bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration of intrinsic hand function by superficial radial nerve: an anatomical study
Authors: Liang Shuo , Liu Yu-Zhou , Hu Xiao-Qian , Zhao Xin , Lao Jie
Published: August 2023

Background

The contralateral seventh cervical (cC7) nerve root transfer represents a cornerstone technique in treating total brachial plexus avulsion injury. Traditional cC7 procedures employ the entire ulnar nerve as a graft, which inevitably compromises its restorative capacity.

Objective

Our cadaveric study seeks to assess this innovative approach aimed at preserving the motor branch of the ulnar nerve (MBUN). This new method aims to enable future repair stages, using the superficial radial nerve (SRN) as a bridge connecting cC7 and MBUN.

Methods

We undertook a comprehensive dissection of ten adult cadavers, generously provided by the Department of Anatomy, Histology, and Embryology at Fudan University, China. It allowed us to evaluate the feasibility of our proposed technique. For this study, we harvested only the dorsal and superficial branches of the ulnar nerve, as well as the SRN, to establish connections between the cC7 nerve and recipient nerves (both the median nerve and MBUN). We meticulously dissected the SRN and the motor and sensory branches of the ulnar nerve. Measurements were made from the reverse point of the SRN to the wrist flexion crease and the coaptation point of the SRN and MBUN. Additionally, we traced the MBUN from distal to proximal ends, recording its maximum length. We also measured the diameters of the nerve branches and tallied the number of axons.

Results

Our modified approach proved technically viable in all examined limbs. The distances from the reverse point of the SRN to the wrist flexion crease were 8.24 ± 1.80 cm and to the coaptation point were 6.60 ± 1.75 cm. The maximum length of the MBUN was 7.62 ± 1.03 cm. The average axon diameters in the MBUN and the anterior and posterior branches of the SRN were 1.88 ± 0.42 mm、1.56 ± 0.38 mm、2.02 ± 0.41 mm,respectively. The corresponding mean numbers of axons were 1426.60 ± 331.39 and 721.50 ± 138.22, and 741.90 ± 171.34, respectively.

Conclusion

The SRN demonstrated the potential to be transferred to the MBUN without necessitating a nerve graft. A potential advantage of this modification is preserving the MBUN’s recovery potential.
Does transvaginal natural orifice transluminal endoscopic surgery affect female sexual function?: a prospective cohort study
Authors: Xu Dingyu , He Li , Lin Yonghong , Zhou Yayu , Gong Zhaolin , Zhang Qian , Hou Qiannan , Huang Lu
Published: August 2023

Background

To evaluate the effect of transvaginal natural orifice transluminal endoscopic surgery (vNOTES) on female sexual function. Methods: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2100050887, 07/09/2021). In this prospective cohort study, we prospectively analyzed the data of the female sexual function index (FSFI) questionnaire of 130 patients who underwent laparoscopy in Chengdu Women’s and Children’s Central Hospital due to gynecological benign diseases. The patients were assigned to the vNOTES group and the control group (underwent traditional laparoscopic surgery or transumbilical laparoendoscopic single-site surgery). Results: There were 4 cases dropout in the vNOTES group and 2 cases dropout in the control group. There was no difference in the ages (31.70 ± 5.02 vs. 30.37 ± 5.74, P>0.05), BMI (body mass index, 21.76 ± 3.16 vs. 23.30 ± 2.69, P>0.05), Education level, surgical types, and FSFI scores (22.31 ± 2.25 vs. 21.55 ± 3.38) between the vNOTES group and the control group before surgery. There was no difference in FSFI scores six months postoperation between the vNOTES group and the control group (21.61 ± 3.22 vs. 20.99 ± 3.26, P>0.05), and there was no difference in FSFI scores pre- and six months postoperation in vNOTES group (21.61 ± 3.22 vs. 22.31 ± 2.25, P>0.05). The time to start sexual life after surgery in the vNOTES group was later than that in the control group (39.34 ± 0.71 d versus 37.86 ± 0.69 d, P < 0.05). Conclusions: vNOTES has no significant adverse effect on female sexual function, however, the time to start sexual life after vNOTES is later than that after trans-abdominal laparoscopy.
Process evaluation of postpartum contraceptive service delivery in Ayder Comprehensive Specialized Hospital Mekelle, Tigray, Ethiopia in 2020
Authors: Hagos Kahsay Negash , Gesese Abreha Addis
Published: August 2023

Background

Postpartum contraceptives during the first year after delivery is a key service for women to prevent unintended pregnancy and reduce the risk of maternal and child mortality by ensuring safe birth intervals. This process evaluation aimed to assess the availability, compliance, and accommodation of Post-Partum Contraceptives (PPC) and the experience of women’s contraception in the first 12 months postpartum in Ayder Comprehensive Specialized Hospital (ACSH).

Methods

A case study evaluation design with a mixed method was employed from February 16/2020 to Mar 30, 2020. Direct observations, 12-month document reviews, and key informant interviews were conducted. The quantitative data were entered into Epi-Data version 3.1 and exported to SPSS version 21 for analysis. In the multivariate logistic regression analysis, variables with < 0.05 p-values and Adjusted Odds Ratio (AOR) with 95% Confidence Interval (CI) were used to declare the association. The qualitative data were transcribed, translated, coded, and analyzed using thematic analysis. The overall process of program implementation was measured based on pre-determined judgmental criteria.

Result

From the total of charts reviewed 302 only 188 (62.3%) postpartum mothers used any method within 12 months of the postpartum period out of which only 27.1% mothers used of long-acting reversible contraceptive (LARC). The overall evaluation of postpartum contraceptives was 84.1% (V/good). Notable gaps observed in this study were poor provision of information in relation to methods given, poor technical performance in following the aseptic procedure, poor utilization of postpartum family planning guidelines and clinical checklists for counseling, and poor use of information education materials compared to the national standards. Residence, number of stillbirths or neonatal loss, counseling status of family planning during ANC visits, and maternal counseling status of family planning during postnatal care visits were factors associated with PPC.

Conclusion

The overall postpartum contraceptive service delivery in ACSH was V/good compared to the national family planning guideline standards. With the notable gaps identified, specific recommendations were suggested to different responsible bodies.
Training the healthcare workforce: the global experience with telementorship for hepatitis B and hepatitis C
Authors: Corcorran Maria A. , Thornton Karla , Struminger Bruce , Easterbrook Philippa , Scott John D.
Published: August 2023

Background

Telementorship has emerged as an innovative strategy to decentralise medical knowledge and increase healthcare capacity across a wide range of disease processes. We report the global experience with telementorship to support healthcare workers delivering hepatitis B virus (HBV) and hepatitis C virus (HCV) care and treatment.

Methods

In early 2020, we conducted a survey of HBV and HCV telementorship programmes, followed by an in-depth interview with programme leads. Programmes were eligible to participate if they were located outside of the United States (U.S.), focused on support to healthcare workers in management of HBV and/or HCV, and were affiliated with or maintained adherence to the Project ECHO model, a telementorship programme pioneered at the University of New Mexico. One programme in the U.S., focused on HCV treatment in the Native American community, was purposively sampled and invited to participate. Surveys were administered online, and all qualitative interviews were performed remotely. Descriptive statistics were calculated for survey responses, and qualitative interviews were assessed for major themes.

Results

Eleven of 18 eligible programmes completed the survey and follow up interview. Sixty-four percent of programmes were located at regional academic medical centers. The majority of programmes (64%) were led by hepatologists. Most programmes (82%) addressed both HBV and HCV, and the remainder focused on HCV only. The median number of participating clinical spoke sites per programme was 22, and most spoke site participants were primary care providers. Most ECHO sessions were held monthly (36%) or bimonthly (27%), with sessions ranging from 45 min to 2 h in length. Programme leaders identified collective learning, empowerment and collaboration to be key strengths of their telementorship programme, while insufficient funding and a lack of protected time for telementorship leaders and participants were identified as major barriers to success.

Conclusion

The Project ECHO model for telementorship can be successfully implemented across high and low-and-middle-income countries to improve provider knowledge and experience in management of viral hepatitis. There is a tremendous opportunity to further expand upon the existing experience with telementorship to support non-specialist healthcare workers and promote elimination of viral hepatitis.
Socioeconomic inequalities in health outcomes among Thai older population in the era of Universal Health Coverage: trends and decomposition analysis
Authors: Kaikeaw Sirinya , Punpuing Sureeporn , Chamchan Chalermpol , Prasartkul Pramote
Published: August 2023

Background

Thailand’s Universal Health Coverage (UHC) has been achieved since 2002 when the entire population are covered by three main public health security schemes: (1) Civil Servant Medical Benefit Scheme (CSMBS); (2) Social Security Scheme (SSS); and (3) Universal Coverage Scheme (UCS). Citizens have access to healthcare services at all life stages and are protected from catastrophic expenditure and medical impoverishment. However, there are health inequalities in both health outcomes and access to healthcare among older Thais. This study aims to: (1) assess the degrees of socioeconomic inequalities in health outcomes among the older Thai population during the period of Thailand’s UHC implementation (2003–2019), and (2) explain socioeconomic inequalities in health outcomes through decomposition of the contributions made by Thailand’s UHC policy and other health determinants.

Methods

Data sets come from a four-year series of the National Health and Welfare Survey (HWS) between 2003 and 2019. The health outcome of interest was obtained from the Thai EQ-5D index. The Erreygers’ concentration index (CI) was used to calculate the socioeconomic inequality in health outcomes. Multivariate methods were employed to decompose inequalities.

Results

Findings indicated Thai older adults (aged 50 and older) are healthier during the UHC implementation. Better health outcomes remain concentrated among the wealthier groups (pro-rich inequality). However, the degree of socioeconomic inequalities in health outcomes significantly declined by almost a factor-of-three (from CI = 0.061 in 2003 to CI = 0.024 in 2019) after the roll-out of the UHC. Decomposed results reported that Thailand’s UHC, urban residence, and household wealth were major contributors in explaining pro-rich inequalities in health outcomes among Thai older adults.

Conclusions

Older persons in Thailand have better health while health inequalities between the rich and the poor have substantially decreased. However, there is inequalities in health outcomes within all three national health security schemes in Thailand. Minimizing differences between schemes continues to be a crucial cornerstone to tackling health inequalities among the older population. At the same time, making Thailand’s UHC sustainable is necessary through preparing financial sustainability and developing health resources to better serve an ageing society.
Dihydromyricetin ameliorated nonalcoholic steatohepatitis in mice by regulating the composition of serous lipids, bile acids and ileal microflora
Authors: Miao Xiaolei , Luo Ping , Liu Jiao , Wang Junjun , Chen Yong
Published: August 2023

Background

Dihydromyricetin (DMY) is a natural flavonoid with anti-nonalcoholic steatohepatitis (NASH) activity. However, the effects of DMY on the composition of lipids and bile acids (BAs) in serum, and gut microbiota (GM) in ileum of mice with NASH are not clear.

Methods

After male C57BL/6 mice was fed with methionine and choline deficiency (MCD) diet and simultaneously administered with DMY (300 mg/kg/day) by gavage for 8 weeks, the pathological changes of liver tissue were observed by Oil Red O, hematoxylin eosin and Masson staining, the levels of serum alaninea minotransferase, aspartate aminotransferase and liver triglyceride, malonic dialdehyde were detected by the detection kits, the composition and contents of serum lipids and BAs were detected by Liquid Chromatograph-Mass Spectrometry, the mRNA levels of hepatic BAs homeostasis-related genes were detected by RT-qPCR, and microbiological diversity in ileum was analyzed by 16S rDNA sequencing.

Results

The results showed that the significant changes including 29 lipids, 4 BAs (23-nor-deoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid and cholic acid), 2 BA transporters (Mrp2 and Oatp1b2) and 8 GMs between MCD and DMY groups. Among them, DMY treatment significantly down-regulated 21 lipids, 4 BAs mentioned above, the ratio of Firmicutes/Bacteroidota and the abundance of Erysipelotrichaceae, Faecalibacuium, significantly up-regulated 8 lipids and 5 GMs (Verrucomicrobiota, Bacteroidota, Actinobacteria, Akkermansiaceae and Akkermansia).

Conclusions

The results suggested that DMY may alleviate MCD diet-induced NASH through decreasing the serum levels of toxic BAs which regulated by liver Oatp1b2 and Mrp2, regulating the metabolism of related lipids, and up-regulating intestinal probiotics (Actinobacteria and Verrucomicrobiota at the phylum level; Akkermansiaceae at the family level; Akkermansiaat at the genus level) and inhibiting intestinal harmful bacteria (Firmicutes at the phylum level; Erysipelotrichaceae at the family level; Faecalibaculum at the genus level).
Costs of syringe vending machines in Tbilisi, Georgia
Authors: Walker Josephine G. , Kirtadze Irma , Tabatadze Mzia , Vickerman Peter , Otiashvili David
Published: August 2023

Background

Syringe vending machines (SVM) can improve access to sterile injecting equipment, but they have not been widely implemented or evaluated. We evaluate the cost of SVM installed between July 2019–December 2020 in Tbilisi, Georgia.

Methods

The SVM were stocked with several kit types, including injecting equipment for opioid or stimulant users, naloxone, male and female condoms, and pregnancy tests. We gathered financial data from the project to estimate fixed (staff time, start-up costs, equipment, running costs, and consumables) and variable (harm reduction kits) costs. We calculated the full cost of the SVM intervention, cost per user, cost per additional syringe accessed by SVM users, and cost per kit distributed (2020 Euros).

Results

SVM access cards were issued to 1132 users, and 29,238 kits were distributed through SVM, total cost €204,358. Staff costs were 51% of total, consumable costs 28%, equipment 10%, and start up, recurrent costs, and overheads 5% or less each. Opioid and stimulant kits were most accessed (35% and 32% of total). Cost per user was €66/year, and cost per transaction €7, of which €5 fixed costs and €2 variable. If monthly transactions increased from the average of 1622/month to highest monthly usage (4714), fixed costs per transaction would decrease to < €1. It cost €0.55 per additional syringe accessed/user/month.

Conclusions

This study provides evidence for governments about the cost of SVM, a novel harm reduction intervention. This is particularly relevant where Global Fund is withdrawing and harm reduction services need to be incorporated into national budgets.
Death pluralism: a proposal
Authors: Díaz-Cobacho Gonzalo , Molina-Pérez Alberto , Rodríguez-Arias David
Published: August 2023

The debate over the determination of death has been raging for more than fifty years. Since then, objections against the diagnosis of brain death from family members of those diagnosed as dead-have been increasing and are causing some countries to take novel steps to accommodate people’s beliefs and preferences in the determination of death. This, coupled with criticism by some academics of the brain death criterion, raises some questions about the issues surrounding the determination of death. In this paper, we discuss some of the main approaches to death determination that have been theoretically proposed or currently put into practice and propose a new approach to death determination called "weak pluralism" as a reasonable ethical and political alternative to respect diversity in death determination.
Ten fraction hypofractionated stereotactic body radiotherapy for the management of ultracentral lung tumors: a retrospective analysis of dosimetry, outcomes, and toxicity
Authors: Rock Crosby , Sood Sumit , Cao Ying , Shelton Shary , Chen Ronald C. , Wang Fen
Published: August 2023

Background

The management of ultracentral thoracic tumors with ablative dose of radiotherapy remains challenging given proximity to critical central structures. We report patient outcomes, toxicity, and dosimetry for ultracentrally located tumors with hypofractionated stereotactic body radiotherapy (hfSBRT).

Methods

Seventy-eight individuals (50 initial radiotherapy, 28 re-irradiation) undergoing 10 fraction hfSBRT for ultracentrally located thoracic tumors treated between 2009 and 2020 at a single institution were retrospectively reviewed. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated. Incidence and grade of treatment related toxicity were evaluated. Dosimetric analysis of treatment plans and critical adjacent OARs was performed.

Results

At a median follow up time of 13 months, 1- and 3-year OS, PFS, and LC were 89%/63%, 37%/18%, and 84%/65%, respectively. Median dose was 65 Gy (BED10 = 107.25 Gy). Median primary bronchial tree maximum dose (Dmax) was 60 Gy (V50 = 0.96 cc). Median esophageal Dmax was 38 Gy (V40 = 0 cc). Median great vessel Dmax was 68 Gy (V50 = 3.53 cc). The most common ≥ grade 2 adverse event was pneumonitis, in 15 individuals (20%). Grade 3 or higher toxicity was observed in 9 individuals (12%): three cases of grade 3 pneumonitis (two re-irradiation, one initial radiotherapy), one grade 3 esophageal stricture following re-irradiation, two grade 3 endobronchial obstructions both following initial radiotherapy, and three grade 5 hemoptysis events (two re-irradiation, one initial radiotherapy). One hemoptysis event was categorized as “possibly” related to treatment, while the remaining two events were categorized as “unlikely” related to treatment in patients with clear evidence of disease progression.

Conclusions

hfSBRT to ultracentral lung tumors delivered over 10 fractions is a safe and effective treatment option, with acceptable rates of toxicity and good rates of tumor control.

Trial registration: IRB registration number 12573.
Discovery and evaluation of active compounds from Xuanfei Baidu formula against COVID-19 via SARS-CoV-2 Mpro
Authors: Zhang Min , Liu Liting , Zhao Yao , Cao Yipeng , Zhu Yan , Han Lifeng , Yang Qi , Wang Yu , Wang Changjian , Zhang Han , Wang Yuefei , Zhang Junhua
Published: August 2023

Background

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is still a widespread concern. As one of the effective traditional Chinese medicine (TCM) formulae, Xuanfei Baidu formula (XFBD) shows significant efficacy for treatment of COVID-19 patients. However, its antiviral active compounds and mechanism are still unclear.

Purpose

In this study, we explored the bioactive compounds of XFBD and its antiviral mechanism by integrating computational analysis and experimental testing.

Methods

Focusing on the SARS-CoV-2 main protease (Mpro), as a key target in virus transcription and replication, the fluorescence resonance energy transfer (FRET) assay was built to screen out satisfactory natural inhibitors in XFBD. The surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were undertaken to verify the binding affinity of ligand-Mpro. Omicron BA.1.1 and BA.2.3 variants were used to evaluate the antiviral activity of the focused compounds in non-cytotoxicity concentrations. For introducing the molecular mechanism, computational modeling and NMR spectra were employed to characterize the ligand-binding modes and identify the ligand-binding site on Mpro.

Results

From a library of 83 natural compounds, acteoside, licochalcone B, licochalcone D, linoleic acid, and physcion showed the satisfactory inhibition effects on Mpro with IC50 ranging from 1.93 to 42.96 µM, which were further verified by SPR. Showing the excellent binding affinity, acteoside was witnessed to gain valuable insights into the thermodynamic signatures by ITC and presented antiviral activity on Omicron BA.1.1 and BA.2.3 variants in vitro. The results revealed that acteoside inhibited Mpro via forming the hydrogen bond between 7-H of acteoside and Mpro.

Conclusion

Acteoside is regarded as a representative active natural compound in XFBD to inhibit replication of SARS-CoV-2, which provides the antiviral evidence and some insights into the identification of SARS-CoV-2 Mpro natural inhibitors.

Graphical Abstract
ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway
Authors: Li Yuanlong , Kong Yao , An Mingjie , Luo Yuming , Zheng Hanhao , Lin Yan , Chen Jiancheng , Yang Jin , Liu Libo , Luo Baoming , Huang Jian , Lin Tianxin , Chen Changhao
Published: August 2023

Background

Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored.

Methods

RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues.

Results

In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression.

Conclusions

Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients.

Graphical Abstract
Acriflavine: an efficient green fluorescent probe for sensitive analysis of aceclofenac in pharmaceutical formulations
Authors: El-Masry Amal A. , Zeid Abdallah M.
Published: August 2023

Acriflavine is a multipurpose drug that shows antibacterial, antiviral, antimalarial, and antifungal activities. The remarkable native fluorescence of acriflavine is exploited in analytical chemistry field as an efficient probe for analysis of pharmaceutical and biological compounds. The fluorescent probe action of acriflavine is based on the remarkable fluorescence turning-off via formation of ion-pair complexes with acidic drugs at a specific pH. Herein, the acidic drug aceclofenac is analysed for the first time using acriflavine as a fluorescent probe. Aceclofenac can form an ion-pair complex with acriflavine at pH 8.5, and hence it partially turns off the fluorescence intensity of acriflavine over a concentration range of 1–20 µg/mL. The fluorescence quenching was monitored at 502 nm following an excitation at 265 or 451 nm. The reaction stoichiometry between acriflavine and aceclofenac was found to be 1:1 using limiting logarithmic method. The type of quenching was confirmed to be static using Stern–Volmer plot. The method showed low values of quantitation limit (0.89 µg/mL) and detection limit (0.29 µg/mL). Moreover, the method was linear (r = 0.9999), accurate, precise (RSD < 1.7%), robust, and specific. The proposed method was successfully employed to analyse aceclofenac in its dosage forms with high %recovery (98–101%). Additionally, GAPI and AGREE approaches were used to guarantee the suggested techniques' greenness, and the findings showed an excellent level of greenness.
Unravelling and engineering an operon involved in the side-chain degradation of sterols in Mycolicibacterium neoaurum for the production of steroid synthons
Authors: Zhao Yun-Qiu , Liu Yong-Jun , Song Lu , Yu Dingyan , Liu Kun , Liu Ke , Gao Bei , Tao Xin-Yi , Xiong Liang-Bin , Wang Feng-Qing , Wei Dong-Zhi
Published: August 2023

Background

Harnessing engineered Mycolicibacteria to convert cheap phytosterols into valuable steroid synthons is a basic way in the industry for the production of steroid hormones. Thus, C-19 and C-22 steroids are the two main types of commercial synthons and the products of C17 side chain degradation of phytosterols. During the conversion process of sterols, C-19 and C-22 steroids are often produced together, although one may be the main product and the other a minor byproduct. This is a major drawback of the engineered Mycolicibacteria for industrial application, which could be attributed to the co-existence of androstene-4-ene-3,17-dione (AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (HBC) sub-pathways in the degradation of the sterol C17 side chain. Since the key mechanism underlying the HBC sub-pathway has not yet been clarified, the above shortcoming has not been resolved so far.

Results

The key gene involved in the putative HBC sub-pathway was excavated from the genome of M. neoaurum by comparative genomic analysis. Interestingly, an aldolase- encoding gene, atf1, was identified to be responsible for the first reaction of the HBC sub-pathway, and it exists as a conserved operon along with a DUF35-type gene chsH4, a reductase gene chsE6, and a transcriptional regulation gene kstR3 in the genome. Subsequently, atf1 and chsH4 were identified as the key genes involved in the HBC sub-pathway. Therefore, an updated strategy was proposed to develop engineered C-19 or C-22 steroid-producing strains by simultaneously modifying the AD and HBC sub-pathways. Taking the development of 4-HBC and 9-OHAD-producing strains as examples, the improved 4-HBC-producing strain achieved a 20.7 g/L production titer with a 92.5% molar yield and a 56.4% reduction in byproducts, and the improved 9-OHAD producing strain achieved a 19.87 g/L production titer with a 94.6% molar yield and a 43.7% reduction in byproduct production.

Conclusions

The excellent performances of these strains demonstrated that the primary operon involved in the HBC sub-pathway improves the industrial strains in the conversion of phytosterols to steroid synthons.
DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis
Authors: Salta Sofia , Lobo João , Magalhães Bruno , Henrique Rui , Jerónimo Carmen
Published: August 2023

Background

Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.

Methods

Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.

Results

Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63–0.72) and 0.75 (CI 95% 0.71–0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74–0.82) and 0.74 (CI 95% 0.69–0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.

Conclusions

This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study
Authors: Miller Rachel G. , Mychaleckyj Josyf C. , Onengut-Gumuscu Suna , Feingold Eleanor , Orchard Trevor J. , Costacou Tina
Published: August 2023

Background

The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.

Results

CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.

Conclusions

These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.
Total transcriptome analysis of Candida auris planktonic cells exposed to tyrosol
Authors: Balla Noémi , Jakab Ágnes , Kovács Fruzsina , Ragyák Ágota , Tóth Zoltán , Balázsi Dávid , Forgács Lajos , Bozó Aliz , Al Refai Farah , Borman Andrew M , Majoros László , Kovács Renátó
Published: August 2023

Tyrosol, a secondary metabolite of Candida species, regulates fungal morphogenesis, and its application may represent a novel innovative therapy against emerging multi-resistant fungal superbug such as Candida auris. In the current study, the effects of tyrosol on growth, redox homeostasis, intracellular microelement contents and activities of virulence-related enzymes released by C. auris were examined. To gain further information about the effect of tyrosol exposure, we revealed gene transcriptional changes using total transcriptome sequencing (RNA-Seq). At a concentration of 15 mM, tyrosol significantly decrease the growth of fungal cells within 2 h of its addition (5.6 × 107±1.2 × 107 and 2.5 × 107±0.6 × 107 colony forming unit/mL for control and tyrosol-treated cells, respectively). Furthermore, it enhanced the release of reactive oxygen species as confirmed by a dichlorofluorescein (DCF) assay (7.3 ± 1.8 [nmol DCF (OD640)−1] versus 16.8 ± 3.9 [nmol DCF (OD640)−1]), which was coincided with elevated superoxide dismutase, catalase and glutathione peroxidase activities. Tyrosol exerted in a 37%, 25%, 34% and 55% decrease in intracellular manganese, iron, zinc and copper contents, respectively, compared to control cells. The tyrosol treatment led to a 142 and 108 differentially transcripted genes with at least a 1.5-fold increase or decrease in transcription, respectively. Genes related to iron and fatty acid metabolism as well as nucleic acid synthesis were down-regulated, whereas those related to the antioxidative defence, adhesion and oxoacid metabolic processes were up-regulated. This study shows that tyrosol significantly influences growth, intracellular physiological processes and gene transcription in C. auris, which could highly support the development of novel treatment approaches against this important pathogen.
APP family member dimeric complexes are formed predominantly in synaptic compartments
Authors: Schilling Sandra , August Alexander , Meleux Mathieu , Conradt Carolin , Tremmel Luisa M. , Teigler Sandra , Adam Virginie , Müller Ulrike C. , Koo Edward H. , Kins Stefan , Eggert Simone
Published: August 2023

Background

The amyloid precursor protein (APP), a key player in Alzheimer’s disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions.

Results

We investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with co-immunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, only about 20% of APP is dimerized in cultured cells whereas up to 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls.

Conclusions

Together, we suggest that loss of full-length APP dimers might correlate with loss of synapses in the process of AD.
In-situ monitoring of 3He/4He in summit gases of Kilauea Volcano (Hawaii) prior to the 2020 eruption
Authors: McMurtry Gary M. , Dasilveira Luis A.
Published: August 2023

We present He isotope (3He/4He) data from a fumarole and near-ground gases measured in-situ at the Sulfur Banks solfatara field at the summit of Kilauea Volcano, Hawaii. We used a field-deployable mass-spectrometer-based system: the Helium Isotope Monitor (HIM) previously described in McMurtry et al. (2019a, b). The in-situ instrument was deployed using solar power for the first time and results were ground-truthed against data determined using conventional gas analytical and noble gas mass spectrometry techniques. The HIM instrumentation, associated Vent Gas Purification System (VGPS), and related sampling equipment and strategy are described. Cloudy and rainy weather conditions hampered the deployment, which was reorganized to reduce power loads and resulted in less sampling than planned. Nevertheless, we obtained daily sampling of the volcanic vent gas. Results from the Old Well fumarole indicate a ~ 2 RA increase in 3He/4He on the day of the December 20th, 2020 eruption of nearby Halema‘uma‘u Crater, reaching 17.0 RA using the in-situ instrument and 16.0 ± 0.67 RA using conventional techniques. This finding suggests that a new 3He-enriched magma source is driving the current, ongoing eruption phase of Kilauea and, if so, confirms that the deep summit caldera fault system that hosts the Sulfur Banks field is connected to the Halema‘uma‘u Crater magmatic system. Overall, these findings illustrate how time-series helium isotope data, which are well established by ongoing discrete monitoring at low temporal resolution, can help forecast forthcoming eruptive events that may not be foreseen by other volcanic monitoring methods.
Protocol for the development of guidance for collaborator and partner engagement in health care evidence syntheses
Authors: Tugwell Peter , Welch Vivian , Magwood Olivia , Todhunter-Brown Alex , Akl Elie A. , Concannon Thomas W. , Khabsa Joanne , Morley Richard , Schunemann Holger , Lytvyn Lyubov , Agarwal Arnav , Antequera Alba , Avey Marc T. , Campbell Pauline , Chang Christine , Chang Stephanie , Dans Leonila , Dewidar Omar , Ghersi Davina , Graham Ian D. , Hazlewood Glen , Hilgart Jennifer , Horsley Tanya , John Denny , Jull Janet , Maxwell Lara J. , McCutcheon Chris , Munn Zachary , Nonino Francesco , Pardo Pardo Jordi , Parker Roses , Pottie Kevin , Rada Gabriel , Riddle Alison , Synnot Anneliese , Ghogomu Elizabeth Tanjong , Tomlinson Eve , Toupin-April Karine , Petkovic Jennifer
Published: August 2023

Background

Involving collaborators and partners in research may increase relevance and uptake, while reducing health and social inequities. Collaborators and partners include people and groups interested in health research: health care providers, patients and caregivers, payers of health research, payers of health services, publishers, policymakers, researchers, product makers, program managers, and the public. Evidence syntheses inform decisions about health care services, treatments, and practice, which ultimately affect health outcomes.

Our objectives are to:

A. Identify, map, and synthesize qualitative and quantitative findings related to engagement in evidence syntheses

B. Explore how engagement in evidence synthesis promotes health equity

C. Develop equity-oriented guidance on methods for conducting, evaluating, and reporting engagement in evidence syntheses

Methods

Our diverse, international team will develop guidance for engagement with collaborators and partners throughout multiple sequential steps using an integrated knowledge translation approach:

1. Reviews. We will co-produce 1 scoping review, 3 systematic reviews and 1 evidence map focusing on (a) methods, (b) barriers and facilitators, (c) conflict of interest considerations, (d) impacts, and (e) equity considerations of engagement in evidence synthesis.

2. Methods study, interviews, and survey. We will contextualise the findings of step 1 by assessing a sample of evidence syntheses reporting on engagement with collaborators and partners and through conducting interviews with collaborators and partners who have been involved in producing evidence syntheses. We will use these findings to develop draft guidance checklists and will assess agreement with each item through an international survey.

3. Consensus. The guidance checklists will be co-produced and finalised at a consensus meeting with collaborators and partners.

4. Dissemination. We will develop a dissemination plan with our collaborators and partners and work collaboratively to improve adoption of our guidance by key organizations.

Conclusion

Our international team will develop guidance for collaborator and partner engagement in health care evidence syntheses. Incorporating partnership values and expectations may result in better uptake, potentially reducing health inequities.
The cost of inadequate postharvest management of pulse grain: Farmer losses due to handling and storage practices in Uganda
Authors: Ariong Richard M. , Okello Daniel M. , Otim Michael Hilary , Paparu Pamela
Published: August 2023

Background

Investing in postharvest technologies is one way of reducing food losses with the aim of achieving food security, but it is often overlooked. In this study, we assessed the losses and costs associated with the harvest and postharvest practices used by smallholder bean farmers in Uganda. We also estimated the grain Moisture Content (MC) associated with traditional storage practices.

Results

Harvest and postharvest handling practices result in a loss of about 22% of the crop harvest. The cost associated with this loss is 17% of the output value. In addition, the common storage practices used by farmers are unable to maintain the required grain MC of ≤ 13%. As even a slight change in grain MC can significantly impact storage duration, we found that 74% of farmers fail to meet the required MC, resulting in a loss of anticipated price premiums over an average storage duration of 80 days. Our econometric estimates suggest that storing grain in bags placed above the floor surface could reduce MC by an additional 1.5%.

Conclusions

Our predictions indicate that farmers who use traditional practices should store bean grains for less than 60 days, or they should adopt better storage practices to increase shelf life and ensure food safety. If more farmers had placed their grain above the floor surface, 48% rather than 26% would have met the required MC at 90 days. It is worth noting that poor postharvest handling has significant economic implications and can lead to food safety concerns due to quality failures in the grain. To address these issues, there is a need to scale up interventions that increase farmer access to postharvest technologies.
Oligofructose improves small intestinal lipid-sensing mechanisms via alterations to the small intestinal microbiota
Authors: Weninger Savanna N. , Herman Chloe , Meyer Rachel K. , Beauchemin Eve T. , Kangath Archana , Lane Adelina I. , Martinez Taylor M. , Hasneen Tahia , Jaramillo Sierra A. , Lindsey Jason , Vedantam Gayatri , Cai Haijiang , Cope Emily K. , Caporaso J. Gregory , Duca Frank A.
Published: August 2023

Background

Upper small intestinal dietary lipids activate a gut-brain axis regulating energy homeostasis. The prebiotic, oligofructose (OFS) improves body weight and adiposity during metabolic dysregulation but the exact mechanisms remain unknown. This study examines whether alterations to the small intestinal microbiota following OFS treatment improve small intestinal lipid-sensing to regulate food intake in high fat (HF)-fed rats.

Results

In rats fed a HF diet for 4 weeks, OFS supplementation decreased food intake and meal size within 2 days, and reduced body weight and adiposity after 6 weeks. Acute (3 day) OFS treatment restored small intestinal lipid-induced satiation during HF-feeding, and was associated with increased small intestinal CD36 expression, portal GLP-1 levels and hindbrain neuronal activation following a small intestinal lipid infusion. Transplant of the small intestinal microbiota from acute OFS treated donors into HF-fed rats also restored lipid-sensing mechanisms to lower food intake. 16S rRNA gene sequencing revealed that both long and short-term OFS altered the small intestinal microbiota, increasing Bifidobacterium relative abundance. Small intestinal administration of Bifidobacterium pseudolongum to HF-fed rats improved small intestinal lipid-sensing to decrease food intake.

Conclusion

OFS supplementation rapidly modulates the small intestinal gut microbiota, which mediates improvements in small intestinal lipid sensing mechanisms that control food intake to improve energy homeostasis.
A synbiotic mixture of selected oligosaccharides and bifidobacteria assists murine gut microbiota restoration following antibiotic challenge
Authors: Hoedt Emily C. , Hueston Cara M. , Cash Nora , Bongers Roger S. , Keane Jonathan M. , van Limpt Kees , Ben Amor Kaouther , Knol Jan , MacSharry John , van Sinderen Douwe
Published: August 2023

Background

Typically, animal models studying gastrointestinal microbiotas compromised in early life have employed either germ-free animals or mice treated with a cocktail of antibiotics. Such studies intend to mimic scenarios of infants born by caesarean section and/or subjected to antibiotic treatment. However, the antibiotics used in these studies are rarely prescribed to infants. Therefore, an early life model was developed in which the murine gastrointestinal microbiota was severely disrupted by clindamycin treatment.

Results

In this mouse model, we investigated the extent supplementation with a synbiotic mixture of prebiotics, being scGOS/lcFOS with the human milk oligosaccharide 2’-Fucosyllactose (2’-FL), in combination with or without single strain or mix of “infant type” bifidobacteria, can rescue an antibiotic-compromised microbiota. Shotgun metagenomic sequencing showed that the microbiota was severely disrupted by the clindamycin challenge. No recovery was observed 3 weeks post-challenge in the scGOS/lcFOS/2’FL group, while the group that received the synbiotic treatment of scGOS/lcFOS/2’-FL with Bifidobacterium breve NRBB01 showed partial recovery. Strikingly in the scGOS/lcFOS/2’-FL group receiving the mixture of bifidobacteria resulted in a recovery of the microbiota disruption. Histological analyses showed that the clindamycin-treated animals at the end of the experiment still suffered from mild oedema and villi/colonic crypt irregularities which was ameliorated by the synbiotic intervention.

Conclusion

Our study demonstrates that supplementation of synbiotic mixture of scGOS/lcFOS/2’-FL in combination with a specific mix of infant-type bifidobacterial strains is able to partially revive an antibiotic-perturbed gastrointestinal microbiota.