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OBJECTIVES: Natural alternatives to synthetic additives are being explored as a means to enhance laying hen performance and egg quality. The study conducted a systematic review and meta-analysis to evaluate the effect of dietary supplementation with Thymus vulgaris (thyme) on productive performance and egg quality in laying hens. METHODS: A comprehensive search of databases identified 18 eligible studies. Data were analysed using random-effects models, with subgroup analyses based on the thyme form (powder, essential oil, extract) and supplementation duration (≤ 8 weeks, > 8 weeks). The unstandardized mean difference was used to calculate the effect size, and confidence intervals were generated to estimate the range of the true effect size. RESULTS: Thyme significantly improved egg weight, egg mass, yolk colour, yolk index and shell thickness (p < 0.05), with very large effect sizes for egg weight and mass. However, albumen quantity decreased, while egg production rate, Haugh unit, and shell weight remained unchanged. Powdered thyme was particularly effective at enhancing egg weight and mass, while essential oils and extracts improved yolk colour. Longer supplementation periods (> 8 weeks) yielded greater benefits for egg mass and weight, whereas shorter durations (≤ 8 weeks) improved shell thickness. CONCLUSIONS: These findings suggest that thyme supplementation, particularly in powdered form and over extended periods, can enhance egg quality, offering a natural alternative to synthetic additives. This research demonstrates thyme's efficacy as a phytogenic feed additive, offering a natural solution to improve egg quality and meet the rising demand for sustainable and high-quality poultry products. SUMMARY: Thyme supplementation improves egg weight, egg mass, yolk colour and shell thickness in laying hens. Powdered thyme shows the most significant benefits for egg weight and mass. Longer supplementation periods (> 8 weeks) enhance yolk colour and egg quality traits. Thyme offers a natural, sustainable alternative to synthetic feed additives in poultry production. © 2025 The Author(s). Veterinary Medicine and Science published by John Wiley & Sons Ltd.

BACKGROUND: The Mediterranean Diet (MedDiet) is the dietary pattern par excellence for managing and preventing metabolic diseases, such as Type 2 Diabetes (T2DM). The MedDiet incorporates spices and aromatic herbs, which are abundant sources of bioactive compounds. The aim of this study was to analyze the effect of all aromatic herbs and spices included in the MedDiet, such as black cumin, clove, parsley, saffron, thyme, ginger, black pepper, rosemary, turmeric, basil, oregano, and cinnamon, on the glycemic profile in T2DM subjects. METHODS: PubMed, Web of Science, and Scopus databases were searched for interventional studies investigating the effect of these aromatic herbs and spices on the glycemic profile in T2DM subjects. RESULTS: This systematic review retrieved 6958 studies, of which 77 were included in the qualitative synthesis and 45 were included in the meta-analysis. Our results showed that cinnamon, turmeric, ginger, black cumin, and saffron significantly improved the fasting glucose levels in T2DM subjects. The most significant decreases in fasting glucose were achieved after supplementation with black cumin, followed by cinnamon and ginger, which achieved a decrease of between 27 and 17 mg/dL. CONCLUSIONS: Only ginger and black cumin reported a significant improvement in glycated hemoglobin, and only cinnamon and ginger showed a significant decrease in insulin.

BACKGROUND: Quality of life and symptom burden of patients with myelofibrosis are well recognized and compounded in those with anemia; however, the effects of transfusion burden or anemia severity on quality of life have not been comprehensively characterized. This post hoc descriptive analysis explored the association between transfusion status or hemoglobin improvement and patient-reported outcomes (PROs). METHODS: The analysis used pooled populations across treatment arms from 3 clinical trials (SIMPLIFY-1, SIMPLIFY-2, MOMENTUM); sample sizes for each PRO measure were dependent on the trials in which they were administered. RESULTS: At both baseline and week 24, transfusion independence was associated with umerically greater mean SF-36v2 and EORTC QLQ-C30 scores than transfusion dependence; in the subgroup that was transfusion dependent at baseline, those who achieved transfusion independence at week 24 had greater PRO improvements than those who remained reliant on transfusions. Regardless of transfusion status, patients who achieved a hemoglobin improvement ≥ 1, ≥ 1.5, or ≥ 2 g/dL from baseline also had clinically meaningful improvements in quality of life (assessed via mean EQ-5D-5L or SF-36v2 scores) and symptoms (assessed via PGIC or MPN-SAF/MFSAF Total Symptom Score) at week 24 compared with those who did not. CONCLUSIONS: Collectively, these results provide preliminary insights into the associations of transfusion status and anemia severity with quality of life in myelofibrosis; as current PRO measures do not directly evaluate the relationship between symptoms such as fatigue and anemia, development of new measures to more comprehensively capture the patient experience for those with anemia in myelofibrosis may be warranted. TRIAL REGISTRATION: NCT01969838, NCT02101268, NCT04173494. © 2026 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.

BACKGROUND: The global prevalence of systemic diseases and subsequent drug consumption, which is strongly associated with xerostomia, has become increasingly prominent. Considering the significance of maintaining good oral health and hypothesizing that natural salivary stimulants could serve as a safe and effective treatment option, we assessed the therapeutic efficiency of thyme honey mouthwash in treating individuals with polypharmacy-induced xerostomia. METHODS: A randomized controlled trial performed at Ain Shams University's Faculty of Dentistry, Egypt, on 64 patients consuming two or more xerostomia-inducing medications and complaining of dry mouth. Patients were randomly assigned to receive thyme honey oral rinse (Study Group) or normal saline oral rinse (Control Group) (3/day/4weeks). Unstimulated salivary flow rate (USFR), subjective (SDS), and clinical oral dryness scores (CODS) were evaluated at baseline and after 2 and 4 weeks. The salivary nitric oxide levels (SNO) and xerostomia-related quality of life scale (XeQoLS) were assessed at baseline and after 4 weeks. RESULTS: The USFR showed a notable increase (P < 0.001) in the study group (161.82 ± 89.57 %) compared to the control group (17.11 ± 10.53 %) after 4 weeks, accompanied by an improvement in oral dryness scores. XeQoLS values showed significant improvement, and the SNO levels significantly decreased after using thyme honey mouth rinse for 4 weeks. CONCLUSION: The study concluded that the thyme honey mouth rinse effectively increased the salivary secretion, decreased SNO levels and oral dryness scores, and improved the quality of life for patients experiencing polypharmacy-induced xerostomia.

BackgroundMachine learning (ML) algorithms may improve the prognosis for serious illnesses such as cancer, identifying patients who may benefit from earlier palliative care (PC) or advance care planning (ACP). We evaluated the impact of various presentation strategies of a hypothetical ML algorithm on clinician prognostic accuracy and decision making.MethodsThis was a randomized clinical vignette survey study among medical oncologists who treat metastatic non-small-cell lung cancer (mNSCLC). Between March and June 2023, clinicians were shown 3 vignettes of patients presenting with mNSCLC. The vignettes varied by prognostic risk, as defined from the Lung Cancer Prognostic Index (LCPI). Clinicians estimated life expectancy in months and made recommendations about PC and ACP. Clinicians were then shown the same vignette with a hypothetical survival estimate from a black-box ML algorithm; clinicians were randomized to receive the ML prediction using absolute and/or reference-dependent prognostic estimates. The primary outcome was prognostic accuracy relative to the LCPI.ResultsAmong 51 clinicians with complete responses, the median years in practice was 7 (interquartile range 3.5-19), 14 (27.5%) were female, 23 (45.1%) practiced in a community oncology setting, and baseline accuracy was 54.9% (95% confidence interval [CI] 47.0-62.8) across all vignettes. ML presentation improved accuracy (mean change relative to baseline 20.9%, 95% CI 13.9-27.9, P < 0.001). ML outputs using an absolute presentation strategy alone (mean change 27.4%, 95% 16.8-38.1, P < 0.001) or with reference dependence (mean change 33.4%, 95% 23.9-42.8, P < 0.001) improved accuracy, but reference dependence alone did not (mean change 2.0% [95% CI -11.1 to 15.0], P = 0.77). ML presentation did not change the rates of recommending ACP nor PC referral (mean change 1.3% and 0.7%, respectively).LimitationsThe singular use case of prognosis in mNSCLC, low initial response rate.ConclusionsML-based assessments may improve prognostic accuracy but not result in changed decision making.ImplicationsML prognostic algorithms prioritizing explainability and absolute prognoses may have greater impact on clinician

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora Boiss. (Shirazi thyme) is traditionally used for digestive disorders and inflammatory conditions. Despite its known anti-inflammatory, immunomodulatory, and antioxidant properties, there is limited clinical evidence on its efficacy for ulcerative colitis (UC). AIM OF THE STUDY: To evaluate the effectiveness of Zataria multiflora Boiss. (Z. multiflora) extract in alleviating UC symptoms, reducing inflammatory markers, and modulating immune-related gene expression. MATERIALS AND METHODS: In a multicenter, randomized, placebo-controlled, triple-blind trial in Iran, 92 participants received Z. multiflora extract (6 mg/kg/day) or a placebo for two months. Inflammatory markers and gene expression were analyzed from blood samples. Disease activity was assessed using the Partial Mayo Score (p-Mayo) and the Gastrointestinal Symptom Rating Scale (GSRS). Data were analyzed with SPSS software. RESULTS: The Z. multiflora group showed significant reductions in C-reactive protein (CRP) (p < 0.001), Interleukin-17 (IL-17) (p = 0.001), Interferon-gamma (IFN-γ) (p = 0.002), Nuclear Factor kappa B (NF-κB) (p = 0.002), T-box Transcription Factor T-bet (T-bet) (p = 0.006), and Retinoic Acid-Related Orphan Receptor gamma t (ROR-γt) (p < 0.001). No significant changes were observed in Erythrocyte Sedimentation Rate (ESR) (p = 0.25), GATA Binding Protein 3 (GATA3) (p = 0.09), and Forkhead Box P3 (FOXP3) (p = 0.17). Symptoms such as heartburn, acid reflux, bloating, diarrhea, and fecal urgency improved (p < 0.05). The GSRS score improved (p < 0.001), while the p-Mayo score did not show a significant change (p = 0.24). CONCLUSION: Z. multiflora extract significantly alleviated UC symptoms and reduced inflammatory markers, indicating its potential as a complementary treatment for UC. However, the study was limited by its short intervention period and the absence of biopsy analysis to assess local tissue effects. Further longitudinal studies are required to validate these findings and determine long-term efficacy.

IMPORTANCE: Among patients with advanced solid malignant tumors, early specialty palliative care (PC) is guideline recommended, but strategies to increase PC access and effectiveness in community oncology are lacking. OBJECTIVE: To test whether algorithm-based defaults with opting out and accountable justification embedded in the electronic health record (EHR) increase completed PC visits. DESIGN, SETTING, AND PARTICIPANTS: This 2-arm cluster randomized clinical trial was conducted from November 1, 2022, to December 31, 2023. Eligible patients from 15 urban or rural clinics within a large community oncology network in Tennessee had advanced lung or noncolorectal gastrointestinal cancer and were identified by an automated EHR algorithm adapted from national guidelines. Data were analyzed between November 1, 2023, and March 4, 2024. INTERVENTION: At sites randomized to control, clinicians received weekly reports detailing PC referral rates compared with peer clinicians (peer comparison) and referred patients to PC at their discretion. At sites randomized to intervention, clinicians also received default PC orders using the EHR. Clinicians who opted out of PC consultation were asked to provide justification (accountable justification). If clinicians did not opt out, a study coordinator contacted patients to introduce and schedule PC visits using a standardized, predefined script. MAIN OUTCOMES AND MEASURES: The primary outcome was a completed PC consultation within 12 weeks of enrollment. Exploratory outcomes included quality of life, feeling heard and understood, and intensive end-of-life care. Outcomes were analyzed using clustered generalized linear and logistic regression models. RESULTS: The trial enrolled 562 patients (mean [SD] age, 68.5 [10.1] years; 288 male [51.2%]), of whom 433 (77.0%) had lung cancer. There were 130 of 296 patients (43.9%) randomized to the intervention group and 22 of 266 (8.3%) randomized to the control group who completed PC visits (adjusted odds ratio, 8.9 [95% CI, 5.5-14.6]; P < .001). Among 179 patients who died at the 24-week follow-up, 6 of 92 (6.5%) in the intervention group compared with 14 of 87 (16.1%) in the control group r

Symptoms are often underdetected during cancer treatment. To determine if symptom monitoring with electronic patient-reported outcomes (PROs) improves clinical outcomes, we conducted a cluster-randomized trial in which 52 oncology practices were assigned to PRO or usual care. At PRO practices, patients with metastatic cancer were invited to complete weekly symptom surveys. Severe or worsening symptoms generated alerts to the care team. The primary outcome was overall survival, and secondary outcomes included emergency visits, time to deterioration of physical function, symptoms, health-related quality of life (HRQL) and patient satisfaction with PRO. Among 1,191 enrolled patients, there was no difference in survival (hazard ratio (HR) 0.99 (95% confidence interval (CI), 0.83-1.17); P = 0.86). Time to first emergency visit was significantly prolonged with PRO compared to usual care (HR 0.84 ((95% CI, 0.71-0.98); P = 0.03), with a 6.1% reduction in the cumulative incidence of emergency visits and fewer mean visits at 12 months with PRO (1.02 versus 1.30; P < 0.001). Benefits also significantly favored PRO for delayed deterioration of physical function (median 12.6 versus 8.5 months, HR 0.73; P = 0.002), symptoms (12.7 versus 9.9, HR 0.69; P < 0.001) and HRQL (15.6 versus 12.2, HR 0.72; P = 0.001), which remained significant when considering deaths in analyses. Most patients felt that PRO improved discussions with the care team (77.0% (188/244)), made them feel more in control of their care (84.0% (205/244)) and would recommend it to other patients (91.4% (223/244)). Patients completed 91.5% (20,565/22,486) of expected weekly symptom surveys. These findings demonstrate that symptom monitoring with PRO meaningfully improves clinical outcomes, the patient experience and utilization of services and should be included as a standard part of quality cancer clinical care. Future studies of PRO in clinical care should focus on these outcomes rather than mortality as primary endpoints. ClinicalTrials.gov registration: NCT03249090. © 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.

Limited data exist on factors associated with early quality-of-life (QOL) response to palliative care (PC) in patients undergoing hematopoietic cell transplantation (HCT). We conducted a secondary analysis from 2 randomized clinical trials of PC vs usual care in adults with hematologic malignancies undergoing HCT. We measured patient-reported QOL, physical and psychological symptoms, and coping (categorized as approach-oriented and avoidant) at the time of HCT admission and 2 weeks, 3 months, and 6 months after HCT. PC clinicians completed weekly surveys documenting PC domains addressed. We defined early QOL response to PC as the change in Functional Assessment of Cancer Therapy-Bone Marrow Transplant total score from HCT admission to week 2, using the median split to define "high" responders. A total of 252 participants were included in analyses. The median change in QOL from HCT admission to week 2 was -10.7 (range, -77.0 to +52.0). Minoritized race (odds ratio [OR], 3.2; P < .001), lower baseline QOL (OR, 0.97; P < .001), and higher physical (OR, 1.02; P = .004) and posttraumatic stress disorder symptoms (OR, 1.04; P = .008) were associated with being a high PC responder. High PC responders reported greater use of approach-oriented coping at week 2 (Δ = 2.5; P = .002) and 3 months (Δ = 1.7; P = .04) and 6 months after HCT (Δ = 2.6; P = .003). Based on PC clinician surveys during HCT, high responders' PC visits focused on coping, illness/HCT education, and symptom education, whereas low responders' visits focused on symptom management. These findings provide insights into factors associated with early QOL response to PC in HCT and help identify those most likely to benefit in real-world practice. These trials were registered at www.ClinicalTrials.gov as #NCT02207322 and #NCT03641378. © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

The current study aimed to assess the effect of thyme honey on pain relief in patients with minor aphthous ulcers as a primary objective, its healing effect on ulcer size reduction, and the Oral Health Impact Profile (OHIP-14). In this randomized clinical trial, 30 patients (15 in each group) having minor aphthous ulcers at the oral diagnostic clinic at the British University in Egypt were treated with either thyme honey or triamcinolone acetonide in orabase. Different clinical parameters were recorded for both groups at various intervals, such as pain intensity using the Visual Analog Scale (VAS), size of ulcers in mm, and OHIP-14. Thyme honey intervention showed more significant ulcer size reduction than the triamcinolone acetonide group on days 5, and 7, and a more substantial decrease in pain intensity on days 3, 5, and 7. Additionally, the thyme honey group showed significantly lower OHIP values than the triamcinolone acetonide group after 7 days. The current clinical trial furnished evidence of the effectiveness of thyme honey in managing minor aphthous ulcers for the first time and revealed clinical efficiency with satisfactory patient outcomes. © 2024 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.

IMPORTANCE: Serious illness conversations (SICs) that elicit patients' values, goals, and care preferences reduce anxiety and depression and improve quality of life, but occur infrequently for patients with cancer. Behavioral economic implementation strategies (nudges) directed at clinicians and/or patients may increase SIC completion. OBJECTIVE: To test the independent and combined effects of clinician and patient nudges on SIC completion. DESIGN, SETTING, AND PARTICIPANTS: A 2 × 2 factorial, cluster randomized trial was conducted from September 7, 2021, to March 11, 2022, at oncology clinics across 4 hospitals and 6 community sites within a large academic health system in Pennsylvania and New Jersey among 163 medical and gynecologic oncology clinicians and 4450 patients with cancer at high risk of mortality (≥10% risk of 180-day mortality). INTERVENTIONS: Clinician clusters and patients were independently randomized to receive usual care vs nudges, resulting in 4 arms: (1) active control, operating for 2 years prior to trial start, consisting of clinician text message reminders to complete SICs for patients at high mortality risk; (2) clinician nudge only, consisting of active control plus weekly peer comparisons of clinician-level SIC completion rates; (3) patient nudge only, consisting of active control plus a preclinic electronic communication designed to prime patients for SICs; and (4) combined clinician and patient nudges. MAIN OUTCOMES AND MEASURES: The primary outcome was a documented SIC in the electronic health record within 6 months of a participant's first clinic visit after randomization. Analysis was performed on an intent-to-treat basis at the patient level. RESULTS: The study accrued 4450 patients (median age, 67 years [IQR, 59-75 years]; 2352 women [52.9%]) seen by 163 clinicians, randomized to active control (n = 1004), clinician nudge (n = 1179), patient nudge (n = 997), or combined nudges (n = 1270). Overall patient-level rates of 6-month SIC completion were 11.2% for the active control arm (112 of 1004), 11.5% for the clinician nudge arm (136 of 1179), 11.5% for the patient nudge arm (115 of 997), and 14.1% for the combined nudge arm (179

BACKGROUND: Patients with advanced cancer undergoing chemotherapy experience significant symptoms and declines in functional status, which are associated with poor outcomes. Remote monitoring of patient-reported outcomes (PROs; symptoms) and step counts (functional status) may proactively identify patients at risk of hospitalization or death. OBJECTIVE: The aim of this study is to evaluate the association of (1) longitudinal PROs with step counts and (2) PROs and step counts with hospitalization or death. METHODS: The PROStep randomized trial enrolled 108 patients with advanced gastrointestinal or lung cancers undergoing cytotoxic chemotherapy at a large academic cancer center. Patients were randomized to weekly text-based monitoring of 8 PROs plus continuous step count monitoring via Fitbit (Google) versus usual care. This preplanned secondary analysis included 57 of 75 patients randomized to the intervention who had PRO and step count data. We analyzed the associations between PROs and mean daily step counts and the associations of PROs and step counts with the composite outcome of hospitalization or death using bootstrapped generalized linear models to account for longitudinal data. RESULTS: Among 57 patients, the mean age was 57 (SD 10.9) years, 24 (42%) were female, 43 (75%) had advanced gastrointestinal cancer, 14 (25%) had advanced lung cancer, and 25 (44%) were hospitalized or died during follow-up. A 1-point weekly increase (on a 32-point scale) in aggregate PRO score was associated with 247 fewer mean daily steps (95% CI -277 to -213; P<.001). PROs most strongly associated with step count decline were patient-reported activity (daily step change -892), nausea score (-677), and constipation score (524). A 1-point weekly increase in aggregate PRO score was associated with 20% greater odds of hospitalization or death (adjusted odds ratio [aOR] 1.2, 95% CI 1.1-1.4; P=.01). PROs most strongly associated with hospitalization or death were pain (aOR 3.2, 95% CI 1.6-6.5; P<.001), decreased activity (aOR 3.2, 95% CI 1.4-7.1; P=.01), dyspnea (aOR 2.6, 95% CI 1.2-5.5; P=.02), and sadness (aOR 2.1, 95% CI 1.1-4.3; P=.03). A decrease in 1000 steps was associated wi

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant public health concern due to its resistance to multiple antibiotics, primarily mediated by the gene mecA, which encodes penicillin-binding protein 2a (PBP2a), considering the growing global demand for novel antimicrobial strategies. MATERIALS AND METHODS: A clinical MRSA strain harboring the gene mecA was identified. Antimicrobial susceptibility testing was performed to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Shirazi thyme (Zataria multiflora) essential oil. The strain's susceptibility to multiple antibiotics was assessed and the synergistic effect of Z. multiflora essential oil and cefoxitin was also evaluated. Gas chromatography-mass spectrometry (GC-MS) was employed to identify the bioactive compounds in the essential oil. Molecular docking studies were performed to evaluate the competitive binding affinity of those compounds to PBP2x. RESULTS: The MRSA strain exhibited resistance to all tested antibiotics except linezolid. The MIC and MBC values for Z. multiflora essential oil were 3.125 mg.mL- 1 and 6.25 mg.mL- 1, respectively, for the reference S. aureus strain (ATCC 25923), and 6.25 mg.mL- 1 for both MIC and MBC for the clinical MRSA strain. The synergy assay demonstrated an enhanced inhibition zone for cefoxitin in combination with Z. multiflora essential oil, indicating a synergistic interaction. Molecular docking studies revealed strong binding interactions between spathulenol, isospathulenol, and aromadendrene comparable to clinically used β-lactam antibiotics. CONCLUSION: The findings highlight the significant antibacterial activity of Z. multiflora essential oil against MRSA and its potential to enhance the efficacy of cefoxitin through synergistic interactions among the inhibitors of natural origin for PBP2x. © 2026. The Author(s), under exclusive licence to Springer Nature B.V.

While researchers continue to search for new antibacterial agents, combination therapy as well as nanotechnology-based treatments allure as promising approaches to tackle antibiotic resistance. The present study aimed to phytosynthesize magnesium oxide NPs (MgO NPs and evaluate their potential antibacterial synergistic behaviour with different essential oils (EOs). MgO NPs phytosynthesized using thyme aqueous extract were quasi-spherical with an average size of 55.2 ± 12.8 nm and an elemental composition of 35.39% Mg and 51.07% O, as determined by SEM-EDX. FTIR elicited characteristic functional group peaks, while XRD confirmed their cubic crystal structure. The phytosynthesized MgO NPs and four EOs displayed variable antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. The checkerboard assay revealed that only clove and thyme EOs showed synergistic effects in combination with MgO NPs. Notably, MgO NPs-clove EO combination caused significant bacterial membrane damage as compared to their single counterparts in both S. aureus and E. coli. Moreover, oxidative stress was induced, as observed by the significant increase in the antioxidant enzyme activities (superoxide dismutase and catalase). Conclusively, the present results provide insights into the promising compounding of green-synthesized MgO NPs and clove EO as a bio-efficacious and eco-friendly approach to curtail antibiotic resistance. © 2025. The Author(s). Antifungal Activity of Thymus vulgaris L. Essential Oil Against Candida Species Causing Otomycosis: Anti-Virulence Activity, Synergistic Potential, and Cell Wall Effect. Stojanović-Radić Z(1), Stojković O(1), Radulović N(2), Dimitrijević M(2), Ranđelović M(3)(4), Otašević S(3)(4). Author information: (1)Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Niš, Serbia. (2)Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Niš, Serbia. (3)Medical Faculty, University of Niš, Niš, Serbia. (4)Public Health Institute Niš, Niš, Serbia. Otomycosis is a fungal infection of the external auditory canal, predominantly caused

15. Chem Biodivers. 2025 Dec;22(12):e01145. doi: 10.1002/cbdv.202501145. Epub 2025 Sep 5. Antifungal Activity of Thymus vulgaris L. Essential Oil Against Candida Species Causing Otomycosis: Anti-Virulence Activity, Synergistic Potential, and Cell Wall Effect. Stojanović-Radić Z(1), Stojković O(

Bacterial diseases are a global problem that threatens human health and cause many deaths each year. The alarming rise in bacterial resistance to modern antimicrobials is particularly concerning. In practice, this necessitates increasing the dosage of antimicrobial agents, posing a potential risk of adverse effects on human health. Additionally, the development of antibiotic resistance is one of the main factors contributing to the ever-growing costs of the global healthcare system. For these reasons, natural and safe antimicrobial agents are increasingly sought after. In this study, the antibacterial activity of 31 different essential oils (EOs) was investigated against Escherichia coli and Staphylococcus aureus. The most effective EOs were further tested both individually and in dual combinations. Minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs) were determined to reveal synergistic effects, suggesting potential practical applications. The main bioactive compounds of the EOs with the highest inhibitory activity were identified and quantified using GC-MS/MS analysis. Of the tested EOs, seven demonstrated a strong antimicrobial effect against E. coli, most notably oregano (MIC 128 µg/mL) and the thyme/oregano combination (MIC 64 µg/mL, FIC 0.75), while thirteen were effective against S. aureus, most notably oregano and garlic (MIC 128 µg/mL),and the pelargonium/garlic combination (MIC 32 µg/mL, FIC 0.375). The pharmaceutical, agricultural, and food industries are promising fields for the application of these safe and natural antimicrobial agents, offering a new range of solutions to combat serious bacterial pathogens.

Dermatophyte infections globally account for 20 to 25% of fungal infections. Dermatophytes have begun exhibiting antifungal drug resistance, making it challenging to treat this particular infection. Essential oils could be used as alternative solutions as they have been used for a long period to treat different infections. The research has demonstrated the antifungal efficacy of cinnamon, clove, lemongrass, tea tree, thyme, and garlic essential oils, and the impact of their combinations was assayed against Microsporum canis, Trichophyton tonsurans, T. violaceum, T. verrucosum, and Epidermophyton floccosum. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) was used to identify the most prevalent M. canis. The accession number of M. canis was obtained as ON007275. All tested essential oils exhibited antidermatophytic action except garlic. A synergistic effect was attained by cinnamon + clove, cinnamon + lemongrass, clove + lemongrass, clove + tea tree, and thyme + tea tree combinations. Concerning antifungal activity, M. canis was the most susceptible dermatophytic species, except in the case of thyme T. violaceum, which was the most susceptible dermatophytic species. The maximum inhibition was recorded in the cases of cinnamon and cinnamon + lemongrass combination against M. canis. The least minimum inhibitory concentrations were attained by cinnamon and clove against M. canis, cinnamon + clove against M. canis and T. violaceum, and cinnamon + lemongrass against M. canis, T. violaceum, T. verrucosum, and E. floccosum. The least minimum fungicidal concentration showed by cinnamon against M. canis, cinnamon + clove against M. canis and T. violaceum, cinnamon + lemongrass against M. canis, T. violaceum, T. verrucosum, and E. floccosum, and clove + lemongrass against M. canis. © 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

OBJECTIVE: Trichomonas vaginalis is a sexually transmitted protozoan parasite that usually causes infections in women. Metronidazole is used as the first choice in the treatment of this parasitic disease, but there is a need for new drugs since 1980's with increasing numbers of reported resistance. In this study, it was aimed to determine the antitrichomonal activity of the major components of Cinnamomum zeylanicum (cinnamon) and Thymus vulgaris (thyme) essential oils, cinnamaldehyde, carvacrol and thymol against metronidazole resistant and susceptible T. vaginalis strains, and to determine their interaction with metronidazole by checkerboard method. METHODS: Cinnamaldehyde, carvacrol, thymol and metronidazole were obtained commercially. Two clinical isolates and one metronidazole resistant T. vaginalis reference strain were used in the study. MIC50 and MLC values of essential oil components and metronidazole were determined by broth microdilution method. The combinations of essential oil components with metronidazole were determined by the checkerboard method. RESULTS: According to in vitro activity tests, cinnamaldehyde was determined to be most effective essential oil component. Clinical isolates were susceptible to metronidazole. In combination study, metronidazole showed synergy with cinnamaldehyde and carvacrol, and partial synergy with thymol. CONCLUSION: It was determined that cinnamaldehyde, carvacrol and thymol, which are known to have high antimicrobial activity, also have strong activity against T. vaginalis isolates and show a synergistic interaction with metronidazole. The use of metronidazole at lower doses in the synergistic interaction may contribute to the literature in terms of reducing drug side effects, creating a versatile antimicrobial target, and reducing the rate of resistance development. Publisher: AMAÇ: Trichomonas vaginalis genellikle kadınlarda enfeksiyona neden olan ve cinsel yolla bulaşan bir protozoon parazittir. Parazitin neden olduğu hastalığın tedavisinde ilk tercih olarak metronidazol kullanılmaktadır. Ancak 1980 yılından sonra artan sayılarda direnç gelişiminin rapor edilmesi ile yeni ilaç arayışlarına ihtiyaç duyulmuştur.

Hypertension is a highly prevalent population-level disease that represents an important risk factor for several cardiovascular complications and occupies a leading position in mortality statistics. Antihypertensive therapy includes a wide variety of drugs. Additionally, the potential antihypertensive and cardioprotective effects of several phytotherapy products have been evaluated, as these could also be a valuable therapeutic option for the prevention, improvement or treatment of hypertension and its complications. The present review includes an evaluation of the cardioprotective and antihypertensive effects of garlic, Aloe vera, green tea, Ginkgo biloba, berberine, ginseng, Nigella sativa, Apium graveolens, thyme, cinnamon and ginger, and their possible interactions with antihypertensive drugs. A literature search was undertaken via the PubMed, Google Scholar, Embase and Cochrane databases. Research articles, systematic reviews and meta-analyses published between 2010 and 2023, in the English, Hungarian, and Romanian languages were selected.

BACKGROUND: P-glycoprotein (P-gp), is an ATP-dependent efflux transporter and overexpressed in cancer cells which is responsible for drug resistance and transportation of anticancer agents out of cells. Hence, P-gp inhibition is a promising way to reverse multi-drug resistance, finding a suitable inhibitor is essential. Carvacrol, an active compound of thyme, has been shown anticancer properties in several types of cancers but the mechanisms underlying this effect remain unclear. Here, we evaluated the inhibitory effects of carvacrol on P-gp by In-silco and in-vitro studies. METHOD: carvacrol was docked against P-gp via autodock vina software to identify the potential binding of this agent. Verapamil, a well-known P-gp inhibitor, was selected as the control ligands. Cell proliferation and apoptosis were assessed using MTT assay and ELISA cell death assay, respectively. RESULTS: It was observed that carvacrol exhibited appropriate affinity (-7 kcal/mol) to drug binding pocket of P-gp when compared with verapamil that showed binding affinities of -8 kcal/mol. The result of MTT assay showed a dose-dependent inhibitory effect of carvacrol and 5-FU. Data of apoptosis assay showed that combining carvacrol with 5-FU increased apoptotic effect of 5-FU 6.7-Fold rather than the control group. This ability to enhance apoptosis is more than the combination of verapamil and 5-FU (4.26-Fold). CONCLUSION: These results provide important evidence that carvacrol may be a promising agent able to overcome P-gp-mediated MDR. Thieme. All rights reserved.

This study reported the volatile profile, the antimicrobial activity and the synergistic potential of essential oil (EO) from the Moroccan endemic Thymus atlanticus (Ball) Roussine, in combination with the antibiotics ciprofloxacin and fluconazole for the first time, to the best of our knowledge. The EO chemical composition was determined by gas chromatography coupled to mass spectrometry (GC-MS) analysis and the antimicrobial activity assessed by the disc diffusion method against three Gram positive (Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus) and three Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli and one clinical isolate, Klebsiella pneumonia). The antifungal activity was evaluated in four pathogenic yeasts (Candida albicans, C. glabrata, C. krusei and C. parapsilosis). The minimum inhibition concentration (MIC) and the synergistic effect with ciprofloxacin and fluconazole were determined by the two-fold dilution technique and checkerboard test, respectively. Twenty-one constituents were identified by GC-MS in the EO, including carvacrol (21.62%) and borneol (21.13%) as the major components. The EO exhibited a significant antimicrobial activity with inhibition zones ranging from 0.7 mm to 22 mm for P. aeruginosa and B. subtilis, respectively, and MIC values varying from 0.56 mg/mL to 4.47 mg/mL. The fractional inhibitory concentration index (FICI) values ranged from 0.25 to 0.50 for bacteria and from 0.25 to 0.28 for yeasts. The maximum synergistic effect was observed for K. pneumonia with a 256-fold gain of antibiotic MIC. Our results have suggested that EO from T. atlanticus may be used alone or in association with antibiotics as a new potential alternative to prevent and control the emergence of resistant microbial strains both in the medical field and in the food industry.

The aim of this work was to evaluate the antifungal activity in vapor phase of thymol, p-cymene, and γ-terpinene, the red thyme essential oil compounds (RTOCs). The Minimum Inhibitory Concentration (MIC) of RTOCs was determined against postharvest spoilage fungi of the genera Botrytis, Penicillium, Alternaria, and Monilinia, by measuring the reduction of the fungal biomass after exposure for 72 h at 25 °C. Thymol showed the lowest MIC (7.0 µg/L), followed by γ-terpinene (28.4 µg/L) and p-cymene (40.0 µg/L). In the case of P. digitatum ITEM 9569, resistant to commercial RTO, a better evaluation of interactions among RTOCs was performed using the checkerboard assay and the calculation of the Fractional Inhibitory Concentration Index (FICI). During incubation, changes in the RTOCs concentration were measured by GC-MS analysis. A synergistic effect between thymol (0.013 ± 0.003 L/L) and γ-terpinene (0.990 ± 0.030 L/L) (FICI = 0.50) in binary combinations, and between p-cymene (0.700 ± 0.010 L/L) and γ-terpinene (0.290 ± 0.010 L/L) in presence of thymol (0.008 ± 0.001 L/L) (FICI = 0.19), in ternary combinations was found. The synergistic effect against the strain P. digitatum ITEM 9569 suggests that different combinations among RTOCs could be defined to control fungal strains causing different food spoilage phenomena.

OBJECTIVES: To elucidate the benefits, pitfalls and risks of phytotherapy in the clinical practice of otorhinolaryngology. MATERIAL AND METHODS: The PubMed and Cochrane databases were searched using the following keywords: phytotherapy, phytomedicine, herbs, otology, rhinology, laryngology, otitis, rhinitis, laryngitis and otorhinolaryngology. Seventy-two articles (18 prospective randomized studies, 4 Cochrane analyses, 4 meta-analysis and 15 reviews of the literature) devoted to clinical studies were analyzed. Articles devoted to in vitro or animal studies, biochemical analyses or case reports (including fewer than 10 patients) and articles dealing with honey, aromatherapy or minerals were excluded. RESULTS: Per os ginkgo biloba has no indications in tinnitus, presbycusis or anosmia following viral rhinitis. Traditional Asian medicine has no proven benefit in sudden deafness or laryngeal papillomatosis. Per os mistletoe extracts associated to conventional treatment for head and neck squamous cell carcinoma does not increase 5-year survival. Extracts of various herbs, notably echinacea, eucalyptus, petasites hybridus, pelargonium sidoides, rosemary, spirulina and thyme, show superiority over placebo for rhinosinusitis and allergic rhinitis, as does gingko biloba for selected vertigo. There have been encouraging preliminary results for intratumoral injection of mistletoe in head and neck carcinoma and acupoint herbal patching for allergic rhinitis. Herb intake should be screened for in case of certain unexplained symptoms such as epistaxis, headache or dizziness, or signs suggesting allergy. Phytotherapy should be interrupted ahead of surgery and/or chemotherapy. CONCLUSION: Scientific proof of the benefit of phytotherapy in otorhinolaryngology remains to be established but, given its widespread use and the reported data, knowledge of this form of treatment needs to be developed.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral mucosal condition affecting over 2.5 billion people worldwide. Although 0.1% triamcinolone acetonide is a standard treatment, its comparative efficacy remains uncertain. OBJECTIVE: To evaluate and compare systematically the efficacy of 0.1% triamcinolone acetonide with those of alternative therapies for RAS management. METHODS: A systematic review and meta-analysis were conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. From December 2024 to April 2025, PubMed and the Cochrane Central Register of Controlled Trials, Semantic Scholar, and ScienceDirect were searched for randomized controlled trials (RCTs) evaluating 0.1% triamcinolone acetonide in minor RAS treatment. Eligible studies reported the outcomes of pain reduction, ulcer size, or healing time. Risk of bias was assessed by using the Cochrane Risk of Bias Tool, and meta-analysis pooled estimates were calculated by employing a random effects model. RESULTS: Twenty-five RCTs involving 1474 participants were included. Thyme honey, sumac gel, and laser therapies were significantly more effective than 0.1% triamcinolone acetonide in reducing pain and ulcer size. CBD oil, hyaluronic acid, curcumin, amlexanox, and nanoformulated triamcinolone exhibited comparable efficacies as 0.1% triamcinolone acetonide. The outcomes under chamomile, acemannan, and doxycycline benzocaine gel treatments were less favorable than those under 0.1% triamcinolone acetonide treatment. Laser therapy, sumac gel, and Punica granatum extract significantly reduced healing time compared with 0.1% triamcinolone acetonide. The meta-analysis demonstrated that 0.1% triamcinolone acetonide was significantly more effective than thyme honey, Rhus coriaria gel, and nanobased triamcinolone in reducing ulcer size and shortened healing time compared with Salvizan and P. granatum gels. However, no significant effect was observed in pain reduction when 0.1% triamcinolone acetonide was compared with either other treatments or the placebo, and no significant difference in healing time was found when 0.1% triamcinolone aceton

OBJECTIVE: This systematic review and meta-analysis evaluated the efficacy of topical applications, compared to placebo or other treatments, for the management of xerostomia in older adults. The PICO focus question set for this study was, "What is the most effective topical therapy as opposed to systemic or other therapies for the treatment of xerostomia and salivary gland hypofunction, in elderly patients?" DATA AND SOURCES: Electronic searches of PubMed, CENTRAL, MEDLINE and Web of Science were conducted using the PICO framework. 7459 studies published until April of 2024 were screened. Prospective studies reporting on treatment of xerostomia and hyposalivation in elderly patients were selected. STUDY SELECTION: Nineteen studies [17 randomized controlled trials (RCTs) and 2 quasi-experimental studies] were included. Seven RCTs provided information for meta-analysis. Pilocarpine mouthwash/mucoadhesive tablets, 1 % malic acid, thyme-honey mouth rinse, significantly reduced xerostomia when compared against placebo (Z = 5.78; p < 0.001; I2 = 34.0 %; 4 studies) but there was no change in the stimulated (Z = 1.14; p = 0.25; I2 = 15.0 %; 3 studies) or unstimulated (Z = 1.46; p = 0.14; I2 = 91.0 %; 3 studies) salivary flow rates. Comparison of oxygenated glycerol triester (OGT) oral spray versus other over-the-counter products demonstrated no differences (Z = 0.32; p = 0.75; I2 = 68.0 %; 2 studies) in alleviating xerostomia. Quality assessment of the included studies revealed a moderate- to high- risk of bias. CONCLUSIONS: This systematic review concluded that the topical applications for the treatment of dry mouth provided symptomatic relief in older adults, however, their role in the improvement of salivary flow rates was inconclusive due to a lack of sufficient evidence. CLINICAL SIGNIFICANCE: Topical applications in elderly patients with dry mouth may offer effective symptom relief, particularly when systemic approaches are contraindicated. Although, these interventions may not significantly improve salivation, clinicians should consider them as part of a multimodal approach to improve patients' comfort and quality of life. PROSPERO REGISTRATION: CRD42024532652.

BACKGROUND: Wrestling is a popular combat sport that requires muscular strength, power, agility, and endurance. Weight classes have motivated wrestlers to compete at a lower weight to optimise power-to-weight ratio and performance. To achieve these characteristics, athletes may use dietary supplements, however, their efficacy in wrestlers has not been systematically evaluated. OBJECTIVE: The purpose was to systematically review the literature to determine the efficacy of dietary supplements to improve body composition, physiological status, and performance in wrestlers. METHODS: A systematic search was conducted in PubMed, ProQuest Medline, Web of Science, Cochrane Library, and Scopus on the 21st of January 2024 and updated on the 6th of January 2025. Studies were included if the participants were healthy wrestlers ingesting any type of dietary supplement in comparison to a control. Data associated with intervention type and characteristics, target populations, outcomes, and analysis methods were extracted. RESULTS: A total of 24 eligible original articles were included that assessed various supplementation strategies on body composition, exercise performance, and metabolic markers in wrestlers. Individual studies revealed significant effects of sodium citrate, creatine monohydrate, spirulina, green tea and oolong tea extracts, and branched-chain amino acids on body mass or composition. β-Hydroxy-β-methylbutyrate (HMB-FA), creatine monohydrate, and iron supplementation improved recovery and may improve exercise performance. Beet-root juice supplementation enhanced muscular strength and balance. BCAA supplementation produced mixed results on muscle damage biomarkers and performance, while sodium citrate, creatine, and spirulina can act as buffering agents. Thyme tea appears to improve antioxidant capacity. CONCLUSIONS: Overall, individual studies show some promise for several dietary supplements to alter body mass and body composition, improve exercise recovery and performance, delay fatigue, and modify serum biomarkers; nevertheless, effect sizes were often small, and results were often mixed. © 2025. The Author(s).

BACKGROUND: Zataria multiflora (Z. multiflora), also known as Shirazi thyme, is recognized for its medicinal properties, including antioxidant, anti-inflammatory, and immunomodulatory effects. Its longstanding use in traditional medicine for respiratory ailments underscores its significance. Given the widespread prevalence of respiratory disorders and inconclusive outcomes from previous trials, this research aims to conduct a systematic review and meta-analysis to evaluate Z. multiflora's impact on respiratory symptoms, pulmonary function, and oxidative stress markers using available randomized controlled trials (RCTs). METHODS: In this systematic review and meta-analysis, a comprehensive search of published literature was conducted up to January 2024, encompassing databases such as PubMed, Scopus, Web of Science, and the Cochrane Central for Randomized Clinical Trials. The assessment of the quality of each eligible study was conducted using the Cochrane risk-of-bias tool. The random-effects model was used in the meta-analysis to determine the weighted mean difference (WMD) with 95% confidence intervals (CIs). All statistical analyses were conducted using STATA (version 15). RESULTS: A total of 9 studies involving 394 participants were included. The administration of Z. multiflora showed significant effects on cough (WMD: -0.99; 95% CI: -1.66, -0.33; P = 0.003), day wheezing (WMD: -1.18; 95% CI: -1.44, -0.92; P < 0.001), night wheezing (WMD: -0.74; 95% CI: -1.09, -0.37; P < 0.001), chest wheezing (WMD: -1.15; 95% CI: -1.65, -0.64; P < 0.001), forced expiratory volume (WMD: 11.38; 95% CI: 7.40, 15.35; P < 0.001), forced vital capacity (WMD: 16.01; 95% CI: 12.26, 19.75; P < 0.001), and peak expiratory flow (WMD: 8.78; 95% CI: 4.13, 13.43; P < 0.001) compared to the control group. Additionally, Z. multiflora significantly reduced malondialdehyde levels (SMD: -1.54; 95% CI: -2.17, -0.90; P < 0.001) and increased catalase levels (SMD: 0.97; 95% CI: 0.46, 1.46; P < 0.001). CONCLUSION: Z. multiflora shows potential as a complementary treatment for respiratory diseases by improving symptoms, pulmonary functions, and reducing oxidative stress. However, due to the limited

Oral mucositis (OM) is a frequent complication in cancer patients who are undergoing chemotherapy or radiotherapy. It manifests as an inflammation of the oral mucosa, sometimes provoking severe consequences such as eating limitations, difficulty in speaking, and possibly superinfection. AIM: The aim of this review was to update the evidence published during the last five years on the treatment of oral mucositis induced by radiotherapy and/or chemotherapy in patients with cancer. MATERIALS AND METHOD: A search was conducted in Pubmed, Scielo and Scopus, using the search terms mucositis, stomatitis, therapy, treatment, oral cancer, oral squamous cell carcinoma, head and neck cancer and head and neck carcinoma, with Mesh terms and free terms, from 2017 to January 2023. The systematic review was conducted in accordance with the PRISMA guidelines. RESULTS: A total 287 articles were retrieved, of which 86 were selected by title and abstract, and 18 were included after full-text analysis. The most frequently assessed variables were OM severity, pain intensity and healing time. Treatment types were diverse, and included drugs, mouthwashes, medicines based on plant extracts, cryotherapy and low-intensity laser therapies. CONCLUSION: Dentoxol mouthwashes, Plantago major extract, thyme honey extract, zinc oxide paste, vitamin B complex combined with GeneTime, and the consumption of L-glutamine are effective in diminishing the severity of OM. Pain intensity was lower with doxepin mouthwashes and diphenhydramine-lidocaine-antacid mouthwashes. Publisher: La mucositis oral (MO) es una complicación frecuente en pacientes oncológicos sometidos a quimioterapia o radioterapia. Se manifiesta como una inflamación de la mucosa oral, provocando en ocasiones graves consecuencias como limitaciones en la alimentación, dificultad para hablar y posiblemente sobreinfección. Objetivo: El objetivo de esta revisión fue actualizar la evidencia publicada durante los últimos cinco años sobre el tratamiento de la mucositis oral inducida por radioterapia y/o quimioterapia, en pacientes con cáncer. Materiales y Método: Se realizó una búsqueda en Pubmed, Scielo y Scopus, con las palabras de búsqueda

Radiation-induced oral mucositis (RIOM) is one of the common toxic reactions from ionizing radiation and normal tissue injuries as a complication of radiation therapy and chemotherapy. Radiation therapy is an option for the treatment of head and neck cancer (HNC). The use of natural products is an alternative therapy for RIOM. This review aimed to describe the effectiveness of natural-based products (NBPs) in reducing the severity, pain score, incidence, oral lesion size, and other symptoms such as dysphagia, dysarthria, and odynophagia. This systematic review follows the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Pubmed, ScienceDirect, and Ebscohost-CINAHL Plus databases were used for article searches. The inclusion criteria were studies published from 2012 to 2022 with full text available, in English, a study in humans, and a Randomized Clinical Trial (RCT) that evaluate the effect of NBPs therapy in RIOM patients diagnosed with HNC. This study's population was HNC patients who had oral mucositis after receiving radiation or chemical therapy. The NBPs were manuka honey, thyme honey, aloe vera, calendula, zataria multiflora, Plantago major L., and turmeric. Eight of the twelve included articles showed significant effectiveness against RIOM in various parameters, such as a decrease in severity, incidence rate, pain score, oral lesion size, and the other symptoms of oral mucositis such as dysphagia and burning mouth syndrome. This review concludes that NBPs therapy is effective for RIOM in HNC patients.

OBJECTIVE: To synthesize the best available evidence on the effectiveness of nursing interventions in radiotherapy patient care and to summarize the evidence on the experience and acceptability of interventions reported by health professionals involved in the prevention and treatment of side effects. METHOD: A mixed-method systematic review. Quantitative and qualitative studies are presented. RESULTS: Twelve studies published between 2013 and 2017 were included. Most interventions found focused on skin care, oral care, nausea and vomiting and nursing consultation. In accordance with high level of evidence and recommendation grade of the studies, the use of Calendula officinalis and thyme honey were considered effective for preventing and treating radiodermatitis and mucositis, respectively. CONCLUSION: The quality of evidence of nursing interventions is weak. Although there are studies with a strong design and a high level of evidence, publication of nursing interventions is not enough and does not present a high quality to support practice to plan an effective patient-centered care.