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Clinical Microbiology and Infection :... Apr 2022These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant...
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine).
SCOPE
These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy.
METHODS
An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak).
RECOMMENDATIONS
The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
Topics: Anti-Bacterial Agents; Carbapenems; Communicable Diseases; Critical Care; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans
PubMed: 34923128
DOI: 10.1016/j.cmi.2021.11.025 -
JACC. Heart Failure Feb 2022This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction.
BACKGROUND
The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized.
METHODS
We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor-neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]).
RESULTS
We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses.
CONCLUSIONS
In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i.
Topics: Aged; Angiotensin Receptor Antagonists; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Network Meta-Analysis; Stroke Volume
PubMed: 34895860
DOI: 10.1016/j.jchf.2021.09.004 -
Signal Transduction and Targeted Therapy Mar 2023The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription... (Review)
Review
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
Topics: Humans; Tumor Suppressor Protein p53; Apoptosis; Autophagy; Cell Cycle; Ferroptosis
PubMed: 36859359
DOI: 10.1038/s41392-023-01347-1 -
International Journal of Molecular... Feb 2023Around 40-50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC).... (Review)
Review
Around 40-50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC). The identification of biomarkers predicting the response to NAC could be helpful for personalized treatment. This systematic review provides an overview of putative biomarkers at baseline that are predictive for a pCR following NAC. Embase, Medline and Web of Science were searched for articles published between January 2010 and August 2022. The articles had to meet the following criteria: patients with primary invasive TNBC without distant metastases and patients must have received NAC. In total, 2045 articles were screened by two reviewers resulting in the inclusion of 92 articles. Overall, the most frequently reported biomarkers associated with a pCR were a high expression of Ki-67, an expression of PD-L1 and the abundance of tumor-infiltrating lymphocytes, particularly CD8+ T cells, and corresponding immune gene signatures. In addition, our review reveals proteomic, genomic and transcriptomic markers that relate to cancer cells, the tumor microenvironment and the peripheral blood, which also affect chemo-sensitivity. We conclude that a prediction model based on a combination of tumor and immune markers is likely to better stratify TNBC patients with respect to NAC response.
Topics: Humans; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Proteomics; Lymphocytes, Tumor-Infiltrating; Biomarkers; Tumor Microenvironment
PubMed: 36769287
DOI: 10.3390/ijms24032969 -
Fertility and Sterility Aug 2022To identify the most robust molecular biomarkers in sperm and seminal plasma for the diagnosis of male infertility, and to evaluate their clinical use. (Review)
Review
OBJECTIVE
To identify the most robust molecular biomarkers in sperm and seminal plasma for the diagnosis of male infertility, and to evaluate their clinical use.
DESIGN
Systematic review.
SETTING
Not applicable.
PATIENT(S)
Accessible studies reporting well-defined (in)fertile populations and semen molecular biomarkers were included in this review.
INTERVENTION(S)
A systematic search of the literature published in MEDLINE-PubMed and EMBASE databases was performed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
MAIN OUTCOME MEASURE(S)
The primary outcome was the content, expression, or activity of molecular biomarkers in human semen samples. Only studies reporting a receiver-operating characteristic (ROC) analysis values were included.
RESULT(S)
Eighty-nine studies were included. Direct evaluation of sperm DNA damage has high potential as a diagnostic biomarker of fertility and assisted reproductive technology outcomes (area under the curve [AUCs] median = 0.67). Regarding strand break-associated chromatin modifications, γH2AX levels show good predictive value for the diagnosis of male infertility (AUCs median = 0.93). Some noncoding ribonucleic acid (RNA) exhibit excellent predictive values; miR-34c-5p in semen is the most well-characterized and robust transcriptomic biomarker (AUCs median = 0.78). While many proteins in semen show fair diagnostic value for sperm quality and fertilizing capacity, the levels of some, such as TEX101, in seminal plasma have an excellent diagnostic potential (AUCs median = 0.69). Although individual metabolites and metabolomic profiles in seminal plasma present good predictive value, the latter seem to be better than the former when inferring sperm quality and fertilizing capacity.
CONCLUSION(S)
The current review supports that some Omics (e.g., DNA structure and integrity, genomics and epigenomics, transcriptomics, metabolomics, and proteomics) could be considered relevant molecular biomarkers that may help identify infertility etiologies and fertilization prognosis with cost-effective, simple, and accurate diagnosis.
Topics: Biomarkers; Fertility; Humans; Infertility, Male; Male; Semen; Semen Analysis; Spermatozoa
PubMed: 35718545
DOI: 10.1016/j.fertnstert.2022.04.028 -
Survey of Ophthalmology 2022The human tear film is at the interface between the ocular surface and the external environment. Although investigation has been hindered by its small volume,... (Review)
Review
The human tear film is at the interface between the ocular surface and the external environment. Although investigation has been hindered by its small volume, improvements in preanalytical and analytical methods have allowed the omics approach to represent an innovative biomarker search strategy. There is still a significant lack of standardization, representing a barrier for performing between-studies comparisons and transferring experimental findings into clinical use and trials. We summarize the preanalytical and analytical procedures, describe the biomarkers that can be found using the metabo-lipidomics approach, and provide our expert opinion for omics investigations in human tears. For this systematic review of 38 studies, we searched PubMed by combining Boolean operators with the following keywords: tear, metabolomic, lipidomic, -omics. The human tear metabo-lipidome has been well-characterized in normal individuals using high-resolution liquid chromatography coupled with mass spectrometry. Lipid and metabolite profiles were influenced by ocular (e.g., dry eye disorders; Meibomian gland dysfunction; contact lens wear; glaucoma; keratoconus; pterygium) and systemic conditions (e.g., multiple sclerosis). Investigating the tear metabo-lipidome could improve our understanding of the pathogenesis of both ocular and systemic diseases, but also provide diagnostic as well as prognostic biomarkers.
Topics: Biomarkers; Dry Eye Syndromes; Humans; Lipidomics; Meibomian Glands; Metabolomics; Tears
PubMed: 35093405
DOI: 10.1016/j.survophthal.2022.01.010 -
Critical Reviews in Food Science and... 2023Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of...
Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. was the most relevant nootropic regarding perceptual and motor functions. improves language, learning and memory. (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2021137.
Topics: Humans; Nootropic Agents; Plant Extracts; Cognition; Phytotherapy
PubMed: 34978226
DOI: 10.1080/10408398.2021.2021137 -
Journal of Neurochemistry Mar 2021Similar to dementia, the risk for developing type 2 diabetes mellitus (T2DM) increases with age, and T2DM also increases the risk for dementia, particularly Alzheimer's...
Similar to dementia, the risk for developing type 2 diabetes mellitus (T2DM) increases with age, and T2DM also increases the risk for dementia, particularly Alzheimer's disease (AD). Although T2DM is primarily a peripheral disorder and AD is a central nervous system disease, both share some common features as they are chronic and complex diseases, and both show involvement of oxidative stress and inflammation in their progression. These characteristics suggest that T2DM may be associated with AD, which gave rise to a new term, type 3 diabetes (T3DM). In this study, we searched for matching peripheral proteomic biomarkers of AD and T2DM based in a systematic review of the available literature. We identified 17 common biomarkers that were differentially expressed in both patients with AD or T2DM when compared with healthy controls. These biomarkers could provide a useful workflow for screening T2DM patients at risk to develop AD.
Topics: Alzheimer Disease; Animals; Biomarkers; Diabetes Mellitus, Type 2; Humans; Proteomics
PubMed: 32909269
DOI: 10.1111/jnc.15166 -
JAMA Psychiatry Aug 2022Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective for this symptomatic dimension. Studies have suggested that noninvasive brain stimulation (NIBS) interventions may be effective in treating negative symptoms. However, the comparative efficacy of different NIBS protocols for relieving negative symptoms remains unclear.
OBJECTIVE
To compare the efficacy and acceptability of different NIBS interventions for treating negative symptoms.
DATA SOURCES
The ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science electronic databases were systematically searched from inception through December 7, 2021.
STUDY SELECTION
A frequentist model network meta-analysis was conducted to assess the pooled findings of trials that evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation, transcranial random noise stimulation, transcutaneous vagus nerve stimulation, and transcranial direct current stimulation on negative symptoms in schizophrenia. Randomized clinical trials (RCTs) examining NIBS interventions for participants with schizophrenia were included.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were independently extracted by multiple observers. The pair-wise meta-analytic procedures were conducted using a random-effects model.
MAIN OUTCOMES AND MEASURES
The coprimary outcomes were changes in the severity of negative symptoms and acceptability (ie, dropout rates owing to any reason). Secondary outcomes were changes in positive and depressive symptoms.
RESULTS
Forty-eight RCTs involving 2211 participants (mean [range] age, 38.7 [24.0-57.0] years; mean [range] proportion of female patients, 30.6% [0%-70.0%]) were included. Compared with sham control interventions, excitatory NIBS strategies (standardized mean difference [SMD]: high-definition transcranial random noise stimulation, -2.19 [95% CI, -3.36 to -1.02]; intermittent theta-burst stimulation, -1.32 [95% CI, -1.88 to -0.76]; anodal transcranial direct current stimulation, -1.28 [95% CI, -2.55 to -0.02]; high-frequency rTMS, -0.43 [95% CI, -0.68 to -0.18]; extreme high-frequency rTMS, -0.45 [95% CI, -0.79 to -0.12]) over the left dorsolateral prefrontal cortex with or without other inhibitory stimulation protocols in the contralateral regions of the brain were associated with significantly larger reductions in negative symptoms. Acceptability did not significantly differ between the groups.
CONCLUSIONS AND RELEVANCE
In this network meta-analysis, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with significantly large improvements in the severity of negative symptoms. Because relatively few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted.
Topics: Adult; Brain; Female; Humans; Male; Middle Aged; Network Meta-Analysis; Schizophrenia; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation; Young Adult
PubMed: 35731533
DOI: 10.1001/jamapsychiatry.2022.1513 -
Nature Communications Jul 2021There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional... (Meta-Analysis)
Meta-Analysis
There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma.
Topics: Alcohol Drinking; Animals; Calcium; Carcinoma, Basal Cell; Coffee; Dairy Products; Diet; Liver Neoplasms; Milk; Neoplasms; Risk Factors
PubMed: 34321471
DOI: 10.1038/s41467-021-24861-8