bluuebunny/crossref_metadata_2025 huggingface dataset:
Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA
Authors: Wu Chen-Fei , Lin Li , Mao Yan-Ping , Deng Bin , Lv Jia-Wei , Zheng Wei-Hong , Wen Dan-Wan , Kou Jia , Chen Fo-Ping , Yang Xing-Li , Xu Si-Si , Ma Jun , Zhou Guan-Qun , Sun Ying
Published: August 2021

Background

The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective.

Methods

For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed.

Results

For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk.

Conclusions

The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.
Improving citric acid production of an industrial Aspergillus niger CGMCC 10142: identification and overexpression of a high-affinity glucose transporter with different promoters
Authors: Xue Xianli , Bi Futi , Liu Boya , Li Jie , Zhang Lan , Zhang Jian , Gao Qiang , Wang Depei
Published: August 2021

Background

Glucose transporters play an important role in the fermentation of citric acid. In this study, a high-affinity glucose transporter (HGT1) was identified and overexpressed in the industrial strain A. niger CGMCC 10142. HGT1-overexpressing strains using the PglaA and Paox1 promoters were constructed to verify the glucose transporter functions.

Result

As hypothesized, the HGT1-overexpressing strains showed higher citric acid production and lower residual sugar contents. The best-performing strain A. niger 20-15 exhibited a reduction of the total sugar content and residual reducing sugars by 16.5 and 44.7%, while the final citric acid production was significantly increased to 174.1 g/L, representing a 7.3% increase compared to A. niger CGMCC 10142. Measurement of the mRNA expression levels of relevant genes at different time-points during the fermentation indicated that in addition to HGT1, citrate synthase and glucokinase were also expressed at higher levels in the overexpression strains.

Conclusion

The results indicate that HGT1 overexpression resolved the metabolic bottleneck caused by insufficient sugar transport and thereby improved the sugar utilization rate. This study demonstrates the usefulness of the high-affinity glucose transporter HGT1 for improving the citric acid fermentation process of Aspergillus niger CGMCC 10142.
Allele frequency deviation (AFD) as a new prognostic model to predict overall survival in lung adenocarcinoma (LUAD)
Authors: Al-Dherasi Aisha , Liao Yuwei , Al-Mosaib Sultan , Hua Rulin , Wang Yichen , Yu Ying , Zhang Yu , Zhang Xuehong , Jalayta Raeda , Mousa Haithm , Al-Danakh Abdullah , Alnadari Fawze , Almoiliqy Marwan , Baldi Salem , Shi Leming , Lv Dekang , Li Zhiguang , Liu Quentin
Published: August 2021

Background

Lung adenocarcinoma (LUAD) remains one of the world’s most known aggressive malignancies with a high mortality rate. Molecular biological analysis and bioinformatics are of great importance as they have recently occupied a large area in the studies related to the identification of various biomarkers to predict survival for LUAD patients. In our study, we attempted to identify a new prognostic model by developing a new algorithm to calculate the allele frequency deviation (AFD), which in turn may assist in the early diagnosis and prediction of clinical outcomes in LUAD.

Method

First, a new algorithm was developed to calculate AFD using the whole-exome sequencing (WES) dataset. Then, AFD was measured for 102 patients, and the predictive power of AFD was assessed using Kaplan–Meier analysis, receiver operating characteristic (ROC) curves, and area under the curve (AUC). Finally, multivariable cox regression analyses were conducted to evaluate the independence of AFD as an independent prognostic tool.

Result

The Kaplan–Meier analysis showed that AFD effectively segregated patients with LUAD into high-AFD-value and low-AFD-value risk groups (hazard ratio HR = 1.125, 95% confidence interval CI 1.001–1.26, p = 0.04) in the training group. Moreover, the overall survival (OS) of patients who belong to the high-AFD-value group was significantly shorter than that of patients who belong to the low-AFD-value group with 42.8% higher risk and 10% lower risk of death for both groups respectively (HR for death = 1.10; 95% CI 1.01–1.2, p = 0.03) in the training group. Similar results were obtained in the validation group (HR = 4.62, 95% CI 1.22–17.4, p = 0.02) with 41.6%, and 5.5% risk of death for patients who belong to the high and low-AFD-value groups respectively. Univariate and multivariable cox regression analyses demonstrated that AFD is an independent prognostic model for patients with LUAD. The AUC for 5-year survival were 0.712 and 0.86 in the training and validation groups, respectively.

Conclusion

AFD was identified as a new independent prognostic model that could provide a prognostic tool for physicians and contribute to treatment decisions.
Clustering of malaria in households in the Greater Mekong Subregion: operational implications for reactive case detection
Authors: Mukaka Mavuto , Peerawaranun Pimnara , Parker Daniel M. , Kajeechiwa Ladda , Nosten Francois H. , Nguyen Thuy-Nhien , Hien Tran Tinh , Tripura Rupam , Peto Thomas J. , Phommasone Koukeo , Mayxay Mayfong , Newton Paul N. , Imwong Mallika , Day Nicholas P. J. , Dondorp Arjen M. , White Nicholas J. , von Seidlein Lorenz
Published: August 2021

Background

Malaria reactive case detection is the testing and, if positive, treatment of close contacts of index cases. It is included in national malaria control programmes of countries in the Greater Mekong Subregion to accelerate malaria elimination. Yet the value of reactive case detection in the control and elimination of malaria remains controversial because of the low yield, limited evidence for impact, and high demands on resources.

Methods

Data from the epidemiological assessments of large mass drug administration (MDA) studies in Myanmar, Vietnam, Cambodia and Laos were analysed to explore malaria infection clustering in households. The proportion of malaria positive cases among contacts screened in a hypothetical reactive case detection programme was then determined. The parasite density thresholds for rapid diagnostic test (RDT) detection was assumed to be > 50/µL (50,000/mL), for dried-blood-spot (DBS) based PCR > 5/µL (5000/mL), and for ultrasensitive PCR (uPCR) with a validated limit of detection at 0.0022/µL (22/mL).

Results

At baseline, before MDA, 1223 Plasmodium infections were detected by uPCR in 693 households. There was clustering of Plasmodium infections. In 637 households with asymptomatic infections 44% (278/637) had more than one member with Plasmodium infections. In the 132 households with symptomatic infections, 65% (86/132) had more than one member with Plasmodium infections. At baseline 4% of households had more than one Plasmodium falciparum infection, but three months after MDA no household had more than one P. falciparum infected member. Reactive case detection using DBS PCR would have detected ten additional cases in six households, and an RDT screen would have detected five additional cases in three households among the 169 households with at least one RDT positive case. This translates to 19 and 9 additional cases identified per 1000 people screened, respectively. Overall, assuming all febrile RDT positive patients would seek treatment and provoke reactive case detection using RDTs, then 1047 of 1052 (99.5%) Plasmodium infections in these communities would have remained undetected.

Conclusion

Reactive case detection in the Greater Mekong subregion is predicted to have a negligible impact on the malaria burden, but it has substantial costs in terms of human and financial resources.
Impact of cattle on the abundance of indoor and outdoor resting malaria vectors in southern Malawi
Authors: Mburu Monicah M. , Zembere Kennedy , Mzilahowa Themba , Terlouw Anja D. , Malenga Tumaini , van den Berg Henk , Takken Willem , McCann Robert S.
Published: August 2021

Background

Understanding the blood feeding preferences and resting habits of malaria vectors is important for assessing and designing effective malaria vector control tools. The presence of livestock, such as cattle, which are used as blood meal hosts by some malaria vectors, may impact malaria parasite transmission dynamics. The presence of livestock may provide sufficient blood meals for the vectors, thereby reducing the frequency of vectors biting humans. Alternatively, the presence of cattle may enhance the availability of blood meals such that infectious mosquitoes may survive longer, thereby increasing the risk of malaria transmission. This study assessed the effect of household-level cattle presence and distribution on the abundance of indoor and outdoor resting malaria vectors.

Methods

Houses with and without cattle were selected in Chikwawa district, southern Malawi for sampling resting malaria vectors. Prokopack aspirators and clay pots were used for indoor and outdoor sampling, respectively. Each house was sampled over two consecutive days. For houses with cattle nearby, the number of cattle and the distances from the house to where the cattle were corralled the previous night were recorded. All data were analysed using generalized linear models fitted with Poisson distribution.

Results

The malaria vectors caught resting indoors were Anopheles gambiae sensustricto (s.s.), Anopheles arabiensis and Anopheles funestuss.s. Outdoor collections consisted primarily of An. arabiensis. The catch sizes of indoor resting An. gambiae sensulato (s.l.) were not different in houses with and without cattle (P = 0.34). The presence of cattle near a house was associated with a reduction in the abundance of indoor resting An. funestuss.l. (P = 0.04). This effect was strongest when cattle were kept overnight ≤ 15 m away from the houses (P = 0.03). The blood meal hosts varied across the species.

Conclusion

These results highlight differences between malaria vector species and their interactions with potential blood meal hosts, which may have implications for malaria risk. Whereas An. arabiensis remained unaffected, the reduction of An. funestuss.s. in houses near cattle suggests a potential protective effect of cattle. However, the low abundance of mosquitoes reduced the power of some analyses and limited the generalizability of the results to other settings. Therefore, further studies incorporating the vectors’ host-seeking behaviour/human biting rates are recommended to fully support the primary finding.
Direct detection of resistance to fluoroquinolones/SLIDs in sputum specimen by GenoType MTBDRsl v.2.0 assay A study from Eastern Uttar Pradesh, India
Authors: Singh Kamal , Kumari Richa , Gupta Smita , Tripathi Rajneesh , Srivastava Anjali , Shakya Vidisha , Gupta Ankush , Anupurba Shampa
Published: August 2021

Background

According to World Health Organization (WHO), drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance globally and continues to be a public health threat. Annually, about half a million people fall ill with DR-TB globally. The gradual increase in resistance to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs), poses a serious threat to effective TB control and adequate patient management. Therefore, WHO suggests the use of GenoType MTBDRsl v.2.0 assay for detection of multiple mutations associated with FQs and SLIDs. Hence, the study was conducted to determine the prevalence of resistance to FQs and SLIDs by comparing direct GenoType MTBDRsl v.2.0 assay with phenotypic drug susceptibility testing (DST).

Methods

The study was conducted on 1320 smear positive sputum samples from a total of 2536 RR-TB, confirmed by GeneXpert MTB/RIF. The smear positive specimens were decontaminated, and DNA extraction was performed. Furthermore, the extracted DNA was used for GenoType MTBDRsl v.2.0 assay. While 20% of the decontaminated specimens were inoculated in Mycobacterium growth indicator tube (MGIT) for drug susceptibility testing (DST).

Results

Out of 1320 smear positive sputum samples, 1178 were identified as Mycobacterium tuberculosis complex (MTBC) and remaining were negative by GenoType MTBDRsl v.2.0 assay. Of the 1178 MTBC positive, 26.6% were sensitive to both FQs and SLIDs, whereas 57.3% were only FQs resistant and 15.9% were resistant to both FQs and SLIDs. Further DST of 225 isolates by liquid culture showed that 17% were sensitive to both FQs and SLIDs, 61.3% were only FQs resistant and 21.3% were resistant to both. The specificity for FQs and SLIDs was 92.31% and 100% whereas sensitivity was 100% respectively by GenoType MTBDRsl v.2.0 assay in direct sputum samples.

Conclusions

Our study clearly suggests that GenoType MTBDRsl v.2.0 assay is a reliable test for the rapid detection of resistance to second-line drugs after confirmation by GeneXpert MTB/RIF assay for RR-TB. Though, high rate FQ (ofloxacin) resistance was seen in our setting, moxifloxacin could be used as treatment option owing to very low resistance.
Retinol-binding protein 4 in combination with lipids to predict the regression phenomenon of autism spectrum disorders
Authors: Chen Jianling , Chen Jing , Xu Yun , Cheng Peipei , Yu Shunying , Fu Yingmei , Du Yasong
Published: August 2021

Background

About 20–40 % of autistic people experience a phenomenon of regression. Retinol binding protein 4 (RBP4) plays an important role as an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis. Abnormal fatty acid metabolism and lipid mediators have been reported to be related to the etiological mechanism in autism, and amelioration of impaired lipid metabolism can be recognized as a treatment strategy for autism. The purpose of this study is to explore the relationship between RBP4, lipids, and the autistic regression phenomenon, and to discuss their potentials as biomarkers for the autistic regression phenomenon.

Methods

A total of 60 autistic individuals (18 with regression phenomenon, 42 without regression phenomenon) (ASD group) and 36 healthy controls were enrolled in this case-control study. The levels of RBP4, total cholesterol (TC), high-density lipoprotein (HDLC), low–density lipoprotein (LDLC), and triglyceride (TG) were measured. Childhood Autism Rating Scale (CARS) is used to assess the severity of autism. Ethical measures were performed in compliance with the current Declaration of Helsinki and written informed consent was obtained from the parents before enrollment of the children and adolescents.

Results

Compared with control subjects, autistic individuals had lower levels of TC (P = 0.007), RBP4 (P = 0.001), and HDLC (P = 0.027). The levels of RBP4 in ASD group were positively correlated with TG (r = 0.355, P = 0.005), HDLC (r = 0.257, P = 0.047), TG/TC (r = 0.376, P = 0.003) and TG/LDLC (r = 0.363, P = 0.004), and were negatively correlated with CARS (r=-0.296, P = 0.003). Further logistic regression demonstrated that decreased RBP4 concentration was associated with the presentation of the autistic regression phenomenon even after the adjustment of the potential confounding factors.

Conclusions

Serum RBP4 is associated with the autistic regression phenomenon and the severity of ASD. Further studies are needed to expound whether decreased RBP4 participates in the development of the autistic regression phenomenon.
A drug-related Good Samaritan Law and calling emergency medical services for drug overdoses in a Canadian setting
Authors: Moallef Soroush , Choi JinCheol , Milloy M.-J. , DeBeck Kora , Kerr Thomas , Hayashi Kanna
Published: August 2021

Background

People who use drugs (PWUD) are known to fear calling emergency medical services (EMS) for drug overdoses. In response, drug-related Good Samaritan Laws (GSLs) have been widely adopted in the USA and Canada to encourage bystanders to call emergency medical services (EMS) in the event of a drug overdose. However, the effect of GSLs on EMS-calling behaviours has been understudied. We sought to identify factors associated with EMS-calling, including the enactment of the Canadian GSL in May 2017, among PWUD in Vancouver, Canada, a setting with an ongoing overdose crisis.

Methods

Data were derived from three prospective cohort studies of PWUD in Vancouver in 2014–2018. Multivariable logistic regression was used to determine factors associated with EMS-calling among PWUD who witnessed an overdose event. An interrupted time series (ITS) analysis was employed to assess the impact of GSL on monthly prevalence of EMS-calling.

Results

Among 540 eligible participants, 321 (59%) were males and 284 (53%) reported calling EMS. In multivariable analysis, ever having administered naloxone three or more times (adjusted odds ratio [AOR] 2.00; 95% confidence interval [CI] 1.08–3.74) and residence in the Downtown Eastside (DTES) neighbourhood of Vancouver (AOR 1.96; 95% CI 1.23–3.13) were positively associated with EMS-calling, while living in a single occupancy hotel (SRO) was negatively associated with EMS-calling (AOR 0.51; 95% CI 0.30–0.86). The post-GSL enactment period was not associated with EMS-calling (AOR 0.81; 95% CI 0.52–1.25). The ITS found no significant difference in the monthly prevalence of EMS-calling between pre- and post-GSL enactment periods.

Conclusion

We observed EMS being called about half the time and the GSL did not appear to encourage EMS-calling. We also found that individuals living in SROs were less likely to call EMS, which raises concern given that fatal overdose cases are concentrated in SROs in our setting. The link between many naloxone administrations and EMS-calling could indicate that those with prior experience in responding to overdose events were more willing to call EMS. Increased efforts are warranted to ensure effective emergency responses for drug overdoses among PWUD.
Drug use, homelessness and health: responding to the opioid overdose crisis with housing and harm reduction services
Authors: Milaney Katrina , Passi Jenna , Zaretsky Lisa , Liu Tong , O’Gorman Claire M. , Hill Leslie , Dutton Daniel
Published: August 2021

Background

Canada is in the midst of an opioid overdose crisis and Alberta has one of the highest opioid use rates across the country. Populations made vulnerable through structural inequities who also use opioids, such as those who are unstably housed, are at an increased risk of experiencing harms associated with opioid use. The main purpose of this study was to explore if there was an association between unstable housing and hospital use for people who use opioids.

Methods

Analysis utilized self-reported data from the Alberta Health and Drug Use Survey which surveyed 813 Albertans in three cities. Hospital use was modeled using a logistic regression with our primary variable of interest being housing unstable status. Chi square tests were conducted between hospital use and variables associated with demographics, characteristics of drug use, health characteristics, and experiences of receiving services to establish model inclusion.

Results

Results revealed a significant association between housing instability and hospital use with unstably housed individuals twice as likely torequire hospital care.

Conclusions

Results highlight the importance of concurrently addressing housing instability alongside the provision of harm reduction services such as safe supply and supervised consumption sites. These findings have significant implications for policy and policymakers during the opioid overdose epidemic, and provide a foundation for future areas of research.
Method for reconstructing mortality by educational groups
Authors: Németh László , Jasilionis Domantas , Brønnum-Hansen Henrik , Jdanov Dmitri A.
Published: August 2021

Background

The lack of classification by educational attainment in death and population exposure data at older ages is an important constraint for studying changes and patterns of mortality disparities by education in Denmark and Sweden. The missing educational distribution of population also restricts analyses aiming at estimating contributions of compositional change to the improvements in national longevity. This study proposes a transparent approach to solve the two methodological issues allowing to obtain robust education-specific mortality estimates and population weights.

Methods

Using nonparametric approach, we redistribute the unknown cases and extrapolate the mortality curves of these sub-populations with the help of population-level data on an aggregate level from the Human Mortality Database.

Results

We present reconstructed and harmonized education-specific abridged and complete life tables for Sweden and Denmark covering 5-year-long periods from 1991–1995 to 2011–2015. The newly estimated life tables are in good agreement with the national life tables and show plausible age- and education-specific patterns. The observed changes in life expectancy by education suggest about the widening longevity gap between the highest and lowest educated for males and females in both countries.

Conclusions

The proposed simple and transparent method can be applied in similar country-specific cases showing large proportions of missing education or other socio-economic characteristics at older ages.
Applying low coverage whole genome sequencing to detect malignant ovarian mass
Authors: Chen Ming , Zhong Pengqiang , Hong Mengzhi , Tan Jinfeng , Yu Xuegao , Huang Hao , Ouyang Juan , Lin Xiaoping , Chen Peisong
Published: August 2021

To evaluate whether low coverage whole genome sequencing is suitable for the detection of malignant pelvic mass and compare its diagnostic value with traditional tumor markers. We enrolled 63 patients with a pelvic mass suspicious for ovarian malignancy. Each patient underwent low coverage whole genome sequencing (LCWGS) and traditional tumor markers test. The pelvic masses were finally confirmed via pathological examination. The copy number variants (CNVs) of whole genome were detected and the Stouffers Z-scores for each CNV was extracted. The risk of malignancy (RM) of each suspicious sample was calculated based on the CNV counts and Z-scores, which was subsequently compared with ovarian cancer markers CA125 and HE4, and the risk of ovarian malignancy algorithm (ROMA). Receiver Operating Characteristic Curve (ROC) were used to access the diagnostic value of variables. As confirmed by pathological diagnosis, 44 (70%) patients with malignancy and 19 patients with benign mass were identified. Our results showed that CA125 and HE4, the CNV, the mean of Z-scores (Zmean), the max of Z-scores (Zmax), the RM and the ROMA were significantly different between patients with malignant and benign masses. The area under curve (AUC) of CA125, HE4, CNV, Zmax, and Zmean was 0.775, 0.866, 0.786, 0.685 and 0.725 respectively. ROMA and RM showed similar AUC (0.876 and 0.837), but differed in sensitivity and specificity. In the validation cohort, the AUC of RM was higher than traditional serum markers. In conclusion, we develop a LCWGS based method for the identification of pelvic mass of suspicious ovarian cancer. LCWGS shows accurate result and could be complementary with the existing diagnostic methods.
CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy
Authors: Ghaffari Sasan , Khalili Nastaran , Rezaei Nima
Published: August 2021

Cancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.
Dietary treatment of congenital chylothorax with skimmed breast milk
Authors: Höck Michaela , Höller Alexander , Hammerl Marlene , Wechselberger Karina , Krösslhuber Jakob , Kiechl-Kohlendorfer Ursula , Scholl-Bürgi Sabine , Karall Daniela
Published: August 2021

Background

Congenital chylothorax (CC) is a rare but potentially life-threatening condition in newborns. It is defined as an accumulation of chyle in the pleural cavity. The few publications regarding medical management and therapeutic dietary intervention motivated us to share our experience.

Methods

Neonates diagnosed with congenital chylothorax and treated at Innsbruck Medical University Hospital between 2013 and 2020 (n = 6, gestational age: 36 3/7, 32 5/7, 36 4/7, 35 0/7, 35 4/7, 37 3/7 weeks) were eligible for this report.

The cornerstones of treatment for chylothorax conventionally consist of chest tube drainage (CTD), respiratory support, dietary restriction of long-chain triglycerides (LCT) or total parenteral nutrition (TPN). In further course the introduction of a medium-chain triglyceride (MCT)-based formula followed by an overlapping switch to a formula with low LCT and high MCT, containing the essential long-chain fatty acids (LCFA), is attempted. In three patients we used fat-modified (skimmed) breast milk to provide a high protein and low fat diet and to avoid the discontinuation of breast milk.

Results

The outcome of an early introduction of LCFA in the form of skimmed breast milk after resolution of chylothorax diverse. One patient had a favourable outcome, meaning no recurrence of pleural effusion, adequate weight gain and a content mother, while another patient had a relapse of pleural effusion after the administration of skimmed milk and was therefore transitioned back to Basic F® .

The CC of patient 5 was difficult due to Noonan syndrome. Two weeks after the introduction of skimmed breast milk the mother wanted to stop to express breast milk, so nutrition was changed to Basic F®.

Conclusion

The first-line therapy of chylothorax is a combination of respiratory stabilization and dietary modification. The use of skimmed breast milk is advisable in CC and feasible by means of a simple milk defatting procedure. It offers benefits to mothers who wish to resume breast feeding after resolution of chylothorax and has proven positive effects, above all in preterm infants as optimal nutrition with protective components superior to formula feeding. However, the nutritional analysis of the skimmed milk and the correlation to a re-accumulation of pleural fluid remains a question to be answered.
IL-23/Th17 pathway and IL-17A gene polymorphism in Egyptian children with immune thrombocytopenic purpura
Authors: Ismail Ahlam M. , Higazi Aliaa M. , Nomeir Hanan M. , Farag Naglaa M.
Published: August 2021

Background

Immune thrombocytopenic purpura (ITP) is an acquired complex autoimmune thrombocytopenia. Uncontrolled cellular immune response is one of the key triggers for the loss of immune tolerance in ITP patients. The purpose of this study was to investigate the association of IL-23/Th17, IL-17A and IL-17A rs2275913 gene polymorphism with ITP in Egyptian children.

Methods

60 patients with ITP and 50 healthy control children from Minia city- Egypt were involved. Serum levels of IL-23 and IL-17A were determined by enzyme-linked immunosorbent assay. The frequency of Th17 cells was measured using flow cytometer. Genotyping for IL-17A was performed via polymerase chain reaction-restriction fragment length polymorphism.

Results

Comparing children with ITP to controls, serum levels of IL-23 and IL-17A as well as Th17 cells percentage were significantly increased (p <  0.001). Also, higher levels of these ILs and Th17 cells percentage were associated with decreased platelet count within ITP patients (p <  0.001). Analysis of genotype frequencies for IL-17A rs2275913 polymorphism and its alleles (A, G) showed no significant difference between cases and controls. Likewise, no significant differences were demonstrated between acute and chronic ITP regarding both IL-17A rs2275913 polymorphism prevalence and levels of IL-23, IL-17A plus Th17 cells percentage. The frequency of A alleles was 85 and 86% within patients and controls, respectively.

Conclusions

Elevated levels of IL-23, IL-17A and Th17 cells may be involved in ITP pathogenesis while IL-17A polymorphism rs2275913 is not prevalent in Egyptian children with ITP.
Occurrence of tick-borne pathogens in questing Ixodes ricinus ticks from Wester Ross, Northwest Scotland
Authors: Olsthoorn Fanny , Sprong Hein , Fonville Manoj , Rocchi Mara , Medlock Jolyon , Gilbert Lucy , Ghazoul Jaboury
Published: August 2021

Background

Lyme borreliosis and other tick-borne diseases emerge from increased interactions between humans, other animals, and infected ticks. The risk of acquiring a tick-borne infection varies across space and time, so knowledge of the occurrence and prevalence of pathogens in ticks can facilitate disease diagnosis in a specific area and the implementation of mitigation measures and awareness campaigns. Here we identify the occurrence and prevalence of several pathogens in Ixodes ricinus ticks in Wester Ross, Northwest Scotland, a region of high tourism and tick exposure, yet data-poor in terms of tick-borne pathogens.

Methods

Questing I. ricinus nymphs (n = 2828) were collected from 26 sites in 2018 and 2019 and tested for the presence of tick-borne pathogens using PCR-based methods. Prevalence was compared with other regions of Scotland, England, Wales, and the Netherlands.

Results

Anaplasma phagocytophilum (4.7% prevalence), Borrelia burgdorferi sensu lato (s.l.) (2.2%), Babesia from clade X (0.2%), Rickettsia helvetica (0.04%), and Spiroplasma ixodetis (0.4%) were detected, but no Neoehrlichia mikurensis, Borrelia miyamotoi, or Babesia microti. Typing of A. phagocytophilum using a fragment of the GroEL gene identified the presence of both ecotype I and ecotype II. Genospecies identification of Borrelia burgdorferi s.l. revealed B. afzelii (53% of infected nymphs), B. garinii (9%), B. burgdorferi sensu stricto (7%), and B. valaisiana (31%). We found similar prevalence of A. phagocytophilum in Wester Ross as in the Netherlands, but higher than in other parts of Great Britain. We found lower B. burgdorferi s.l. prevalence than in England or the Netherlands, and similar to some other Scottish studies. We found higher prevalence of B. valaisiana and lower prevalence of B. garinii than in other Scottish studies. We found S. ixodetis at much lower prevalence than in the Netherlands, and R. helvetica at much lower prevalence than in England and the Netherlands.

Conclusions

As far as we know, this is the first description of S. ixodetis in Great Britain. The results are relevant for disease surveillance and management for public and veterinary health. The findings can also aid in designing targeted public health campaigns and in raising awareness among outdoor recreationists and professionals.

Graphical abstract
Long non-coding RNA CASC2 restrains high glucose-induced proliferation, inflammation and fibrosis in human glomerular mesangial cells through mediating miR-135a-5p/TIMP3 axis and JNK signaling
Authors: Zhu Dongju , Wu Xiang , Xue Qian
Published: August 2021

Background

Diabetic nephropathy (DN) is a common complication of diabetes. Long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is reported to exert a protective role in DN by a previous study. The working mechanism underlying the protective role of CASC2 in DN progression was further explored in this study.

Methods

The expression of CASC2 and microRNA-135a-5p (miR-135a-5p) was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation ability was assessed by Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-29-deoxyuridine (EDU) assay. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze the production of inflammatory cytokines in the supernatant. Western blot assay was performed to analyze protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the target relationship between miR-135a-5p and CASC2 or tissue inhibitors of metalloproteinase 3 (TIMP3).

Results

High glucose (HG) treatment reduced the expression of CASC2 in human glomerular mesangial cells (HMCs) in a time-dependent manner. CASC2 overexpression suppressed HG-induced proliferation, inflammation and fibrosis in HMCs. miR-135a-5p was validated as a target of CASC2, and CASC2 restrained HG-induced influences in HMCs partly by down-regulating miR-135a-5p. miR-135a-5p bound to the 3ʹ untranslated region (3ʹUTR) of TIMP3, and CASC2 positively regulated TIMP3 expression by sponging miR-135a-5p in HMCs. miR-135a-5p silencing inhibited HG-induced effects in HMCs partly by up-regulating its target TIMP3. CASC2 overexpression suppressed HG-induced activation of Jun N-terminal Kinase (JNK) signaling partly through mediating miR-135a-5p/TIMP3 signaling.

Conclusions

In conclusion, CASC2 alleviated proliferation, inflammation and fibrosis in DN cell model by sponging miR-135a-5p to induce TIMP3 expression.
Labial gland-derived mesenchymal stem cells and their exosomes ameliorate murine Sjögren's syndrome by modulating the balance of Treg and Th17 cells
Authors: Li Boya , Xing Yixiao , Gan Yehua , He Jing , Hua Hong
Published: August 2021

Background

Sjögren's syndrome (SS) is a chronic, systemic autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The disease severely affects the health and life of patients, and the treatment of SS has always been a clinical challenge and essentially palliative. Mesenchymal stem cells (MSCs) have been reported to exert immunomodulatory effects and as a potential novel therapeutic strategy for SS. Labial gland-derived MSCs (LGMSCs) are a population of resident stem cells in the labial gland, first isolated by our group. Exosomes released by MSCs contain a large variety of bioactive molecules and considered to function as an extension of MSCs.

Methods

LGMSCs were isolated from patients who were needed surgery to remove the lip mucocele and LGMSCs derived exosomes (LGMSC-Exos) were isolated by ultracentrifugation. The non-obese diabetic (NOD) mice were treated with LGMSCs or LGMSC-Exos by tail vein injection. The saliva flow rate of mice was determined and salivary glands were dissected and stained with hematoxylin and eosin. In vitro, peripheral blood mononuclear cells (PBMCs) from SS patients were cocultured with LGMSCs or LGMSC-Exos. Percentage of T helper 17 (Th17) cells and regulatory T (Treg) cells were determined by flow cytometry. The serum levels of cytokines in NOD mice and in the supernatant of the co-culture system by ELISA.

Results

Treatment with LGMSCs or LGMSC-Exos reduced inflammatory infiltration in the salivary glands, and restored salivary gland secretory function in NOD mice. Importantly, LGMSCs or LGMSC-Exos were demonstrated to inhibit the differentiation of Th17 cells but promote the induction of Treg cells in NOD mice and PBMCs from SS patients in vitro, accompanied by reduced interleukin 17 (IL-17), interferon gamma, and IL-6 levels and enhanced transforming growth factor beta and IL-10 secretion by T cells.

Conclusions

LGMSCs are potential candidates for MSCs-based therapy and LGMSC-Exos might be utilized for establishing a new cell-free therapy against SS.
Antimicrobial stewardship, therapeutic drug monitoring and infection management in the ICU: results from the international A- TEAMICU survey
Authors: Lanckohr Christian , Boeing Christian , De Waele Jan J. , de Lange Dylan W. , Schouten Jeroen , Prins Menno , Nijsten Maarten , Povoa Pedro , Morris Andrew Conway , Bracht Hendrik
Published: August 2021

Background

Severe infections and multidrug-resistant pathogens are common in critically ill patients. Antimicrobial stewardship (AMS) and therapeutic drug monitoring (TDM) are contemporary tools to optimize the use of antimicrobials. The A-TEAMICU survey was initiated to gain contemporary insights into dissemination and structure of AMS programs and TDM practices in intensive care units.

Methods

This study involved online survey of members of ESICM and six national professional intensive care societies.

Results

Data of 812 respondents from mostly European high- and middle-income countries were available for analysis. 63% had AMS rounds available in their ICU, where 78% performed rounds weekly or more often. While 82% had local guidelines for treatment of infections, only 70% had cumulative antimicrobial susceptibility reports and 56% monitored the quantity of antimicrobials administered. A restriction of antimicrobials was reported by 62%. TDM of antimicrobial agents was used in 61% of ICUs, mostly glycopeptides (89%), aminoglycosides (77%), carbapenems (32%), penicillins (30%), azole antifungals (27%), cephalosporins (17%), and linezolid (16%). 76% of respondents used prolonged/continuous infusion of antimicrobials. The availability of an AMS had a significant association with the use of TDM.

Conclusions

Many respondents of the survey have AMS in their ICUs. TDM of antimicrobials and optimized administration of antibiotics are broadly used among respondents. The availability of antimicrobial susceptibility reports and a surveillance of antimicrobial use should be actively sought by intensivists where unavailable. Results of this survey may inform further research and educational activities.
RSST-ARGM: a data-driven approach to long-term sea surface temperature prediction
Authors: Zhu Linqian , Liu Qi , Liu Xiaodong , Zhang Yonghong
Published: August 2021

For the purpose of exploring the long-term variation of regional sea surface temperature (SST), this paper studies the historical SST in regional sea areas and the emission pattern of greenhouse gases, proposing a Grey model of regional SST atmospheric reflection which can be used to predict SST variation in a long time span. By studying the Grey systematic relationship between historical SST data, the model obtains the development law of temperature variation, and further introduces different greenhouse gas emission scenarios in the future as the indexes coefficient to determine the corresponding changing results of seawater temperature in the next 50 years. Taking the North Atlantic Ocean as an example, the cosine similarity test method is used to verify the model proposed in this paper. The accuracy of the model is as high as 0.99984. The model predicts that the regional SST could reach a maximum of $$15.3\,^{\circ }{\mathrm {C}}$$

15.3

∘

C

by 2070. This model is easy to calculate, with advantages of the high accuracy and good robustness.
Convergence and stability of an iteration process and solution of a fractional differential equation
Authors: Jubair Mohd , Ali Faeem , Ali Javid
Published: August 2021

In this paper, we prove that a three-step iteration process is stable for contractive-like mappings. It is also proved analytically and numerically that the considered process converges faster than some remarkable iterative processes for contractive-like mappings. Furthermore, some convergence results are proved for the mappings satisfying Suzuki’s condition (C) in uniformly convex Banach spaces. A couple of nontrivial numerical examples are presented to support the main results and the visualization is showed by Matlab. Finally, by utilizing our main result the solution of a nonlinear fractional differential equation is approximated.
Prevalence of extensively drug-resistant tuberculosis in a Chinese multidrug-resistant TB cohort after redefinition
Authors: Yao Cong , Guo Haiping , Li Qiang , Zhang Xuxia , Shang Yuanyuan , Li Tongxin , Wang Yufeng , Xue Zhongtan , Wang Lu , Li Liang , Pang Yu
Published: August 2021

Objectives

Recently, the definition of extensively drug-resistant TB (XDR-TB) has been revised. In this study, we conducted a descriptive and retrospective study to determine the prevalence of XDR-TB in a Chinese multidrug-resistant TB (MDR-TB) cohort.

Methods

Broth microdilution method was performed to determine in vitro susceptibilities of Mycobacterium tuberculosis (MTB) isolates to (FQs), bedaquiline (BDQ) and linezolid (LZD). The putative drug target genes conferring drug resistance were screened by DNA sequencing.

Results

A total of 425 MDR-TB isolates were included from 13 pilots in China. LZD and BDQ resistance were noted in 30 (7.1%) and 10 (2.4%) isolates. On the basis of latest definitions, 114 (26.8%) were MDR-TB, 282 (66.4%) were pre-XDR-TB, and 29 (6.8%) were XDR-TB. Among 311 FQ-resistant isolates, 265 harbored genetic mutations within QRDRs. The most common mutations were observed at codon 94 of gyrA, accounting for 47.2% of FQ-resistant MTB isolates. Only mutations within the Rv0678 gene were found to confer BDQ resistance in our cohort, conferring 40.0% of BDQ resistance. For LZD resistance, 53.3% of LZD-resistant isolates carried genetic mutations in rplC or 23S rRNA. The most frequent mutation was Cys154Arg in the rplC gene. In addition, we recorded two MDR-TB patients with resistance to both BDQ and LZD, of which one patient experienced continuous positive culture of MTB despite inclusion of efficacious moxifloxacin.

Conclusion

Our results demonstrate that the low prevalence of XDR-TB holds great promise for MDR-TB treatment with WHO-endorsed regimens containing BDQ-LZD combination, whereas the high prevalence of FQ-resistance in MDR-TB patients warrants national attention.
Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials
Authors: Witzel Simon , Frauhammer Felix , Steinacker Petra , Devos David , Pradat Pierre-François , Meininger Vincent , Halbgebauer Steffen , Oeckl Patrick , Schuster Joachim , Anders Simon , Dorst Johannes , Otto Markus , Ludolph Albert C.
Published: August 2021

Background

Interventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power.

Methods

In 125 patients with ALS from three independent prospective studies—one observational study and two interventional trials—we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS).

Results

Among the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%–66%, 7%–29%).

Conclusion

The use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power.

NCT00868166, registered March
23, 2009; NCT02306590, registered December 2, 2014.
Extended high-frequency audiometry in healthy adults with different age groups
Authors: Wang Mingming , Ai Yu , Han Yuechen , Fan Zhaomin , Shi Peng , Wang Haibo
Published: August 2021

Background

It was well-documented that extended high-frequency (EHF, above 8 kHz) hearing test could be more sensitive comparing with the conventional measurement on frequency below 8 kHz, regarding the early prediction of auditory damage in certain population. However, hardly any age-specific thresholds of EHF in population with normal hearing ability were observed. This study aims to monitor the age-dependent hearing thresholds at EHF (from 9 to 20 kHz) in healthy hearing population.

Methods

A total of 162 healthy participants (from 21 to 70 years) with normal conventional pure tone audiograms were recruited and separated into five groups by age. Conventional pure tone average was performed with frequencies from 0.25 to 8 kHz under air conduction and from 0.25 to 4 kHz under bone conduction. EHF audiometry from 9 to 20 kHz was determined under air conduction.

Results

The effects of aging on hearing were evident at frequencies above 4 kHz. The hearing thresholds of EHF were less than 26 dB HL before 30 years-olds. Hearing abilities in EHF were deteriorated starting from the 31 ∼ 40 group and were most obvious in the 51 ∼ 60 group and the 61 ∼ 70 group with the maximum thresholds of 75 dB HL. Sensitivity of EHF was inversely proportional to the frequency within each age group, and to age among groups. Subjects under 30 years old were totally responsive up to 16 kHz, and 52.2% could respond to 20 kHz. Meanwhile, no responsiveness was recorded to 20 kHz in the 51 ∼ 60 group and even to 18 kHz in the 61 ∼ 70 group. No gender differences in hearing threshold was observed within each age group, except an obvious decline at frequencies of 4, 6, 8, and 9 kHz in male participants of the 41 ∼ 50 group.

Conclusions

Hearing thresholds at EHF from 9 to 20 kHz were more sensitive than at frequencies below 8 kHz for hearing measurement, and aging inversely affected hearing ability at EHF in healthy population. Hearing thresholds at EHF deteriorated with age and raising frequency, while the upper frequency limit decreased with aging.

Graphical Abstract