bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergy of nanodiamond–doxorubicin conjugates and PD-L1 blockade effectively turns tumor-associated macrophages against tumor cells
Authors: Xu Hua-Zhen , Li Tong-Fei , Wang Chao , Ma Yan , Liu Yan , Zheng Mei-Yan , Liu Zhang-Jun-Yan , Chen Jin-Bo , Li Ke , Sun Shi-Kuan , Komatsu Naoki , Xu Yong-Hong , Zhao Li , Chen Xiao
Published: September 2021

Background

Tumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvironment. Turning the TAMs against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype.

Results

Nano-DOX were first shown to stimulate the tumor cells and the TAMs to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAMs. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAMs both by blocking Nano-DOX-induced PD-L1 in the TAMs and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAMs with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner.

Conclusions

PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAMs to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAMs, achieves enhanced activation of TAM-mediated anti-tumor response.

Graphic abstract
Covid-19 lockdown: Ethnic differences in children’s self-reported physical activity and the importance of leaving the home environment; a longitudinal and cross-sectional study from the Born in Bradford birth cohort study
Authors: Bingham Daniel D. , Daly-Smith Andy , Hall Jennifer , Seims Amanda , Dogra Sufyan A. , Fairclough Stuart J. , Ajebon Mildred , Kelly Brian , Hou Bo , Shire Katy A. , Crossley Kirsty L. , Mon-Williams Mark , Wright John , Pickett Kate , McEachan Rosemary , Dickerson Josie , Barber Sally E. ,   the Bradford Institute for Health Research COVID-19 Scientific Advisory Group
Published: September 2021

Background

In England, the onset of COVID-19 and a rapidly increasing infection rate resulted in a lockdown (March-June 2020) which placed strict restrictions on movement of the public, including children. Using data collected from children living in a multi-ethnic city with high levels of deprivation, this study aimed to: (1) report children’s self-reported physical activity (PA) during the first COVID-19 UK lockdown and identify associated factors; (2) examine changes of children’s self-reported PA prior to and during the first UK lockdown.

Methods

This study is part of the Born in Bradford (BiB) COVID-19 Research Study. PA (amended Youth Activity Profile), sleep, sedentary behaviours, daily frequency/time/destination/activity when leaving the home, were self-reported by 949 children (9–13 years). A sub-sample (n = 634) also self-reported PA (Physical Activity Questionnaire for Children) pre-pandemic (2017-February 2020). Univariate analysis assessed differences in PA between sex and ethnicity groups; multivariable logistic regression identified factors associated with children’s PA. Differences in children's levels of being sufficiently active prior to and during the lockdown were examined using the McNemar test; and multivariable logistic regression was used to identify factors explaining change.

Results

During the pandemic, White British (WB) children were more sufficiently active (34.1%) compared to Pakistani Heritage children (PH) (22.8%) or ‘Other’ ethnicity children (O) (22.8%). WB children reported leaving the home more frequently and for longer periods than PH and O children. Modifiable variables related to being sufficiently active were frequency, duration, type of activity, and destination away from the home environment. There was a large reduction in children being sufficiently active during the first COVID-19 lockdown (28.9%) compared to pre-pandemic (69.4%).

Conclusions

Promoting safe extended periods of PA everyday outdoors is important for all children, in particular for children from ethnic minority groups. Children’s PA during the first COVID-19 UK lockdown has drastically reduced from before. Policy and decision makers, and practitioners should consider the findings in order to begin to understand the impact and consequences that COVID-19 has had upon children’s PA which is a key and vital behaviour for health and development.
Biologic medicine inclusion in 138 national essential medicines lists
Authors: Kraus Raphaël , Yeung Rae S. M. , Persaud Nav
Published: September 2021

Background

Essential medicines lists (EMLs) are intended to reflect the priority health care needs of populations. We hypothesized that biologic disease-modifying antirheumatic drugs (DMARDs) are underrepresented relative to conventional DMARDs in existing national EMLs. We aimed to survey the extent to which biologic DMARDs are included in EMLs, to determine country characteristics contributing to their inclusion or absence, and to contrast this with conventional DMARD therapies.

Methods

We searched 138 national EMLs for 10 conventional and 14 biologic DMARDs used in the treatment of childhood rheumatologic diseases. Via regression modelling, we determined country characteristics accounting for differences in medicine inclusion between national EMLs.

Results

Eleven countries (7.97%) included all 10 conventional DMARDs, 115 (83.33%) ≥5, and all countries listed at least one. Gross domestic product (GDP) per capita was associated with the total number of conventional DMARDs included (β11.02 [95% CI 0.39, 1.66];P = 0.00279). Among biologic DMARDs, 3 countries (2.2%) listed ≥10, 15 (10.9%) listed ≥5, and 47 (34.1%) listed at least one. Ninety-one (65.9%) of countries listed no biologic DMARDs. European region (β11.30 [95% CI 0.08, 2.52];P = 0.0367), life expectancy (β1–0.70 [95% CI -1.22, − 0.18];P = 0.0085), health expenditure per capita (β11.83 [95% CI 1.24, 2.42];P < 0.001), and conventional DMARDs listed (β10.70 [95% CI 0.33, 1.07];P < 0.001) were associated with the total number of biologic DMARDs included.

Conclusion

Biologic DMARDs are excluded from most national EMLs. By comparison, conventional DMARDs are widely included. Countries with higher health spending and longer life expectancy are more likely to list biologics.
Sex differences and similarities in the neuroimmune response to central administration of poly I:C
Authors: Posillico Caitlin K. , Garcia-Hernandez Rosa E. , Tronson Natalie C.
Published: September 2021

Background

The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation.

Methods

Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice.

Results

We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus.

Conclusion

Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.
Transmitted drug resistance and transmission clusters among HIV-1 treatment-naïve patients in Guangdong, China: a cross-sectional study
Authors: Lan Yun , Li Linghua , He Xiang , Hu Fengyu , Deng Xizi , Cai Weiping , Li Junbin , Ling Xuemei , Fan Qinghong , Cai Xiaoli , Li Liya , Li Feng , Tang Xiaoping
Published: September 2021

Background

Transmitted drug resistance (TDR) that affects the effectiveness of the first-line antiretroviral therapy (ART) regimen is becoming prevalent worldwide. However, its prevalence and transmission among HIV-1 treatment-naïve patients in Guangdong, China are rarely reported. We aimed to comprehensively analyze the prevalence of TDR and the transmission clusters of HIV-1 infected persons before ART in Guangdong.

Methods

The HIV-1 treatment-naïve patients were recruited between January 2018 and December 2018. The HIV-1 pol region was amplified by reverse transcriptional PCR and sequenced by sanger sequencing. Genotypes, surveillance drug resistance mutations (SDRMs) and TDR were analyzed. Genetic transmission clusters among patients were identified by pairwise Tamura-Nei 93 genetic distance, with a threshold of 0.015.

Results

A total of 2368 (97.17%) HIV-1 pol sequences were successfully amplified and sequenced from the enrolled 2437 patients. CRF07_BC (35.90%, 850/2368), CRF01_AE (35.56%, 842/2368) and CRF55_01B (10.30%, 244/2368) were the main HIV-1 genotypes circulating in Guangdong. Twenty-one SDRMs were identified among fifty-two drug-resistant sequences. The overall prevalence of TDR was 2.20% (52/2368). Among the 2368 patients who underwent sequencing, 8 (0.34%) had TDR to protease inhibitors (PIs), 22 (0.93%) to nucleoside reverse transcriptase inhibitors (NRTIs), and 23 (0.97%) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Two (0.08%) sequences showed dual-class resistance to both NRTIs and NNRTIs, and no sequences showed triple-class resistance. A total of 1066 (45.02%) sequences were segregated into 194 clusters, ranging from 2 to 414 sequences. In total, 15 (28.85%) of patients with TDR were included in 9 clusters; one cluster contained two TDR sequences with the K103N mutation was observed.

Conclusions

There is high HIV-1 genetic heterogeneity among patients in Guangdong. Although the overall prevalence of TDR is low, it is still necessary to remain vigilant regarding some important SDRMs.
The relationship between test anxiety and emotion regulation: the mediating effect of psychological resilience
Authors: Liu Yuguo , Pan Haiyan , Yang Runhuang , Wang Xingjie , Rao Jiawei , Zhang Xingshan , Pan Congcong
Published: September 2021

Background

Test anxiety has been widely found in medical students. Emotion regulation and psychological resilience have been identified as key factors contributing to anxiety. However, studies on relationships were limited. This study investigated the links between psychological resilience, emotion regulation, and test anxiety in addition to exploring the differences about socio-demographic factors.

Methods

A sample of 1266 medical students was selected through cross-sectional survey from a medical university in China during 2019. Data were obtained by network technique using designed questionnaire, which assesses the level of test anxiety, emotion regulation and psychological resilience, respectively.

Results

Medical students experienced test anxiety at different levels, 33.7% of these were seriously. It revealed significant effects of the gender and academic performance on test anxiety. Results of logistic regression indicated that test anxiety was significantly associated with emotion regulation and psychological resilience (p < 0.01). Psychological resilience played a mediating role on the relationship between emotion regulation and test anxiety.

Conclusions

These findings highlight the importance of psychological resilience and emotion regulation in understanding how psychological resilience relates to test anxiety in medical students. Resilience-training intervention may be developed to support students encountering anxiety during the exam.
The fate of patients after failed epicardial ablation of atrial fibrillation
Authors: Nasso Giuseppe , Lorusso Roberto , Motekallemi Arash , Dell’Aquila Angelo M. , Di Bari Nicola , Condello Ignazio , Moscarelli Marco , Iacopino Saverio , Serraino Giuseppe F. , Mastroroberto Pasquale , Santarpino Giuseppe , Speziale Giuseppe
Published: September 2021

Background

Much debate is still going on about the best ablation strategy—via endocardial or epicardial approach—in patients with atrial fibrillation (AF), and evidence gaps exist in current guidelines in this area. More specifically, there are no clear long-term outcome data after failed surgical AF ablation.

Methods

Since June 2008, 549 surgical AF ablation procedures through a right minithoracotomy were performed at our institution. From 2008 to 2011, a unipolar radiofrequency device was used (151 patients), whereas from 2011 to 2020 a bipolar radiofrequency device was used (398 patients). Patients were scheduled for surgery on the basis of the following criteria: recurrent episodes of paroxysmal or persistent lone AF refractory to maximally tolerated antiarrhythmic drug dosing and at least one failed cardioversion attempt. Besides the recommended follow-up by the local cardiologist, starting from 2021, surviving patients were asked to undergo assessment of left ventricular function and to complete a questionnaire addressing quality of life and predisposing factors for recurrent AF.

Results

At a mean follow-up of 77 months, the rate of AF recurrence was 20.7% (n = 114). On multivariate analysis, impaired left ventricular ejection fraction (58 patients, 51%, p = 0.002), worsening of European Heart Rhythm Association (EHRA) symptom class (37 patients, 32%, p = 0.003) and cognitive decline or depression (23 patients, 20%, p = 0.023) during follow-up were found to be significantly associated with AF recurrence.

Conclusions

Surgical AF ablation through a right minithoracotomy is safe, but a better outcome could be achieved using a hybrid approach. Patients after initial failed surgical AF ablation show worsening of cardiac function, clinical status and quality of life at follow-up compared to patients with successful AF ablation.
Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study
Authors: Schräder Nicholas H. B. , Gorell Emily S. , Stewart Roy E. , Duipmans José C. , Harris Nicole , Perez Victoria A. , Tang Jean Y. , Wolff André P. , Bolling Marieke C.
Published: September 2021

Background

Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population.

Objectives

To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications.

Methods

English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects.

Results

Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4 ± 1.5) and route of administration (mean: 2.1 ± 1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0–10; p < 0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%).

Conclusions

CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.
GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis
Authors: Mayweather Brittany A. , Buchanan Sean M. , Rubin Lee L.
Published: September 2021

Growth differentiation factor 11 (GDF11) is a transforming factor-β superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.
Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells
Authors: Jiang Guoyun , Huang Zhenglan , Yuan Ying , Tao Kun , Feng Wenli
Published: September 2021

Background

The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy.

Methods

Anti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML.

Results

The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo.

Conclusions

In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.
NanoCaller for accurate detection of SNPs and indels in difficult-to-map regions from long-read sequencing by haplotype-aware deep neural networks
Authors: Ahsan Mian Umair , Liu Qian , Fang Li , Wang Kai
Published: September 2021

Long-read sequencing enables variant detection in genomic regions that are considered difficult-to-map by short-read sequencing. To fully exploit the benefits of longer reads, here we present a deep learning method NanoCaller, which detects SNPs using long-range haplotype information, then phases long reads with called SNPs and calls indels with local realignment. Evaluation on 8 human genomes demonstrates that NanoCaller generally achieves better performance than competing approaches. We experimentally validate 41 novel variants in a widely used benchmarking genome, which could not be reliably detected previously. In summary, NanoCaller facilitates the discovery of novel variants in complex genomic regions from long-read sequencing.
Gramtools enables multiscale variation analysis with genome graphs
Authors: Letcher Brice , Hunt Martin , Iqbal Zamin
Published: September 2021

Genome graphs allow very general representations of genetic variation; depending on the model and implementation, variation at different length-scales (single nucleotide polymorphisms (SNPs), structural variants) and on different sequence backgrounds can be incorporated with different levels of transparency. We implement a model which handles this multiscale variation and develop a JSON extension of VCF (jVCF) allowing for variant calls on multiple references, both implemented in our software . We find outperforms existing methods for genotyping SNPs overlapping large deletions in M. tuberculosis and is able to genotype on multiple alternate backgrounds in P. falciparum, revealing previously hidden recombination.
Genomic basis underlying the metabolome-mediated drought adaptation of maize
Authors: Zhang Fei , Wu Jinfeng , Sade Nir , Wu Si , Egbaria Aiman , Fernie Alisdair R. , Yan Jianbing , Qin Feng , Chen Wei , Brotman Yariv , Dai Mingqiu
Published: September 2021

Background

Drought is a major environmental disaster that causes crop yield loss worldwide. Metabolites are involved in various environmental stress responses of plants. However, the genetic control of metabolomes underlying crop environmental stress adaptation remains elusive.

Results

Here, we perform non-targeted metabolic profiling of leaves for 385 maize natural inbred lines grown under well-watered as well as drought-stressed conditions. A total of 3890 metabolites are identified and 1035 of these are differentially produced between well-watered and drought-stressed conditions, representing effective indicators of maize drought response and tolerance. Genetic dissections reveal the associations between these metabolites and thousands of single-nucleotide polymorphisms (SNPs), which represented 3415 metabolite quantitative trait loci (mQTLs) and 2589 candidate genes. 78.6% of mQTLs (2684/3415) are novel drought-responsive QTLs. The regulatory variants that control the expression of the candidate genes are revealed by expression QTL (eQTL) analysis of the transcriptomes of leaves from 197 maize natural inbred lines. Integrated metabolic and transcriptomic assays identify dozens of environment-specific hub genes and their gene-metabolite regulatory networks. Comprehensive genetic and molecular studies reveal the roles and mechanisms of two hub genes, Bx12 and ZmGLK44, in regulating maize metabolite biosynthesis and drought tolerance.

Conclusion

Our studies reveal the first population-level metabolomes in crop drought response and uncover the natural variations and genetic control of these metabolomes underlying crop drought adaptation, demonstrating that multi-omics is a powerful strategy to dissect the genetic mechanisms of crop complex traits.
Entomological characterization of Aedes mosquitoes and arbovirus detection in Ibagué, a Colombian city with co-circulation of Zika, dengue and chikungunya viruses
Authors: Carrasquilla María C. , Ortiz Mario I. , León Cielo , Rondón Silvia , Kulkarni Manisha A. , Talbot Benoit , Sander Beate , Vásquez Heriberto , Cordovez Juan M. , González Camila ,   RADAM-LAC Research Team, Sander Beate , Kulkarni Manisha A. , Wu Jianhong , González Camila , Miretti Marcos , Espinel Mauricio , Cevallos Varsovia
Published: September 2021

Background

Dengue, Zika and chikungunya are arboviruses of significant public health importance that are transmitted by Aedes aegypti and Aedes albopictus mosquitoes. In Colombia, where dengue is hyperendemic, and where chikungunya and Zika were introduced in the last decade, more than half of the population lives in areas at risk. The objective of this study was to characterize Aedes spp. vectors and study their natural infection with dengue, Zika and chikungunya in Ibagué, a Colombian city and capital of the department of Tolima, with case reports of simultaneous circulation of these three arboviruses.

Methods

Mosquito collections were carried out monthly between June 2018 and May 2019 in neighborhoods with different levels of socioeconomic status. We used the non-parametric Friedman, Mann–Whitney and Kruskal–Wallis tests to compare mosquito density distributions. We applied logistic regression analyses to identify associations between mosquito density and absence/presence of breeding sites, and the Spearman correlation coefficient to analyze the possible relationship between climatic variables and mosquito density.

Results

We collected Ae. aegypti in all sampled neighborhoods and found for the first time Ae. albopictus in the city of Ibagué. A greater abundance of mosquitoes was collected in neighborhoods displaying low compared to high socioeconomic status as well as in the intradomicile compared to the peridomestic space. Female mosquitoes predominated over males, and most of the test females had fed on human blood. In total, four Ae. aegypti pools (3%) were positive for dengue virus (serotype 1) and one pool for chikungunya virus (0.8%). Interestingly, infected females were only collected in neighborhoods of low socioeconomic status, and mostly in the intradomicile space.

Conclusions

We confirmed the co-circulation of dengue (serotype 1) and chikungunya viruses in the Ae. aegypti population in Ibagué. However, Zika virus was not detected in any mosquito sample, 3 years after its introduction into the country. The positivity for dengue and chikungunya viruses, predominance of mosquitoes in the intradomicile space and the high proportion of females fed on humans highlight the high risk for arbovirus transmission in Ibagué, but may also provide an opportunity for establishing effective control strategies.

Graphical abstract
Bactericidal activity of avian complement: a contribution to understand avian-host tropism of Lyme borreliae
Authors: Sürth Valerie , Lopes de Carvalho Isabel , Núncio Maria Sofia , Norte Ana Cláudia , Kraiczy Peter
Published: September 2021

Complement has been considered as an important factor impacting the host–pathogen association of spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and may play a role in the spirochete’s ecology. Birds are known to be important hosts for ticks and in the maintenance of borreliae. Recent field surveys and laboratory transmission studies indicated that certain avian species act as reservoir hosts for different Borrelia species. Nevertheless, our current understanding of the molecular mechanisms determining host tropism of Borrelia is still in its fledgling stage. Concerning the role of complement in avian-host tropism, only a few bird species and Borrelia species have been analysed so far. Here, we performed in vitro serum bactericidal assays with serum samples collected from four bird species including the European robin Erithacus rubecula, the great tit Parus major, the Eurasian blackbird Turdus merula, and the racing pigeon Columba livia, as well as four Borrelia species (B. afzelii, B. garinii, B. valaisiana, and B. burgdorferi sensu stricto). From July to September 2019, juvenile wild birds were caught using mist nets in Portugal. Racing pigeons were sampled in a loft in October 2019. Independent of the bird species analysed, all Borrelia species displayed an intermediate serum-resistant or serum-resistant phenotype except for B. afzelii challenged with serum from blackbirds. This genospecies was efficiently killed by avian complement, suggesting that blackbirds served as dead-end hosts for B. afzelii. In summary, these findings suggest that complement contributes in the avian–spirochete–tick infection cycle and in Borrelia-host tropism.
Complete mitogenomes of Anopheles peditaeniatus and Anopheles nitidus and phylogenetic relationships within the genus Anopheles inferred from mitogenomes
Authors: Guo Jing , Yan Zhen-Tian , Fu Wen-Bo , Yuan Huan , Li Xu-Dong , Chen Bin
Published: September 2021

Background

Despite the medical importance of mosquitoes of the genus Anopheles in the transmission of malaria and other human diseases, its phylogenetic relationships are not settled, and the characteristics of mitochondrial genome (mitogenome) are not thoroughly understood.

Methods

The present study sequenced and analyzed the complete mitogenomes of An. peditaeniatus and An. nitidus, investigated genome characteristics, and inferred the phylogenetic relationships of 76 Anopheles spp.

Results

The complete mitogenomes of An. peditaeniatus and An. nitidus are 15,416 and 15,418 bp long, respectively, and both include 13 PCGs, 22 tRNAs, two tRNAs and one control region (CR). Mitogenomes of Anopheles spp. are similar to those of other insects in general characteristics; however, the trnR and trnA have been reversed to “trnR-trnA,” as has been reported in other mosquito genera. Genome variations mainly occur in CR length (493–886 bp) with six repeat unit types identified for the first time that demonstrate an evolutionary signal. The subgenera Lophopodomyia, Stethomyia, Kerteszia, Nyssorhynchus, Anopheles and Cellia are inferred to be monophyletic, and the phylogenetic analyses support a new phylogenetic relationship among the six subgenera investigated, in that subgenus Lophopodomyia is the sister to all other five subgenera, and the remaining five subgenera are divided into two clades, one of which is a sister-taxon subgenera Stethomyia + Kerteszia, and the other consists of subgenus Nyssorhynchus as the sister to a sister-group subgenera Anopheles + Cellia. Four series (Neomyzomyia, Pyretophorus, Neocellia and Myzomyia) of the subgenus Cellia, and two series (Arribalzagia and Myzorhynchus) of the subgenus Anopheles were found to be monophyletic, whereas three sections (Myzorhynchella, Argyritarsis and Albimanus) and their subdivisions of the subgenus Nyssorhynchus were polyphyletic or paraphyletic.

Conclusions

The study comprehensively uncovered the characteristics of mitogenome and the phylogenetics based on mitogenomes in the genus Anopheles, and provided information for further study on the mitogenomes, phylogenetics and taxonomic revision of the genus.

Graphical abstract
Schistosoma japonicum peptide SJMHE1 inhibits acute and chronic colitis induced by dextran sulfate sodium in mice
Authors: Shan Wenqi , Zhang Wenzhe , Xue Fei , Ma Yongbin , Dong Liyang , Wang Ting , Zheng Yu , Feng Dingqi , Chang Ming , Yuan Guoyue , Wang Xuefeng
Published: September 2021

Background

Harnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We previously identified a small molecule peptide from Schistosoma japonicum and named it SJMHE1. SJMHE1 can suppress delayed-type hypersensitivity, collagen-induced arthritis and asthma in mice. In this study, we assessed the effects of SJMHE1 on dextran sulfate sodium (DSS)-induced acute and chronic colitis.

Methods

Acute and chronic colitis were induced in C57BL/6 mice by DSS, following which the mice were injected with an emulsifier SJMHE1 or phosphate-buffered saline. The mice were then examined for body weight loss, disease activity index, colon length, histopathological changes, cytokine expression and helper T (Th) cell subset distribution.

Results

SJMHE1 treatment significantly suppressed DSS-induced acute and chronic colitis, improved disease activity and pathological damage to the colon and modulated the expression of pro-inflammatory and anti-inflammatory cytokines in splenocytes and the colon. In addition, SJMHE1 treatment reduced the percentage of Th1 and Th17 cells and increased the percentage of Th2 and regulatory T (Treg) cells in the splenocytes and mesenteric lymph nodes of mice with acute colitis. Similarly, SJMHE1 treatment upregulated the expression of interleukin-10 (IL-10) mRNA, downregulated the expression of IL-17 mRNA and modulated the Th cell balance in mice with chronic colitis.

Conclusions

Our data show that SJMHE1 provided protection against acute and chronic colitis by restoring the immune balance. As a small molecule, SJMHE1 might be a novel agent for the treatment of IBDs without immunogenicity concerns.

Graphical abstract
Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students
Authors: Knitza Johannes , Tascilar Koray , Gruber Eva , Kaletta Hannah , Hagen Melanie , Liphardt Anna-Maria , Schenker Hannah , Krusche Martin , Wacker Jochen , Kleyer Arnd , Simon David , Vuillerme Nicolas , Schett Georg , Hueber Axel J.
Published: September 2021

Background

An increasing number of diagnostic decision support systems (DDSS) exist to support patients and physicians in establishing the correct diagnosis as early as possible. However, little evidence exists that supports the effectiveness of these DDSS. The objectives were to compare the diagnostic accuracy of medical students, with and without the use of a DDSS, and the diagnostic accuracy of the DDSS system itself, regarding the typical rheumatic diseases and to analyze the user experience.

Methods

A total of 102 medical students were openly recruited from a university hospital and randomized (unblinded) to a control group (CG) and an intervention group (IG) that used a DDSS (Ada – Your Health Guide) to create an ordered diagnostic hypotheses list for three rheumatic case vignettes. Diagnostic accuracy, measured as the presence of the correct diagnosis first or at all on the hypothesis list, was the main outcome measure and evaluated for CG, IG, and DDSS.

Results

The correct diagnosis was ranked first (or was present at all) in CG, IG, and DDSS in 37% (40%), 47% (55%), and 29% (43%) for the first case; 87% (94%), 84% (100%), and 51% (98%) in the second case; and 35% (59%), 20% (51%), and 4% (51%) in the third case, respectively. No significant benefit of using the DDDS could be observed. In a substantial number of situations, the mean probabilities reported by the DDSS for incorrect diagnoses were actually higher than for correct diagnoses, and students accepted false DDSS diagnostic suggestions. DDSS symptom entry greatly varied and was often incomplete or false. No significant correlation between the number of symptoms extracted and diagnostic accuracy was seen. It took on average 7 min longer to solve a case using the DDSS. In IG, 61% of students compared to 90% in CG stated that they could imagine using the DDSS in their future clinical work life.

Conclusions

The diagnostic accuracy of medical students was superior to the DDSS, and its usage did not significantly improve students’ diagnostic accuracy. DDSS usage was time-consuming and may be misleading due to prompting wrong diagnoses and probabilities.

Trial registration

DRKS.de, DRKS00024433. Retrospectively registered on February 5, 2021.
Economical and preferred walking speed using body weight support apparatus with a spring-like characteristics
Authors: Abe Daijiro , Sakata Shunsuke , Motoyama Kiyotaka , Toyota Naoki , Nishizono Hidetsugu , Horiuchi Masahiro
Published: September 2021

Background

A specific walking speed minimizing the U-shaped relationship between energy cost of transport per unit distance (CoT) and speed is called economical speed (ES). To investigate the effects of reduced body weight on the ES, we installed a body weight support (BWS) apparatus with a spring-like characteristics. We also examined whether the 'calculated' ES was equivalent to the 'preferred' walking speed (PWS) with 30% BWS.

Methods

We measured oxygen uptake and carbon dioxide output to calculate CoT values at seven treadmill walking speeds (0.67–2.00 m s− 1) in 40 healthy young males under normal walking (NW) and BWS. The PWS was determined under both conditions on a different day.

Results

A spring-like behavior of our BWS apparatus reduced the CoT values at 1.56, 1.78, and 2.00 m s− 1. The ES with BWS (1.61 ± 0.11 m s− 1) was faster than NW condition (1.39 ± 0.06 m s− 1). A Bland-Altman analysis indicated that there were no systematic biases between ES and PWS in both conditions.

Conclusions

The use of BWS apparatus with a spring-like behavior reduced the CoT values at faster walking speeds, resulting in the faster ES with 30% BWS compared to NW. Since the ES was equivalent to the PWS in both conditions, the PWS could be mainly determined by the metabolic minimization in healthy young males. This result also derives that the PWS can be a substitutable index of the individual ES in these populations.
A neonate with Klippel–Trénaunay syndrome: a case report
Authors: Sikakulya Franck Katembo , Egesa Walufu Ivan , Kiyaka Sonye Magugu , Anyama Philip
Published: September 2021

Background

Klippel–Trénaunay syndrome is a rare congenital capillary–lymphatic–venous condition characterized by the clinical triad of capillary malformations (port wine stains), varicose veins with or without venous malformations, and bony and/or soft-tissue hypertrophy. It has a very low incidence of about 1:100,000.

Case presentation

We report the case of 21-day-old neonate Black African female (born in Uganda) with Klippel–Trénaunay syndrome who presented with macrodactyly and ectrodactyly on the left foot, as well as numerous port wine stains on the left thoracoabdominal region and anteroposterior left lower limb. Color Doppler ultrasound examination of the left lower limb and abdomen revealed varicose veins without signs of arteriovenous fistula.

Conclusion

The report presents the case of a neonate with a rare congenital vascular disorder type Klippel–Trénaunay syndrome.
Modeling the health impact of water and sanitation service deficits on waterborne disease transmission
Authors: Chaysiri Rujira , Louis Garrick E. , Chinviriyasit Wirawan
Published: September 2021

Cholera is a waterborne disease that continues to pose serious public health problems in many developing countries. Increasing water and sanitation coverage is a goal for local authorities in these countries, as it can eliminate one of the root causes of cholera transmission. The SIWDR (susceptible–infected–water–dumpsite–recovered) model is proposed here to evaluate the effects of the improved coverage of water and sanitation services in a community at risk of a cholera outbreak. This paper provides a mathematical study of the dynamics of the water and sanitation (WatSan) deficits and their public health impact in a community. The theoretical analysis of the SIWDR model gave a certain threshold value (known as the basic reproductive number and denoted $\mathcal{R}_{0}$

R
0

) to stop the transmission of cholera. It was found that the disease-free equilibrium was globally asymptotically stable whenever $\mathcal{R}_{0} \leq 1$

R
0

≤
1
. The unique endemic equilibrium was globally asymptotically stable whenever $\mathcal{R}_{0} >1$

R
0

>
1
. Sensitivity analysis was performed to determine the relative importance of model parameters to disease transmission and prevention. The numerical simulation results, using realistic parameter values in describing cholera transmission in Haiti, showed that improving the drinking water supply, wastewater and sewage treatment, and solid waste disposal services would be effective strategies for controlling the transmission pathways of this waterborne disease.
Clinical leaders and providers’ perspectives on delivering medications for the treatment of opioid use disorder in Veteran Affairs’ facilities
Authors: Hawkins Eric J. , Danner Anissa N. , Malte Carol A. , Blanchard Brittany E. , Williams Emily C. , Hagedorn Hildi J. , Gordon Adam J. , Drexler Karen , Burden Jennifer L. , Knoeppel Jennifer , Lott Aline , Sayre George G. , Midboe Amanda M. , Saxon Andrew J.
Published: September 2021

Background

Improving access to medication treatment of opioid use disorder (MOUD) is a national priority, yet common modifiable barriers (e.g., limited provider knowledge, negative beliefs about MOUD) often challenge implementation of MOUD delivery. To address these barriers, the VA launched a multifaceted implementation intervention focused on planning and educational strategies to increase MOUD delivery in 18 medical facilities. The purpose of this investigation was to determine if a multifaceted intervention approach to increase MOUD delivery changed providers’ perceptions about MOUD over the first year of implementation.

Methods

Cross-disciplinary teams of clinic providers and leadership from primary care, pain, and mental health clinics at 18 VA medical facilities received invitations to complete an anonymous, electronic survey prior to intervention launch (baseline) and at 12- month follow-up. Responses were summarized using descriptive statistics, and changes over time were compared using regression models adjusted for gender and prescriber status, and clustered on facility. Responses to open-ended questions were thematically analyzed using a template analysis approach.

Results

Survey response rates at baseline and follow-up were 57.1% (56/98) and 50.4% (61/121), respectively. At both time points, most respondents agreed that MOUD delivery is important (94.7 vs. 86.9%), lifesaving (92.8 vs. 88.5%) and evidence-based (85.2 vs. 89.5%). Over one-third (37.5%) viewed MOUD delivery as time-consuming, and only 53.7% affirmed that clinic providers wanted to prescribe MOUD at baseline; similar responses were seen at follow-up (34.5 and 52.4%, respectively). Respondents rated their knowledge about OUD, comfort discussing opioid use with patients, job satisfaction, ability to help patients with OUD, and support from colleagues favorably at both time points. Respondents’ ratings of MOUD delivery filling a gap in care were high but declined significantly from baseline to follow-up (85.7 vs. 73.7%, p < 0.04). Open-ended responses identified implementation barriers including lack of support to diagnose and treat OUD and lack of time.

Conclusions

Although perceptions about MOUD generally were positive, targeted education and planning strategies did not improve providers’ and clinical leaders’ perceptions of MOUD over time. Strategies that improve leaders’ prioritization and support of MOUD and address time constraints related to delivering MOUD may increase access to MOUD in non-substance use treatment clinics.
Intermittent face cooling reduces perceived exertion during exercise in a hot environment
Authors: Miyazawa Taiki , Mizutani Mirai , Sheahan John Patrick , Ichikawa Daisuke
Published: September 2021

Background

Facial cooling (FC) is effective in improving endurance exercise performance in hot environments. In this study, we evaluated the impact of intermittent short-lasting FC on the ratings of perceived exertion (RPE) during exercise.

Methods

Ten healthy men performed 40 continuous minutes of ergometric cycle exercise at 65% of the peak heart rate in a climatic chamber controlled at an ambient temperature of 35 °C and a relative humidity of 50%. In the control (CONT) trial, the participants performed the exercise without FC. In two cooling trials, each participant underwent 10 s of FC at 2- (FC2) and 4-min (FC4) intervals while continuing to exercise. FC was achieved by applying two soft-gel packs (cooled to 0 °C) directly and bilaterally on the forehead, eyes, and cheeks. In another cooling trial, 10 s of FC was performed at 2-min intervals using two soft-gel packs cooled to 20 °C (FC2-20).

Results

The RPE values in the FC4 trial were significantly lower than those in the CONT trial at 20 min (FC4, 11.6 ± 2.2 points; CONT, 14.2 ± 1.3 points; P < 0.01). Further, significant differences in the RPE values were observed between the FC4 and CONT trials at 5–15 min and 25–40 min (P < 0.05). RPE values were also significantly lower in the FC2 trial than in the CONT trial (5–40 min). Although the RPE values in the FC2-20 trial were significantly lower (5–10 min; 15–20 min) than those in the CONT trial, there were no significant differences in the RPE between the FC2-20 and CONT trials at 25–40 min. At 35 min, the RPE values were significantly higher in the FC2-20 trial than in the FC2 trial (P < 0.05).

Conclusion

Intermittent short-lasting FC was associated with a decrease in RPE, with shorter intervals and lower temperatures eliciting greater attenuation of increase in the RPE.