Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Interventions for palliative symptom control in COVID-19 patients.

BACKGROUND: Individuals dying of coronavirus disease 2019 (COVID-19) may experience distressing symptoms such as breathlessness or delirium. Palliative symptom management can alleviate symptoms and improve the quality of life of patients. Various treatment options such as opioids or breathing techniques have been discussed for use in COVID-19 patients. However, guidance on symptom management of COVID-19 patients in palliative care has often been derived from clinical experiences and guidelines for the treatment of patients with other illnesses. An understanding of the effectiveness of pharmacological and non-pharmacological palliative interventions to manage specific symptoms of COVID-19 patients is required. OBJECTIVES: To assess the efficacy and safety of pharmacological and non-pharmacological interventions for palliative symptom control in individuals with COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), medRxiv); Web of Science Core Collection (Science Citation Index Expanded, Emerging Sources); CINAHL; WHO COVID-19 Global literature on coronavirus disease; and COAP Living Evidence on COVID-19 to identify completed and ongoing studies without language restrictions until 23 March 2021. We screened the reference lists of relevant review articles and current treatment guidelines for further literature. SELECTION CRITERIA: We followed standard Cochrane methodology as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We included studies evaluating palliative symptom management for individuals with a confirmed diagnosis of COVID-19 receiving interventions for palliative symptom control, with no restrictions regarding comorbidities, age, gender, or ethnicity. Interventions comprised pharmacological as well as non-pharmacological treatment (e.g. acupressure, physical therapy, relaxation, or breathing techniques). We searched for the following types of studies: randomized controlled trials (RCT), quasi-RCTs, controlled clinical trials, controlled before-after studies, interrupted time series (with comparison group), prospective cohort studies, retrospective cohort studies, (nested) case-control studies, and cross-sectional studies. We searched for studies comparing pharmacological and non-pharmacological interventions for palliative symptom control with standard care. We excluded studies evaluating palliative interventions for symptoms caused by other terminal illnesses. If studies enrolled populations with or exposed to multiple diseases, we would only include these if the authors provided subgroup data for individuals with COVID-19. We excluded studies investigating interventions for symptom control in a curative setting, for example patients receiving life-prolonging therapies such as invasive ventilation.  DATA COLLECTION AND ANALYSIS: We used a modified version of the Newcastle Ottawa Scale for non-randomized studies of interventions (NRSIs) to assess bias in the included studies. We included the following outcomes: symptom relief (primary outcome); quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We rated the certainty of evidence using the GRADE approach.  As meta-analysis was not possible, we used tabulation to synthesize the studies and histograms to display the outcomes.  MAIN RESULTS: Overall, we identified four uncontrolled retrospective cohort studies investigating pharmacological interventions for palliative symptom control in hospitalized patients and patients in nursing homes. None of the studies included a comparator. We rated the risk of bias high across all studies. We rated the certainty of the evidence as very low for the primary outcome symptom relief, downgrading mainly for high risk of bias due to confounding and unblinded outcome assessors. Pharmacological interventions for palliative symptom control We identified four uncontrolled retrospective cohort studies (five references) investigating pharmacological interventions for palliative symptom control. Two references used the same register to form their cohorts, and study investigators confirmed a partial overlap of participants. We therefore do not know the exact number of participants, but individual reports included 61 to 2105 participants. Participants received multimodal pharmacological interventions: opioids, neuroleptics, anticholinergics, and benzodiazepines for relieving dyspnea (breathlessness), delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms.  Primary outcome: symptom relief All identified studies reported this outcome. For all symptoms (dyspnea, delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms), a majority of interventions were rated as completely or partially effective by outcome assessors (treating clinicians or nursing staff). Interventions used in the studies were opioids, neuroleptics, anticholinergics, and benzodiazepines.  We are very uncertain about the effect of pharmacological interventions on symptom relief (very low-certainty evidence). The initial rating of the certainty of evidence was low since we only identified uncontrolled NRSIs. Our main reason for downgrading the certainty of evidence was high risk of bias due to confounding and unblinded outcome assessors. We therefore did not find evidence to confidently support or refute whether pharmacological interventions may be effective for palliative symptom relief in COVID-19 patients. Secondary outcomes We planned to include the following outcomes: quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We did not find any data for these outcomes, or any other information on the efficacy and safety of used interventions. Non-pharmacological interventions for palliative symptom control None of the identified studies used non-pharmacological interventions for palliative symptom control. AUTHORS' CONCLUSIONS: We found very low certainty evidence for the efficacy of pharmacological interventions for palliative symptom relief in COVID-19 patients. We found no evidence on the safety of pharmacological interventions or efficacy and safety of non-pharmacological interventions for palliative symptom control in COVID-19 patients. The evidence presented here has no specific implications for palliative symptom control in COVID-19 patients because we cannot draw any conclusions about the effectiveness or safety based on the identified evidence. More evidence is needed to guide clinicians, nursing staff, and caregivers when treating symptoms of COVID-19 patients at the end of life. Specifically, future studies ought to investigate palliative symptom control in prospectively registered studies, using an active-controlled setting, assess patient-reported outcomes, and clearly define interventions. The publication of the results of ongoing studies will necessitate an update of this review. The conclusions of an updated review could differ from those of the present review and may allow for a better judgement regarding pharmacological and non-pharmacological interventions for palliative symptom control in COVID-19 patients.

Daring to be differential: metabarcoding analysis of soil and plant-related microbial communities using amplicon sequence variants and operational taxonomical units.

BACKGROUND: Microorganisms are not only indispensable to ecosystem functioning, they are also keystones for emerging technologies. In the last 15 years, the number of studies on environmental microbial communities has increased exponentially due to advances in sequencing technologies, but the large amount of data generated remains difficult to analyze and interpret. Recently, metabarcoding analysis has shifted from clustering reads using Operational Taxonomical Units (OTUs) to Amplicon Sequence Variants (ASVs). Differences between these methods can seriously affect the biological interpretation of metabarcoding data, especially in ecosystems with high microbial diversity, as the methods are benchmarked based on low diversity datasets. RESULTS: In this work we have thoroughly examined the differences in community diversity, structure, and complexity between the OTU and ASV methods. We have examined culture-based mock and simulated datasets as well as soil- and plant-associated bacterial and fungal environmental communities. Four key findings were revealed. First, analysis of microbial datasets at family level guaranteed both consistency and adequate coverage when using either method. Second, the performance of both methods used are related to community diversity and sample sequencing depth. Third, differences in the method used affected sample diversity and number of detected differentially abundant families upon treatment; this may lead researchers to draw different biological conclusions. Fourth, the observed differences can mostly be attributed to low abundant (relative abundance < 0.1%) families, thus extra care is recommended when studying rare species using metabarcoding. The ASV method used outperformed the adopted OTU method concerning community diversity, especially for fungus-related sequences, but only when the sequencing depth was sufficient to capture the community complexity. CONCLUSIONS: Investigation of metabarcoding data should be done with care. Correct biological interpretation depends on several factors, including in-depth sequencing of the samples, choice of the most appropriate filtering strategy for the specific research goal, and use of family level for data clustering.

The CEP5 Peptide Promotes Abiotic Stress Tolerance, As Revealed by Quantitative Proteomics, and Attenuates the AUX/IAA Equilibrium in Arabidopsis.

Peptides derived from non-functional precursors play important roles in various developmental processes, but also in (a)biotic stress signaling. Our (phospho)proteome-wide analyses of C-TERMINALLY ENCODED PEPTIDE 5 (CEP5)-mediated changes revealed an impact on abiotic stress-related processes. Drought has a dramatic impact on plant growth, development and reproduction, and the plant hormone auxin plays a role in drought responses. Our genetic, physiological, biochemical, and pharmacological results demonstrated that CEP5-mediated signaling is relevant for osmotic and drought stress tolerance in Arabidopsis, and that CEP5 specifically counteracts auxin effects. Specifically, we found that CEP5 signaling stabilizes AUX/IAA transcriptional repressors, suggesting the existence of a novel peptide-dependent control mechanism that tunes auxin signaling. These observations align with the recently described role of AUX/IAAs in stress tolerance and provide a novel role for CEP5 in osmotic and drought stress tolerance.

Look Closely, the Beautiful May Be Small: Precursor-Derived Peptides in Plants.

During the past decade, a flurry of research focusing on the role of peptides as short- and long-distance signaling molecules in plant cell communication has been undertaken. Here, we focus on peptides derived from nonfunctional precursors, and we address several key questions regarding peptide signaling. We provide an overview of the regulatory steps involved in producing a biologically active peptide ligand that can bind its corresponding receptor(s) and discuss how this binding and subsequent activation lead to specific cellular outputs. We discuss different experimental approaches that can be used to match peptide ligands with their receptors. Lastly, we explore how peptides evolved from basic signaling units regulating essential processes in plants to more complex signaling systems as new adaptive traits developed and how nonplant organisms exploit this signaling machinery by producing peptide mimics.

Diversity of Root-knot Nematodes Associated with Tubers of Yam (Dioscorea spp.) Established Using Isozyme Analysis and Mitochondrial DNA-based Identification.

The root-knot nematodes (RKN), Meloidogyne spp., represent an important threat to yam (Dioscorea spp.) production in West Africa. With the aim to establish the diversity of RKN species affecting yam tubers, for control and resistance screening purposes, surveys were conducted in the main yam producing areas of Nigeria. Galled tubers (N = 48) were collected from farmers' stores and markets in nine states in Nigeria and in one district in Ghana. RKN isolated from yam tubers were identified using enzyme phenotyping (esterase and malate dehydrogenase) and mitochondrial DNA (mtDNA) NADH dehydrogenase subunit 5 (Nad5) barcoding. Examination of 48 populations revealed that yam tubers were infested by Meloidogyne incognita (69%), followed by M. javanica (13%), M. enterolobii (2%), and M. arenaria (2%). Most of the tubers sampled (86%) were infected by a single species, and multiple species of RKN were detected in 14% of the samples. Results of both identification methods revealed the same species, confirming their accuracy for the identification of these tropical RKN species. In addition to M. incognita, M. javanica, and M. enterolobii, we report for the first time M. arenaria infecting yam tubers in Nigeria. This finding extends the list of yam pests and calls for caution when developing practices for yam pest management.

Morphological and molecular characterisation of Scutellonema species from yam (Dioscorea spp.) and a key to the species of the genus.

The yam nematode, Scutellonema bradys, is a major threat to yam (Dioscorea spp.) production across yam-growing regions. In West Africa, this species cohabits with many morphologically similar congeners and, consequently, its accurate diagnosis is essential for control and for monitoring its movement. In the present study, 46 Scutellonema populations collected from yam rhizosphere and yam tubers in different agro-ecological zones in Ghana and Nigeria were characterised by their morphological features and by sequencing of the D2-D3 region of the 28S rDNA gene and the mitochondrial COI genes. Molecular phylogeny, molecular species delimitation and morphology revealed S. bradys, S. cavenessi, S. clathricaudatum and three undescribed species from yam rhizosphere. Only S. bradys was identified from yam tuber tissue, however. For barcoding and identifying Scutellonema spp., the most suitable marker used was the COI gene. Additionally, 99 new Scutellonema sequences were generated using populations obtained also from banana, carrot, maize and tomato, including the first for S. paralabiatum and S. clathricaudatum, enabling the development of a dichotomous key for identification of Scutellonema spp. The implications of these results are discussed.