bluuebunny/crossref_metadata_2025_split huggingface dataset:
Community-Engaged Research Ethics Training (CERET): developing accessible and relevant research ethics training for community-based participatory research with people with lived and living experience using illicit drugs and harm reduction workers
Authors: Morgan Jeffrey , Neufeld Scott D. , Holroyd Heather , Ruiz Jean , Taylor Tara , Nolan Seonaid , Glegg Stephanie 
Published: July 2023

Abstract
Background
Community-based participatory research (CBPR) can directly involve non-academic community members in the research process. Existing resources for research ethics training can be inaccessible to team members without an academic background and do not attend to the full spectrum of ethical issues that arise through community-engaged research practices. We detail an approach to capacity building and training in research ethics in the context of CBPR with people who use(d) illicit drugs and harm reduction workers in Vancouver’s Downtown Eastside neighborhood.

Methods
A project team comprised of academic and community experts in CBPR, research ethics, and harm reduction met over five months to develop the Community-Engaged Research Ethics Training (CERET). The group distilled key principles and content from federal research ethics guidelines in Canada, and developed case examples to situate the principles in the context of research with people who use(d) illicit drugs and harm reduction workers. In addition to content related to federal ethics guidelines, the study team integrated additional content related to ethical issues that arise through community-based research, and ethical principles for research in the Downtown Eastside. Workshops were evaluated using a pre-post questionnaire with attendees.

Results
Over the course of six weeks in January–February 2020, we delivered three in-person workshops for twelve attendees, most of whom were onboarding as peer research assistants with a community-based research project. Workshops were structured around key principles of research ethics: respect for persons, concern for welfare, and justice. The discussion-based format we deployed allowed for the bi-directional exchange of information between facilitators and attendees. Evaluation results suggest the CERET approach was effective, and attendees gained confidence and familiarity with workshop content across learning objectives.

Conclusions
The CERET initiative offers an accessible approach to fulfill institutional requirements while building capacity in research ethics for people who use(d) drugs and harm reduction workers. This approach recognizes community members as partners in ethical decision making throughout the research process and is aligned with values of CBPR. Building capacity around intrinsic and extrinsic dimensions of research ethics can prepare all study team members to attend to ethical issues that arise from CBPR.
The effects of probiotics supplementation on glycaemic control among adults with type 2 diabetes mellitus: a systematic review and meta-analysis of randomised clinical trials
Authors: Li Guang , Feng Hao , Mao Xin-Liang , Deng Yan-Jun , Wang Xiao-Bao , Zhang Qiong , Guo Yan , Xiao Su-Mei 
Published: July 2023

Abstract
Objective
This systematic review and meta-analysis study aimed to evaluate the effectiveness of probiotics supplementation on glycaemic control in patients with type 2 diabetes mellitus (T2DM) based on the data from the randomised clinical trials (RCTs).

Methods
PubMed, Web of Sciences, Embase, and Cochrane Library were searched from the inception to October 2022, and RCTs about probiotics and T2DM were collected. The standardised mean difference (SMD) with 95% confidence interval (CI) was used to estimate the effects of probiotics supplementation on glycaemic control related parameters, e.g. fasting blood glucose (FBG), insulin, haemoglobin A1c (HbA1c), and homeostasis model of assessment of insulin resistance (HOMA-IR).

Results
Thirty RCTs including 1,827 T2MD patients were identified. Compared with the placebo group, the probiotics supplementation group had a significant decrease in the parameters of glycaemic control, including FBG (SMD = − 0.331, 95% CI  − 0.424 to − 0.238, Peffect < 0.001), insulin (SMD = − 0.185, 95% CI  − 0.313 to − 0.056, Peffect = 0.005), HbA1c (SMD = − 0.421, 95% CI  − 0.584 to − 0.258, Peffect < 0.001), and HOMA-IR (SMD = − 0.224, 95% CI  − 0.342 to − 0.105, Peffect < 0.001). Further subgroup analyses showed that the effect was larger in the subgroups of Caucasians, high baseline body mass index (BMI ≥ 30.0 kg/m2), Bifidobacterium and food-type probiotics (Psubgroup < 0.050).

Conclusion
This study supported that probiotics supplementation had favourable effects on glycaemic control in T2DM patients. It may be a promising adjuvant therapy for patients with T2DM.
Motivations for pre-exposure prophylaxis uptake and decline in an HIV-hyperendemic setting: findings from a qualitative implementation study in Lesotho
Authors: Chebet Joy J. , McMahon Shannon A. , Tarumbiswa Tapiwa , Hlalele Hlalele , Maponga Chivimbiso , Mandara Esther , Ernst Kacey , Alaofe Halimatou , Baernighausen Till , Ehiri John E. , Geldsetzer Pascal , Nichter Mark 
Published: July 2023

Abstract
Background
Pre-Exposure Prophylaxis (PrEP) has demonstrated clinical efficacy in preventing HIV infection, yet its uptake remains low. This study, conducted in five PrEP implementing districts in Lesotho, examined factors motivating persons at risk of HIV infection to adopt or reject PrEP when offered freely.

Methods
In-depth interviews were undertaken with stakeholders directly engaged with PrEP policy (n = 5), program implementation (n = 4), and use (current PrEP users = 55, former PrEP users = 36, and PrEP decliners (n = 6)). Focus group discussions (n = 11, 105 total participants) were conducted with health staff directly providing HIV and PrEP services.

Results
Demand for PrEP was reported highest among those at greatest risk for HIV acquisition: those in serodiscordant relationships and/or engaged in sex work. Culturally sensitive PrEP counseling was described as an opportunity to transfer knowledge, build trust, and address user concerns. Conversely, top-down counseling resulted in PrEP distrust and confusion about HIV status. Key motivations for PrEP uptake revolved around sustaining core social relationships, desire for safer conception, and caring for ailing relatives. The decline of PrEP initiation was driven by a combination of individual-level factors (risk perception, perceived side effects, disbelief of the drug’s efficacy and PrEP’s daily pill regimen), societal factors (lack of social support and HIV-related stigma), and structural factors related to PrEP access.

Conclusions
Our findings suggest strategies for effective national PrEP rollout and implementation include: (1) demand creation campaigns which highlight positive aspects of PrEP, while simultaneously addressing apprehensions for uptake; (2) strengthening health provider counseling capacity; and (3) addressing societal and structural HIV-related stigma.
Aberrant expression of miR-33a-3p/IGF2 in postmenopausal osteoporosis patients and its role and mechanism in osteoporosis
Authors: Wang Changxin , Shen Jianfei , Zhang Wei , Wang Xiaoyu , Xu Xiaohong , Lu Xianghui , Xu Dongbin , Yao Lan 
Published: July 2023

Abstract
Background
Postmenopausal osteoporosis (PMOP), the most frequent bone-related disease, is characterized by bone loss and fragile fractures, which is related to low bone density (BMD). This study aimed to illustrate the expression and mechanism of miR-33a-3p in osteoporosis.

Methods
TargetScan and luciferase reporter assay were applied for verifying the relevance between miR-33a-3p and IGF2. Levels of miR-33a-3p, IGF2, Runx2, ALP and Osterix were checked using RT-qPCR and western blotting. hBMSCs proliferation, apoptosis and ALP activity were analyzed by MTT, flow cytometry (FCM) analysis and ALP detection kit, respectively. Moreover, the calcification of cells was assessed using Alizarin Red S staining. The average BMD was evaluated by dual-energy X-ray absorptiometry (DEXA) assay.

Results
IGF2 was a target of miR-33a-3p. The level of miR-33a-3p was substantially higher and IGF2 expression was memorably lower in the serum of osteoporosis patients than that in healthy volunteers. Our results also pointed out that miR-33a-3p was reduced and IGF2 expression was enhanced during osteogenic differentiation. We concluded that miR-33a-3p negatively regulated the level of IGF2 in hBMSCs. Besides, miR-33a-3p mimic inhibited the osteogenic differentiation of hBMSCs via inhibiting the level of Runx2, ALP and Osterix and decreasing ALP activity. IGF2 plasmid dramatically reversed the influence of miR-33a-3p mimic on IGF2 expression, hBMSCs proliferation and apoptosis, and osteogenic differentiation of hBMSCs.

Conclusion
miR-33a-3p affected osteogenic differentiation of hBMSCs by targeting IGF2, indicating a potential use of miR-33a-3p as plasma biomarker and therapeutic target for postmenopausal osteoporosis.
Preclinical and clinical activity of DZD1516, a full blood–brain barrier-penetrant, highly selective HER2 inhibitor
Authors: Zhang Jian , McAndrew Nicholas P. , Wang Xiaojia , Du Yiqun , DiCarlo Brian , Wang Mei , Chen Kan , Yu Wenlei , Hu Xichun 
Published: July 2023

Abstract
Background
Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood–brain barrier (BBB) penetration is highly desirable.

Methods
The design and structure–activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody–drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.

Results
DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25–300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.

Conclusions
DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.
Clinicaltrials.gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.
USP24-dependent stabilization of Runx2 recruits a p300/NCOA3 complex to transactivate ADAMTS genes and promote degeneration of intervertebral disc in chronic inflammation mice
Authors: Li Xingguo , Zhang Jun , Wang Bing , Chen Chao , Zhang Enyu , Lv Zhengpin , He Qicong , Hu Yaoquan , Wang Xuenan , Zhang Fan 
Published: July 2023

Abstract
Background
Intervertebral disc degeneration (IDD) naturally occurs during the aging process. Its occurrence is closely related to chronic inflammation; however, the causal relationship between them is controversial. This study aimed to investigate if inflammation would promote IDD incidence and explore the underlying mechanism.

Methods
A chronic inflammation mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Enzyme-linked immunosorbent assay was performed to determine proinflammatory cytokines in serum. Histological staining was used to evaluate the degeneration of IVDs. Immunoblots and RT-qPCR analyses were performed to measure protein and mRNA expression levels. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation assays were used to determine the assembly of protein complex.

Results
We found that an inflammatory microenvironment activated p38 kinase, which phosphorylated the Runx2 transcription factor at the Ser28 site. The phosphorylated Runx2 (pRunx2) then recruited a deubiquitinase, ubiquitin-specific peptidase 24 (USP24), which stabilized pRunx2 and protected it from ubiquitin-dependent proteasomal degradation. The stabilized pRunx2 recruited histone acetyltransferase p300 and nuclear receptor coactivator 3 (NCOA3) to assemble a complex. This NCOA3-p300-pRunx2 complex then transactivated the expression of 13 ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) genes, thereby promoting the degradation of extracellular matrix (ECM) in intervertebral discs (IVDs) and causing IDD. Administration of either a p38 inhibitor (doramapimod), a NCOA3 inhibitor (bufalin), or a p300 inhibitor (EML425) significantly decreased the expression of the 13 ADAMTS genes and slowed the degeneration of IVDs.

Conclusion
In summary, our results demonstrate that USP24 protects pRunx2 from proteasomal degradation under chronic inflammation conditions, enabling pRunx2 to transactivate ADAMTS genes and degrade ECM. Our findings provide direct evidence that chronic inflammation triggers IDD and offer a therapeutic strategy for retarding IDD in patients with chronic inflammation.
Humans as blood-feeding sources in sylvatic triatomines of Chile unveiled by next-generation sequencing
Authors: San Juan Esteban , Araya-Donoso Raúl , Sierra-Rosales Catalina , Correa Juana P. , Quiroga Nicol , Campos-Soto Ricardo , Solari Aldo , Llewellyn Martin , Bacigalupo Antonella , Botto-Mahan Carezza 
Published: July 2023

Abstract
Background
Triatomines are blood-sucking insects capable of transmitting Trypanosoma cruzi, the parasite that causes Chagas disease in humans. Vectorial transmission entails an infected triatomine feeding on a vertebrate host, release of triatomine infective dejections, and host infection by the entry of parasites through mucous membranes, skin abrasions, or the biting site; therefore, transmission to humans is related to the triatomine–human contact. In this cross-sectional study, we evaluated whether humans were detected in the diet of three sylvatic triatomine species (Mepraia parapatrica, Mepraia spinolai, and Triatoma infestans) present in the semiarid–Mediterranean ecosystem of Chile.

Methods
We used triatomines collected from 32 sites across 1100 km, with an overall T. cruzi infection frequency of 47.1% (N = 4287 total specimens) by conventional PCR or qPCR. First, we amplified the vertebrate cytochrome b gene (cytb) from all DNA samples obtained from triatomine intestinal contents. Then, we sequenced cytb-positive PCR products in pools of 10–20 triatomines each, grouped by site. The filtered sequences were grouped into amplicon sequence variants (ASVs) with a minimum abundance of 100 reads. ASVs were identified by selecting the best BLASTn match against the NCBI nucleotide database.

Results
Overall, 16 mammal (including human), 14 bird, and seven reptile species were identified in the diet of sylvatic triatomines. Humans were part of the diet of all analyzed triatomine species, and it was detected in 19 sites representing 12.19% of the sequences.

Conclusions
Sylvatic triatomine species from Chile feed on a variety of vertebrate species; many of them are detected here for the first time in their diet. Our results highlight that the sylvatic triatomine–human contact is noteworthy. Education must be enforced for local inhabitants, workers, and tourists arriving in endemic areas to avoid or minimize the risk of exposure to Chagas disease vectors.

Graphical Abstract
Gut microbiota signatures and fecal metabolites in postmenopausal women with osteoporosis
Authors: Wang Han , Liu Jing , Wu Zuoxing , Zhao Yangyang , Cao Man , Shi Baohong , Chen Baolong , Chen Ning , Guo Hao , Li Na , Chen Jian , Xu Ren 
Published: July 2023

Abstract
Background
Women suffer from various distress and disturbances after menopause, including osteoporosis, a risk factor associated with multiple diseases. Altered gut microbiota has been implicated in postmenopausal osteoporosis. In this study, to understand gut microbiota signatures and fecal metabolite changes in postmenopausal women with osteoporosis, 108 postmenopausal women were recruited for intestinal microbiota and fecal metabolite detection. Among these participants, 98 patients, who met the inclusion criteria, were divided into postmenopausal osteoporosis (PMO) and non-postmenopausal osteoporosis (non-PMO) groups based on bone mineral density (BMD). The compositions of gut bacteria and fungi were examined by 16 S rRNA gene sequencing and ITS sequencing, respectively. Meanwhile, fecal metabolites were analyzed using liquid chromatography coupled with mass spectrometry (LC-MS).

Results
We found that bacterial α-diversity and β-diversity were significantly altered in PMO compared to non-PMO patients. Interestingly, fungi composition showed larger changes, and the differences in β-diversity were more significant between PMO and non-PMO patients. Metabolomics analysis revealed that fecal metabolites, such as levulinic acid, N-Acetylneuraminic acid, and the corresponding signaling pathways were also changed significantly, especially in the alpha-Linolenic acid metabolism and selenocompound metabolism. The screened differential bacteria, fungi, and metabolites closely correlated with clinical findings between these two groups, for example, the bacterial genus, Fusobacterium, the fungal genus, Devriesia, and the metabolite, L-pipecolic acid, were significantly associated with BMD.

Conclusions
Our findings indicated that there were remarkable changes in gut bacteria, fungi, and fecal metabolites in postmenopausal women, and such changes were notably correlated with patients’ BMD ​​and clinical findings. These correlations provide novel insights into the mechanism of PMO development, potential early diagnostic indicators, and new therapeutic approaches to improve bone health in postmenopausal women.
Outcomes of total hip and knee arthroplasty in special populations: a synopsis and critical appraisal of systematic reviews
Authors: Challoumas Dimitris , Munn David , Stockdale Henrietta , Ng Nigel , McCormick Michael , Altell Tareq , Joiya Shaheer , Horton James , Jones Bryn 
Published: July 2023

Abstract
Introduction
This study aimed to present and critically appraise the best available evidence investigating associations between some pre-defined patient-related characteristics and perioperative complications or other outcomes in THA and TKA.

Methods
Electronic databases were searched (Medline, EMBASE, Scopus, CENTRAL) for systematic reviews assessing the following pre-defined patient-related characteristics as possible risk factors for worse peri-operative outcomes in THA and TKA: smoking, alcohol excess, rheumatoid arthritis, human immunodeficiency virus infection, hepatitis C virus infection, mental health conditions, and solid organ transplantation. Our primary outcome was periprosthetic joint infection. Results were analysed separately for THA, TKA and THA/TKA (mixed data).

Results
Based on at least two systematic reviews being in agreement, the following patient-related characteristics were associated with increased incidence of complications as follows: a) Smoking for all-cause revision in THA, for periprosthetic joint infection in TKA and THA/TKA; b) alcohol excess for periprosthetic joint infection in THA/TKA; c) human immunodeficiency virus for periprosthetic joint infection in THA/TKA; d) hepatitis C virus for overall complications, periprosthetic joint infection and all-cause revision in THA and THA/TKA, and for overall complications in TKA. Our study found conflicting evidence for a) smoking as a risk factor for periprosthetic joint infection and aseptic loosening in THA; b) human immunodeficiency virus as a risk factor for all-cause revision for THA/TKA; c) hepatitis C virus as a risk factor for periprosthetic joint infection and all-cause revision in TKA. No certainty of evidence was assigned to these results as this was not assessed by the authors of the majority of the included systematic reviews.

Conclusion
We found that smoking, excess alcohol consumption, RA, and infection with HIV and HCV were associated with a higher incidence of periprosthetic joint infection in one or both of THA and TKA or mixed THA/TKA data. All our results should be interpreted and communicated to patients with caution as the quality of the included systematic reviews was generally poor.
The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision
Authors: Langouche Lies , Téblick Arno , Gunst Jan , Van den Berghe Greet 
Published: July 2023

Abstract
Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as “relative,” as opposed to “absolute,” adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.