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European Journal of Heart Failure Jun 2024Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and...
A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.
AIMS
Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.
METHODS
We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.
CONCLUSIONS
HuMAIN will test a promising novel agent for obesity-related HFpEF.
PubMed: 38924328
DOI: 10.1002/ejhf.3305 -
PloS One 2024Maternal disorders are the third leading cause of sepsis globally, accounting for 5.7 million (12%) cases in 2017. There are increasing concerns about the emergence of...
INTRODUCTION
Maternal disorders are the third leading cause of sepsis globally, accounting for 5.7 million (12%) cases in 2017. There are increasing concerns about the emergence of antimicrobial resistance (AMR) in bacteria commonly causing maternal sepsis. Our aim is to describe the protocol for a clinical and microbiology laboratory study to understand risk factors for and the bacterial etiology of maternal sepsis in a tertiary Obstetrics and Gynaecology Hospital.
METHODS
This case-control study aims to recruit 100 cases and 200 controls at Tu Du Hospital in Ho Chi Minh City, Vietnam, which had approximately 55,000 births in 2022. Women aged ≥ 18 years and ≥ 28 weeks gestation having a singleton birth will be eligible for inclusion as cases or controls, unless they have an uncomplicated localised or chronic infection, or an infection with SARS-CoV-2. Cases will include pregnant or recently pregnant women with sepsis recognised between the onset of labour and/or time of delivery/cessation of pregnancy for up to 42 days post-partum. Sepsis will be defined as suspected or confirmed infection with an obstetrically modified Sequential Organ Failure Assessment score of ≥ 2, treatment with intravenous antimicrobials and requested cultures of any bodily fluid. Controls will be matched by age, location, parity, mode of delivery and gestational age. Primary and secondary outcomes are risk factors associated with the development of maternal sepsis, the frequency of adverse outcomes due to maternal sepsis, bacterial etiology and AMR profiles of cases and controls.
DISCUSSION
This study will improve understanding of the epidemiology and clinical implications of maternal sepsis management including the presence of AMR in women giving birth in Vietnam. It will help us to determine whether women in this setting are receiving optimal care and to identify opportunities for improvement.
Topics: Humans; Female; Pregnancy; Case-Control Studies; Risk Factors; Sepsis; Vietnam; Pregnancy Complications, Infectious; Adult; Anti-Bacterial Agents
PubMed: 38924013
DOI: 10.1371/journal.pone.0305411 -
Current Protocols Jun 2024The Affective Bias Test (ABT) quantifies acute changes in affective state based on the affective biases they generate in an associative reward learning task. The Reward...
The Affective Bias Test (ABT) quantifies acute changes in affective state based on the affective biases they generate in an associative reward learning task. The Reward Learning Assay (RLA) provides a control assay for the ABT and reward-induced biases generated in this model are sensitive to changes in core affective state. Both tasks involve training animals to associate a specific digging substrate with a food reward. Animals learn to discriminate between two digging substrates placed in ceramic bowls, one rewarded and one unrewarded. In the ABT, the animal learns two independent substrate-reward associations with a fixed reward value following either an affective state or drug manipulation, or under control conditions. Affective biases generated are quantified in a choice test where the animals exhibit a bias (make more choices) for one of the substrates which is specifically related to affective state at the time of learning. The ABT is used to investigate biases generated during learning as well as modulation of biases associated with past experiences. The RLA follows a similar protocol, but the animal remains in the same affective state throughout and a reward-induced bias is generated by pairing one substrate with a higher value reward. The RLA provides a control to determine if drug treatments affect memory retrieval more generally. Studies in depression models and following environmental enrichment suggest that reward-induced biases are sensitive to core changes in affective state. Each task offers different insights into affective processing mechanisms and may help improve the translational validity of animal studies and benefit pre-clinical drug development. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Bowl digging and discrimination training Basic Protocol 2: The reward learning assay Basic Protocol 3: The affective bias test - new learning Basic Protocol 4: The affective bias test - modulation of affective biases associated with past experiences.
Topics: Animals; Reward; Depression; Antidepressive Agents; Rats; Disease Models, Animal; Affect; Neuropsychological Tests; Learning; Rodentia; Mice
PubMed: 38923877
DOI: 10.1002/cpz1.1057 -
Applications of Surface Plasmon Resonance (SPR) to the Study of Diverse Protein-Ligand Interactions.Current Protocols Jun 2024Functional characterization of enzymes/proteins requires determination of the binding affinity of small molecules or other biomolecules with the target proteins. Several...
Functional characterization of enzymes/proteins requires determination of the binding affinity of small molecules or other biomolecules with the target proteins. Several available techniques, such as proteomics and drug discovery strategies, require a precise and high-throughput assay for rapid and reliable screening of potential candidates for further testing. Surface plasmon resonance (SPR), a well-established label-free technique, directly measures biomolecular affinities. SPR assays require immobilization of one interacting component (ligand) on a conductive metal (mostly gold or silver) and a continuous flow of solution containing potential binding partner (analyte) across the surface. The SPR phenomenon occurs when polarized light excites the electrons at the interface of the metal and the dielectric medium to generate electromagnetic waves that propagate parallel to the surface. Changes in the refractive index due to interaction between the ligand and analyte are measured by detecting the reflected light, providing real-time data on kinetics and specificity. A prominent use of SPR is identifying compounds in crude plant extracts that bind to specific molecules. Procedures that utilize SPR are becoming increasingly applicable outside the laboratory setting, and SPR imaging and localized SPR (LSPR) are cheaper and more portable alternative for in situ detection of plant or mammalian pathogens and drug discovery studies. LSPR, in particular, has the advantage of direct attachment to test tissues in live-plant studies. Here, we describe three protocols utilizing SPR-based assays for precise analysis of protein-ligand interactions. © 2024 Wiley Periodicals LLC. Basic Protocol 1: SPR comparison of binding affinities of viral reverse transcriptase polymorphisms Basic Protocol 2: SPR screening of crude plant extract for protein-binding agents Basic Protocol 3: Localized SPR-based antigen detection using antibody-conjugated gold nanoparticles.
Topics: Surface Plasmon Resonance; Ligands; Protein Binding; Proteins; Gold
PubMed: 38923763
DOI: 10.1002/cpz1.1030 -
JMIR MHealth and UHealth Jun 2024Globally, students face increasing mental health challenges, including elevated stress levels and declining well-being, leading to academic performance issues and mental... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Globally, students face increasing mental health challenges, including elevated stress levels and declining well-being, leading to academic performance issues and mental health disorders. However, due to stigma and symptom underestimation, students rarely seek effective stress management solutions. Conversational agents in the health sector have shown promise in reducing stress, depression, and anxiety. Nevertheless, research on their effectiveness for students with stress remains limited.
OBJECTIVE
This study aims to develop a conversational agent-delivered stress management coaching intervention for students called MISHA and to evaluate its effectiveness, engagement, and acceptance.
METHODS
In an unblinded randomized controlled trial, Swiss students experiencing stress were recruited on the web. Using a 1:1 randomization ratio, participants (N=140) were allocated to either the intervention or waitlist control group. Treatment effectiveness on changes in the primary outcome, that is, perceived stress, and secondary outcomes, including depression, anxiety, psychosomatic symptoms, and active coping, were self-assessed and evaluated using ANOVA for repeated measure and general estimating equations.
RESULTS
The per-protocol analysis revealed evidence for improvement of stress, depression, and somatic symptoms with medium effect sizes (Cohen d=-0.36 to Cohen d=-0.60), while anxiety and active coping did not change (Cohen d=-0.29 and Cohen d=0.13). In the intention-to-treat analysis, similar results were found, indicating reduced stress (β estimate=-0.13, 95% CI -0.20 to -0.05; P<.001), depressive symptoms (β estimate=-0.23, 95% CI -0.38 to -0.08; P=.003), and psychosomatic symptoms (β estimate=-0.16, 95% CI -0.27 to -0.06; P=.003), while anxiety and active coping did not change. Overall, 60% (42/70) of the participants in the intervention group completed the coaching by completing the postintervention survey. They particularly appreciated the quality, quantity, credibility, and visual representation of information. While individual customization was rated the lowest, the target group fitting was perceived as high.
CONCLUSIONS
Findings indicate that MISHA is feasible, acceptable, and effective in reducing perceived stress among students in Switzerland. Future research is needed with different populations, for example, in students with high stress levels or compared to active controls.
TRIAL REGISTRATION
German Clinical Trials Register DRKS 00030004; https://drks.de/search/en/trial/DRKS00030004.
Topics: Humans; Male; Female; Stress, Psychological; Pilot Projects; Students; Mentoring; Switzerland; Adult; Mobile Applications; Adolescent; Surveys and Questionnaires; Young Adult
PubMed: 38922677
DOI: 10.2196/54945 -
Brazilian Dental Journal 2024Studies regarding cytotoxic effects attributed to the use of adhesive bonding agents on pulp tissue are not conclusive. To point out whether these materials are safe for...
Studies regarding cytotoxic effects attributed to the use of adhesive bonding agents on pulp tissue are not conclusive. To point out whether these materials are safe for clinical use, in vivo exposure of dental pulp to adhesive bonding agents was simulated using an experimental setup in which Human Dental Pulp Stem Cells (hDPSC) are exposed to the action of two kinds of adhesives: self-etching adhesives and two-step bonding agents through a dentine barrier. Cytotoxic effects on these cells were evaluated by MTT assay protocol and fluorescence microscopy, and their results were contrasted to those obtained through Raman spectra taken on single hDPSCs. Overall, no significant cytotoxic effects were observed by combining all the techniques, and cell viability close to 90% was achieved for a dentine barrier of at least 1 mm thick. Moreover, Raman spectroscopy was able to detect structural DNA damage in some dental pulp cells when exposed to two-step bonding agents, suggesting that this technique could be considered a complementary tool with the potential to evaluate cell toxicity beyond cell viability.
Topics: Humans; Dental Pulp; Stem Cells; Spectrum Analysis, Raman; Dentin-Bonding Agents; Cell Survival; Microscopy, Fluorescence; Cells, Cultured
PubMed: 38922248
DOI: 10.1590/0103-6440202405529 -
Veterinary Sciences May 2024Metagenomics offers the potential to replace and simplify classical methods used in the clinical diagnosis of human and veterinary infectious diseases. Metagenomics... (Review)
Review
Metagenomics offers the potential to replace and simplify classical methods used in the clinical diagnosis of human and veterinary infectious diseases. Metagenomics boasts a high pathogen discovery rate and high specificity, advantages absent in most classical approaches. However, its widespread adoption in clinical settings is still pending, with a slow transition from research to routine use. While longer turnaround times and higher costs were once concerns, these issues are currently being addressed by automation, better chemistries, improved sequencing platforms, better databases, and automated bioinformatics analysis. However, many technical options and steps, each producing highly variable outcomes, have reduced the technology's operational value, discouraging its implementation in diagnostic labs. We present a case for utilizing non-targeted RNA sequencing (NT-RNA-seq) as an ideal metagenomics method for the detection of infectious disease-causing agents in humans and animals. Additionally, to create operational value, we propose to identify best practices for the "core" of steps that are invariably shared among many human and veterinary protocols. Reference materials, sequencing procedures, and bioinformatics standards should accelerate the validation processes necessary for the widespread adoption of this technology. Best practices could be determined through "implementation research" by a consortium of interested institutions working on common samples.
PubMed: 38921986
DOI: 10.3390/vetsci11060239 -
Pathogens (Basel, Switzerland) May 2024Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, commonly associated with nosocomial transmission. Gram-negative... (Review)
Review
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, commonly associated with nosocomial transmission. Gram-negative bacterial species are particularly problematic due to the release of the lipopolysaccharide toxins upon cell death. The lipopolysaccharide toxin of has a greater immunogenic potential than that of other Gram-negative bacteria. The resultant dysregulation of the immune system is associated with organ failure and mortality, with pregnant women, ICU patients, and neonates being particularly vulnerable. Additionally, sepsis recovery patients have an increased risk of re-hospitalisation, chronic illness, co-morbidities, organ damage/failure, and a reduced life expectancy. The emergence and increasing prevalence of antimicrobial resistance in bacterial and fungal species has impacted the treatment of sepsis patients, leading to increasing mortality rates. Multidrug resistant pathogens including vancomycin-resistant Enterococcus, beta lactam-resistant , and carbapenem-resistant species are associated with an increased risk of mortality. To improve the prognosis of sepsis patients, predominantly high-risk neonates, advances must be made in the early diagnosis, triage, and control of sepsis. The identification of suitable biomarkers and biomarker combinations, coupled with machine learning and artificial intelligence, show promise in early detection protocols. Rapid diagnosis of sepsis in patients is essential to inform on clinical treatment, especially with resistant infectious agents. This timely review aims to discuss sepsis prevalence, aetiology, and recent advances towards disease mitigation and control.
PubMed: 38921759
DOI: 10.3390/pathogens13060461 -
Nephrologie & Therapeutique Jun 2024The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation...
The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation Commission of the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) conducted a survey on the management of immunosuppressants (IS) after KTF among nephrologists at transplant centres and general nephrologists in France, Switzerland and Belgium between March and June 2023. We analysed 232 replies from 58 nephrologists at transplant centres and 174 general nephrologists, aged 43.6 (+10.6) years. In the first three months following KTF, nephrologists reported discontinuing antimetabolite, calcineurin inhibitor (CNI) and corticosteroid treatment in 83%, 39.9% and 25.8% of cases respectively. Conversely, some nephrologists reported that they were continuing to use CNI (14%) and corticosteroids (19.1%) on a long-term basis. The patient’s comorbidities associated with the discontinuation of IS treatment are cancer and opportunistic infections as KT’s complications and presence of diabetes mellitus at KTF, whereas humoral rejection encourages the IS to be maintained. Transplantectomy is proposed by nephrologists most often for graft intolerance syndrome (86.5%), more rarely to discontinue IS (17.6%) or in the absence of plans of new transplantation (9.3%). In multivariate analyses, the presence of a protocol in the centre facilitated the management of IS by the general nephrologists. The management of IS after AFG by French-speaking nephrologists is heterogeneous. Specific prospective studies are needed to establish new best practice recommendations, based on more robust evidence, which could encourage better adherence by nephrologists.
Topics: Humans; Kidney Transplantation; Immunosuppressive Agents; France; Practice Patterns, Physicians'; Surveys and Questionnaires; Nephrologists; Nephrology; Graft Rejection
PubMed: 38920047
DOI: 10.1684/ndt.2024.79 -
BMC Infectious Diseases Jun 2024Healthcare-Associated Infections (HAIs) are a global public health issue, representing a significant burden of disease that leads to prolonged hospital stays,...
BACKGROUND
Healthcare-Associated Infections (HAIs) are a global public health issue, representing a significant burden of disease that leads to prolonged hospital stays, inappropriate use of antimicrobial drugs, intricately linked to the development of resistant microorganisms, and higher costs for healthcare systems. The study aimed to measure the prevalence of HAIs, the use of antimicrobials, and assess healthcare- and patient-related risk factors, to help identify key intervention points for effectively reducing the burden of HAIs.
METHODS
A total of 28 acute care hospitals in the Lombardy region, Northern Italy, participated in the third European Point Prevalence Survey (PPS-3) coordinated by ECDC for the surveillance of HAIs in acute care hospitals (Protocol 6.0).
RESULTS
HAIs were detected in 1,259 (10.1%, 95% CI 9.6-10.7%) out of 12,412 enrolled patients. 1,385 HAIs were reported (1.1 HAIs per patient on average). The most common types of HAIs were bloodstream infections (262 cases, 18.9%), urinary tract infections (237, 17.1%), SARS-CoV-2 infections (236, 17.0%), pneumonia and lower respiratory tract infections (231, 16.7%), and surgical site infections (152, 11.0%). Excluding SARS-CoV-2 infections, the overall prevalence of HAIs was 8.4% (95% CI 7.9-8.9%). HAIs were significantly more frequent in patients hospitalized in smaller hospitals and in intensive care units (ICUs), among males, advanced age, severe clinical condition and in patients using invasive medical devices. Overall, 5,225 patients (42.1%, 95% CI 41.3-43.0%) received systemic antimicrobial therapy. According to the WHO's AWaRe classification, the Access group accounted for 32.7% of total antibiotic consumption, while Watch and Reserve classes accounted for 57.0% and 5.9% respectively. From a microbiological perspective, investigations were conducted on only 64% of the HAIs, showing, however, a significant pattern of antibiotic resistance.
CONCLUSIONS
The PPS-3 in Lombardy, involving data collection on HAIs and antimicrobial use in acute care hospitals, highlights the crucial need for a structured framework serving both as a valuable benchmark for individual hospitals and as a foundation to effectively channel interventions to the most critical areas, prioritizing future regional health policies to reduce the burden of HAIs.
Topics: Humans; Italy; Male; Cross Infection; Female; Aged; Middle Aged; Prevalence; Adult; Aged, 80 and over; Adolescent; Young Adult; Hospitals; Child, Preschool; Child; Risk Factors; Infant; Infant, Newborn; COVID-19; Anti-Infective Agents; Anti-Bacterial Agents; Surveys and Questionnaires; Urinary Tract Infections
PubMed: 38918691
DOI: 10.1186/s12879-024-09487-7