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The Journal of Maternal-fetal &... Dec 2024To derive accurate estimates of risk of maternal and neonatal complications in women with gestational diabetes mellitus (GDM) and to investigate the association of the...
AIMS
To derive accurate estimates of risk of maternal and neonatal complications in women with gestational diabetes mellitus (GDM) and to investigate the association of the effect size of these risks on subgroups of GDM managed with dietary modification, metformin and insulin therapy.
METHODS
This was a large retrospective cohort study undertaken at a large maternity unit in the United Kingdom between January 2010 and June 2022. We included singleton pregnancies that booked at our unit at 11-13 weeks' gestation. The rates of maternal and neonatal complications in pregnancies with GDM that were managed by a multidisciplinary team (MDT) in the specialist high-risk clinic were compared to those in non-diabetic pregnancies. We stratified pregnancies with GDM into those that were managed with diet, metformin and insulin to pregnancies without diabetes. Logistic regression analysis was carried out to determine risks of pregnancy complications in pregnancies with GDM and its treatment subgroups. Risks were expressed as absolute risks (AR) and odds ratio (OR) (95% confidence intervals [CI]). Forest plots were used to graphically demonstrate risks.
RESULTS
The study population included 51,211 singleton pregnancies including 2089 (4.1%) with GDM and 49,122 (95.9%) controls without diabetes. In pregnancies with GDM, there were 1247 (59.7%) pregnancies managed with diet, 451 (21.6%) with metformin and 391 (18.7%) who required insulin for maintaining euglycaemia. Pregnancies with GDM had higher maternal age, body mass index (BMI), higher rates of Afro-Caribbean and South Asian racial origin and higher rates of chronic hypertension. In pregnancies with GDM compared to non-diabetic controls, there was an increased rate of preterm delivery, delivery of LGA neonate, polyhydramnios, preeclampsia, need for IOL, elective and emergency CS and PPH whereas the rate of delivery of SGA neonates and likelihood of an unassisted vaginal delivery were lower. In pregnancies with GDM, there is significantly increased risk of maternal and neonatal complications in those that require insulin compared to those that are managed on dietary modification alone.
CONCLUSIONS
There is a linear association between the risk of adverse outcomes and the severity of GDM with those on insulin treatment demonstrating an increased association with complications compared to those that have milder disease requiring only dietary modification.
Topics: Humans; Female; Pregnancy; Diabetes, Gestational; Retrospective Studies; Adult; Hypoglycemic Agents; Metformin; Infant, Newborn; Insulin; Pregnancy Outcome; United Kingdom; Severity of Illness Index; Case-Control Studies
PubMed: 38844413
DOI: 10.1080/14767058.2024.2356031 -
JMIR Research Protocols Jun 2024Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often...
BACKGROUND
Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often inaccessible, particularly in settings where medication prescribing is prioritized.
OBJECTIVE
This study aims to test the feasibility of a live-instructor, web-based 1-session pain relief skills class in an underserved and potentially at-risk population: people with chronic pain prescribed methadone or buprenorphine either solely for pain or for comorbid opioid use disorder (OUD).
METHODS
This is a national, prospective, single-arm, uncontrolled feasibility trial. The trial is untethered from medical care; to enhance participants' willingness to join the study, no medical records or drug-monitoring records are accessed. At least 45 participants will be recruited from outpatient pain clinics and from an existing research database of individuals who have chronic pain and are taking methadone or buprenorphine. Patient-reported measures will be collected at 6 time points (baseline, immediately post treatment, 2 weeks, and months 1-3) via a web-based platform, paper, or phone formats to include individuals with limited internet or computer access and low literacy skills. At baseline, participants complete demographic questions and 13 study measures (Treatment Expectations, Body Pain Map, Medication Use, Pain Catastrophizing Scale [PCS], Patient-Reported Outcomes Measurement Information System [PROMIS] Measures, and Opioid Craving Scale). Immediately post treatment, a treatment satisfaction and acceptability measure is administered on a 0 (very dissatisfied) to 10 (completely satisfied) scale, with 3 of these items being the primary outcome (perceived usefulness, participant satisfaction, and likelihood of using the skills). At each remaining time point, the participants complete all study measures minus treatment expectations and satisfaction. Participants who do not have current OUD will be assessed for historical OUD, with presence of OUD (yes or no), and history of OUD (yes or no) reported separately. Feasibility threshold is set as an overall group treatment satisfaction rating of 8 of 10. In-depth qualitative interviews will be conducted with about 10 participants to obtain additional data on patient perceptions, satisfactions, needs, and wants. To assess preliminary efficacy, we will examine changes in pain catastrophizing, pain intensity, pain bothersomeness, sleep disturbance, pain interference, depression, anxiety, physical function, global impression of change, and opioid craving at 1 month post treatment.
RESULTS
This project opened to enrollment in September 2021 and completed the recruitment in October 2023. The data collection was completed in February 2024. Results are expected to be published in late 2024.
CONCLUSIONS
Results from this trial will inform the feasibility and preliminary efficacy of Empowered Relief in this population and will inform the design of a future randomized controlled trial testing web-based Empowered Relief in chronic pain and comorbid OUD.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05057988; https://clinicaltrials.gov/study/NCT05057988.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/53784.
Topics: Humans; Buprenorphine; Chronic Pain; Methadone; Feasibility Studies; Prospective Studies; Male; Female; Analgesics, Opioid; Adult; Pain Management; Opiate Substitution Treatment; Internet-Based Intervention; Internet; Opioid-Related Disorders; Middle Aged
PubMed: 38843513
DOI: 10.2196/53784 -
Antimicrobial Resistance and Infection... Jun 2024Although uncommon, infections associated with peripheral intravenous catheters (PIVCs) may be responsible for severe life-threatening complications and increase... (Randomized Controlled Trial)
Randomized Controlled Trial
Insertion site and risk of peripheral intravenous catheter colonization and/or local infection: a post hoc analysis of the CLEAN 3 study including more than 800 catheters.
AIM
Although uncommon, infections associated with peripheral intravenous catheters (PIVCs) may be responsible for severe life-threatening complications and increase healthcare costs. Few data are available on the relationship between PIVC insertion site and risk of infectious complications.
METHODS
We performed a post hoc analysis of the CLEAN 3 database, a randomized 2 × 2 factorial study comparing two skin disinfection procedures (2% chlorhexidine-alcohol or 5% povidone iodine-alcohol) and two types of medical devices (innovative or standard) in 989 adults patients requiring PIVC insertion before admission to a medical ward. Insertion sites were grouped into five areas: hand, wrist, forearm, cubital fossa and upper arm. We evaluated the risk of risk of PIVC colonization (i.e., tip culture eluate in broth showing at least one microorganism in a concentration of at least 1000 Colony Forming Units per mL) and/or local infection (i.e., organisms growing from purulent discharge at PIVC insertion site with no evidence of associated bloodstream infection), and the risk of positive PIVC tip culture (i.e., PIVC-tip culture eluate in broth showing at least one microorganism regardless of its amount) using multivariate Cox models.
RESULTS
Eight hundred twenty three PIVCs with known insertion site and sent to the laboratory for quantitative culture were included. After adjustment for confounding factors, PIVC insertion at the cubital fossa or wrist was associated with increased risk of PIVC colonization and/or local infection (HR [95% CI], 1.64 [0.92-2.93] and 2.11 [1.08-4.13]) and of positive PIVC tip culture (HR [95% CI], 1.49 [1.02-2.18] and 1.59 [0.98-2.59]).
CONCLUSION
PIVC insertion at the wrist or cubital fossa should be avoided whenever possible to reduce the risk of catheter colonization and/or local infection and of positive PIVC tip culture.
Topics: Humans; Female; Male; Catheterization, Peripheral; Catheter-Related Infections; Middle Aged; Aged; Chlorhexidine; Adult; Disinfection; Povidone-Iodine; Risk Factors; Anti-Infective Agents, Local; Equipment Contamination; Wrist
PubMed: 38840171
DOI: 10.1186/s13756-024-01414-4 -
Journal of Pain and Symptom Management Jun 2024Strong opioids are the cornerstone in the treatment of cancer-related pain.
CONTEXT
Strong opioids are the cornerstone in the treatment of cancer-related pain.
OBJECTIVES
This study aims to compare analgesic effectiveness of different strong opioids for the treatment of cancer-related pain.
METHODS
PubMed and Embase were searched for RCTs that compared strong opioids for treatment of cancer-related pain against one another. A network meta-analysis was conducted and the related Surface Under the Cumulative RAnking (SUCRA)-based treatment ranks were calculated. Primary outcome was pain intensity (numerical rating scale (NRS)) and/or the percentage of patients with ≥50% pain reduction, after 1 and 2-4 weeks.
RESULTS
Sixteen RCTs (1813 patients) were included. Methadone showed, with a high certainty of evidence, increased ORs for treatment success at 1 week, compared with morphine, buprenorphine, fentanyl, and oxycodone, range 3.230-36.833. Methadone had the highest likelihood to be the treatment of preference (ToP) (SUCRA 0.9720). For fentanyl, ORs were lower, however significant and with high certainty. After 2-4 weeks, methadone again showed the highest likelihood for ToP, however, with moderate certainty and nonsignificant ORs. The combination of morphine/methadone, compared with morphine, buprenorphine, fentanyl, hydromorphone, methadone, and oxycodone achieved a treatment effect of mean NRS difference after 2-4 weeks between -1.100 and -1.528 and had the highest likelihood for ToP.
CONCLUSION
The results suggest that methadone possibly deserves further promotion as first-line treatment for the treatment of cancer-related pain.
PubMed: 38838946
DOI: 10.1016/j.jpainsymman.2024.05.022 -
Biomaterials Science Jun 2024Current treatment strategies for infection of chronic wounds often result in compromised healing and necrosis due to antibiotic toxicity, and underlying biomarkers...
Current treatment strategies for infection of chronic wounds often result in compromised healing and necrosis due to antibiotic toxicity, and underlying biomarkers affected by treatments are not fully known. Here, a multifunctional dressing was developed leveraging the unique wound-healing properties of chitosan, a natural polysaccharide known for its numerous benefits in wound care. The dressing consists of an oxygenating perfluorocarbon functionalized methacrylic chitosan (MACF) hydrogel incorporated with antibacterial polyhexamethylene biguanide (PHMB). A non-healing diabetic infected wound model with emerging metabolomics tools was used to explore the anti-infective and wound healing properties of the resultant multifunctional dressing. Direct bacterial bioburden assessment demonstrated superior antibacterial properties of hydrogels over a commercial dressing. However, wound tissue quality analyses confirmed that sustained PHMB for 21 days resulted in tissue necrosis and disturbed healing. Therefore, a follow-up comparative study investigated the best treatment course for antiseptic application ranging from 7 to 21 days, followed by the oxygenating chitosan-based MACF treatment for the remainder of the 21 days. Bacterial counts, tissue assessments, and lipidomics studies showed that 14 days of application of MACF-PHMB dressings followed by 7 days of MACF dressings provides a promising treatment for managing infected non-healing diabetic skin ulcers.
Topics: Chitosan; Anti-Bacterial Agents; Hydrogels; Wound Healing; Animals; Bandages; Biguanides; Wound Infection; Male; Oxygen; Chronic Disease; Fluorocarbons
PubMed: 38836321
DOI: 10.1039/d4bm00355a -
Scientific Reports Jun 2024Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this...
Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify L-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swim speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest L-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy.
Topics: Animals; Zebrafish; Lamin Type A; Animals, Genetically Modified; Mutation; Muscle, Skeletal; Creatine; Carnitine; Disease Models, Animal; Laminopathies; Swimming; Transcriptome; Humans
PubMed: 38834813
DOI: 10.1038/s41598-024-63711-7 -
International Journal of Biological... Jun 2024To explore the adjuvant therapy drugs of low-dose metformin, one homogeneous polysaccharide named APS-D1 was purified from Astragalus membranaceus by DEAE-52 cellulose...
To explore the adjuvant therapy drugs of low-dose metformin, one homogeneous polysaccharide named APS-D1 was purified from Astragalus membranaceus by DEAE-52 cellulose and Sephadex G-100 column chromatography. Its chemical structure was characterized by molecular weight distribution, monosaccharide composition, infrared spectrum, methylation analysis, and NMR. The results revealed that APS-D1 (7.36 kDa) consisted of glucose, galactose, and arabinose (97.51 %:1.56 %:0.93 %). It consisted of →4)-α-D-Glcp-(1→ residue backbone with →3)-β-D-Galp-(1→ residue and terminal-α/β-D-Glcp-(1→ side chains. APS-D1 could significantly improve inflammation (TNF-α, LPS, and IL-10) in vivo. Moreover, APS-D1 improved the curative effect of low-dose metformin without adverse events. APS-D1 combined with low-dose metformin regulated several gut bacteria, in which APS-D1 enriched Staphylococcus lentus to produce l-carnitine (one of 136 metabolites of S. lentus). S. lentus and l-carnitine could improve diabetes, and reduction of S. lentusl-carnitine production impaired diabetes improvement. The combination, S. lentus, and l-carnitine could promote fatty acid oxidation (CPT1) and inhibit gluconeogenesis (PCK and G6Pase). The results indicated that APS-D1 enhanced the curative effect of low-dose metformin to improve diabetes by enriching S. lentus, in which the effect of S. lentus was mediated by l-carnitine. Collectively, these findings support that low-dose metformin supplemented with APS-D1 may be a favorable therapeutic strategy for type 2 diabetes.
Topics: Metformin; Animals; Polysaccharides; Staphylococcus; Mice; Astragalus Plant; Male; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Molecular Weight
PubMed: 38834117
DOI: 10.1016/j.ijbiomac.2024.132860 -
Clinical Oral Investigations Jun 2024This single-center randomized, parallel design, clinical trial with a 2-week follow-up involved patients affected by periodontitis undergoing periodontal surgery. The... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This single-center randomized, parallel design, clinical trial with a 2-week follow-up involved patients affected by periodontitis undergoing periodontal surgery. The aim was to evaluate periodontal surgical wound healing with the use of chlorhexidine-based mouth rinses versus an untreated control group.
MATERIALS AND METHODS
Periodontal surgery was performed following a standardized protocol. Patients were randomly prescribed i) chlorhexidine (CHX) + anti-discoloration system (ADS) + hyaluronic acid (HA), ii) CHX + ADS or iii) no treatment (control group). Plaque score, gingival inflammation, and Early Healing Index (EHI), assessing the degree of wound closure and the presence of fibrin and necrosis, were evaluated at 3, 7 and 14 days after surgery.
RESULTS
In total, 33 patients were enrolled. Patients were comparable at baseline for all measured clinical parameters. At 3-days wound healing was significantly improved in all patients treated with CHX + ADS-based mouth rinses with a lower EHI score at the interdental papillae compared with control group (p < 0.01). CHX + ADS + HA group presented improved healing across all time points in terms of EHI, plaque containment, and gingival inflammation when compared to control group (p < 0.01).
CONCLUSIONS
The usage of CHX-ADS following periodontal surgery improved early wound healing, reduced plaque accumulation and gingival inflammation. During the early post-operative period the adjunct of HA further improved soft tissue closure.
CLINICAL RELEVANCE
This study aims at evaluating the response of gingival tissues to mouth rinsing with chlorhexidine and anti-discoloration system (CHX + ADS) or CHX + ADS + hyaluronic acid (CHX + ADS + HA) versus no rinse in terms of healing of the periodontal surgical wound. CHX + ADS mouth rinses enhanced early soft tissue closure after periodontal surgery and contributed to the reduction in plaque accumulation and gingival inflammation. The adjunct of HA may be beneficial especially in the early post-operative period. CHX + ADS administration following periodontal surgery may improve soft tissue healing in the first two post-operative weeks.
Topics: Humans; Chlorhexidine; Wound Healing; Female; Male; Mouthwashes; Middle Aged; Hyaluronic Acid; Treatment Outcome; Anti-Infective Agents, Local; Adult; Periodontitis; Periodontal Index; Dental Plaque Index
PubMed: 38833009
DOI: 10.1007/s00784-024-05643-0 -
Cell Communication and Signaling : CCS Jun 2024Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis,...
BACKGROUND
Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown.
METHODS
The impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated.
RESULTS
In this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation.
CONCLUSIONS
In conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation.
Topics: Uterine Cervical Neoplasms; Humans; Acetylation; Female; Histones; AMP-Activated Protein Kinases; Cell Proliferation; Animals; p300-CBP Transcription Factors; Metformin; Mice; Mice, Nude; Cell Line, Tumor; Enzyme Activation
PubMed: 38831454
DOI: 10.1186/s12964-024-01687-7 -
Analytical Chemistry Jun 2024In drug discovery, ligands are sought that modulate the (mal-)function of medicinally relevant target proteins. In order to develop new drugs, typically a multitude of...
In drug discovery, ligands are sought that modulate the (mal-)function of medicinally relevant target proteins. In order to develop new drugs, typically a multitude of potential ligands are initially screened for binding and subsequently characterized for their affinity. Nuclear magnetic resonance (NMR) is a well-established and highly sensitive technology for characterizing such interactions. However, it has limited throughput, because only one sample can be measured at a time. In contrast, magnetic resonance imaging (MRI) is inherently parallel and MR parameters can conveniently be encoded in its images, potentially offering increased sample throughput. We explore this application using a custom-built 9-fold sample holder and a F-MRI coil. With this setup, we show that ligand binding can be detected by -weighted F-MRI using 4-(trifluoromethyl)benzamidine (TFBA) and trypsin as the reporter ligand and target protein, respectively. Furthermore, we demonstrate that the affinity of nonfluorinated ligands can be determined in a competition format by monitoring the dose-dependent displacement of TFBA. By comparing F--weighted MR images of TFBA in the presence of different benzamidine (BA) concentrations-all recorded in parallel-the affinity of BA could be derived. Therefore, this approach promises parallel characterization of protein-ligand interactions and increased throughput of biochemical assays, with potential for increased sensitivity when combined with hyperpolarization techniques.
Topics: Ligands; Benzamidines; Protein Binding; Trypsin; Magnetic Resonance Imaging; Proteins
PubMed: 38830623
DOI: 10.1021/acs.analchem.4c00333