gene therapy products) have been approved as new molecular entities (NMEs) or biologics license applications (BLAs). A total of 228 of these 1050 drugs were identified as cancer therapeutics or cancer-related drugs, and 120 of them were classified as therapeutic drugs for solid tumors according to their initial indications. These drugs have evolved from small molecules with broad-spectrum antitumor properties in the early stage to monoclonal antibodies (mAbs) and antibody‒drug conjugates (ADCs) with a more precise targeting effect during the most recent decade. These drugs have extended indications for other malignancies, constituting a cancer treatment system for monotherapy or combined therapy. However, the available targets are still mainly limited to receptor tyrosine kinases (RTKs), restricting the development of antitumor drugs. In this review, these 120 drugs are summarized and classified according to the initial indications, characteristics, or functions. Additionally, RTK-targeted therapies and immune checkpoint-based immunotherapies are also discussed. Our analysis of existing challenges and potential opportunities in drug development may advance solid tumor treatment in the future.
Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Authors: Yi Ming , Niu Mengke , Wu Yuze , Ge Hong , Jiao Dechao , Zhu Shuangli , Zhang Jing , Yan Yongxiang , Zhou Pengfei , Chu Qian , Wu Kongming
Published: October 2022

Background

Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance.

Methods

The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq).

Results

MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes.

Conclusion

Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.
Renaissance of glucocorticoids in critical care in the era of COVID-19: ten urging questions
Authors: Winkler Martin S. , Osuchowski Marcin F. , Payen Didier , Torres Antoni , Dickel Steffen , Skirecki Tomasz
Published: October 2022

The 40-year-old experience with glucocorticosteroids (GCs) in the context of severe infections is complex and troublesome. Recently, however, a clear indication for GCs in severe COVID-19 has been established. This may constitute a harbinger of a wider use of GCs in critical illnesses. A fundamental prerequisite of such an action is a better understanding of the heterogeneity of critical illness and GCs operationalization within the precision medicine approach. In this perspective, we formulate ten major questions regarding the use of GCs in critical illness. Answering them will likely facilitate a new era of effective and personalized GCs use in modern critical care.