Effect of empagliflozin in peripheral diabetic neuropathy of patients with type 2 diabetes mellitus.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most dominant cause of neuropathy worldwide, and there has been no specific treatment until now. The aim of the current study was to assess the probable protective effect of empagliflozin in type 2 diabetics who are suffering from DPN. METHODS: Fifty eligible type 2 diabetes mellitus (T2DM) cases with diabetic peripheral neuropathy were recruited in this study and classified into 2 groups. Group I (n=25) (control group) received placebo tablets once daily. Group II (n=25) (empagliflozin group) received empagliflozin 25mg once daily for three months. Empagliflozin efficacy was evaluated using electrophysiological studies, and HbA1c levels, the brief pain inventory short-form item (BPI-SF) score, the diabetic neuropathy symptom (DNS) score, the atherosclerotic cardiovascular disease (ASCVD) risk score, and the serum levels of neuron-specific enolase (NSE), malondialdehyde (MDA) and calprotectin (Calpro), lipid profile, and random blood glucose level (RBG). RESULTS: After three months, comparing the results of the empagliflozin arm to the control arm showed a significant improvement in the electrophysiological studies and a significant decrease in the BPI-SF score and the mean serum levels of NSE and MDA. However, no significant difference was determined in HbA1c, Calpro, lipid profile, and RBG levels. In addition, the DNS and ASCVD risk scores were not significantly different. The NSE and MDA levels were significantly negatively correlated with the electrophysiological parameters. However, the BPI-SF score showed a non-significant difference. CONCLUSIONS: Empagliflozin may be a promising neuroprotective and therapeutic agent for diabetic peripheral neuropathy. Trial registration Identifier: NCT05977465.

Efficacy and safety of once-weekly insulin icodec compared to once-daily insulin g U-100 in patients with type II diabetes: a systematic review and meta-analysis.

BACKGROUND//OBJECTIVE: Diabetes affects millions of people globally, despite treatment options, adherence and other factors pose obstacles. Once-weekly Insulin Icodec, a novel basal Insulin analog with a week-long half-life, offers potential benefits, enhancing convenience, adherence, and quality of life for improved glycemic control. This systematic review and meta-analysis aimed to assess the efficacy and safety of once-weekly Insulin Icodec compared to once-daily Insulin Glargine U-100 in individuals with type II diabetes (T2D). METHODS: A comprehensive literature search was conducted using PubMed, and Cochrane Library databases before September 2023 to identify relevant Randomized control trials (RCTs) with no language restrictions following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. All statistical analyses were conducted using RevMan (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). RESULT: Four RCTs published from 2020 to 2023 with a cumulative sample size of 1035 were included. The pooled mean difference (MD) revealed a 4.68% longer TIR (%) with Insulin Icodec compared to Insulin Glargine U-100 [{95% CI (0.69, 8.68), p = 0.02}], the estimated mean changes in HbA1c (%) and FPG (mg%) were found to be insignificant between the two groups [MD = - 0.12 {95% CI (- 0.26, 0.01), p = 0.07}] and [MD = - 2.59 {95% CI (- 6.95, 1.78), p = 0.25}], respectively. The overall OR for hypoglycemia was also nonsignificant between the two regimens 1.04 [{95% CI (0.71, 1.52), p = 0.84}]. Other safety parameters were similar between the two groups. CONCLUSIONS: Switching from daily Insulin Glargine U-100 to weekly Insulin Icodec showed longer TIR (%) as well as similar blood glycemic control and safety profile. Hence, it may be a good alternate option for management of longstanding T2D.

Association between rheumatoid arthritis and atrial fibrillation: A systematic review and meta-analysis.

Rheumatoid arthritis (RA) is an autoimmune disorder with a varying range of organs involved leading to adverse outcomes. However, very little is known, with conflicting results about the association between RA and atrial fibrillation (AF). We aim to evaluate the association between RA and AF, and other clinical outcomes. We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until September 10, 2023. Primary clinical outcomes were AF. Secondary outcomes were acute coronary syndrome (ACS), stroke, and all-cause mortality (ACM). A total of 4 679 930 patients were included in the analysis, with 81 677 patients in the RA group and 4 493 993 patients in the nonrheumatoid arthritis (NRA) group. The mean age of the patients was 57.2 years. Pooled analysis of primary outcomes shows that RA groups of patients had a significantly higher risk of AF (odds ratios [OR], 1.53; 95% confidence interval [CI]: [1.16-2.03], p < .001) compared with NRA groups. Secondary Outcomes show that the RA group of patients had significantly higher odds of ACS (OR, 1.39; 95% CI: [1.26-1.52], p < .001), and ACM (OR, 1.19; 95% CI: [1.03-1.37], p = .02) compared with the NRA groups. However, the likelihood of stroke (OR, 1.02; 95% CI: [0.94-1.11], p = .61) was comparable between both groups of patients. Our study shows that RA groups of patients are at increased risk of having AF, ACS, and ACM.

Development of chitosan lipid nanoparticles to alleviate the pharmacological activity of piperine in the management of cognitive deficit in diabetic rats.

The aim of the present study was to prepare and evaluate Piperine (PP) loaded chitosan lipid nanoparticles (PP-CLNPs) to evaluate its biological activity alone or in combination with the antidiabetic drug Metformin (MET) in the management of cognitive deficit in diabetic rats. Piperine was successfully loaded on CLNPs prepared using chitosan, stearic acid, Tween 80 and Tripolyphosphate (TPP) at different concentrations. The developed CLNPs exhibited high entrapment efficiency that ranged from 85.12 to 97.41%, a particle size in the range of 59.56-414 nm and a negatively charged zeta potential values (- 20.1 to - 43.9 mV). In vitro release study revealed enhanced PP release from CLNPs compared to that from free PP suspensions for up to 24 h. In vivo studies revealed that treatment with the optimized PP-CLNPs formulation (F2) exerted a cognitive enhancing effect and ameliorated the oxidative stress associated with diabetes. PP-CLNPs acted as an effective bio-enhancer which increased the potency of metformin in protecting brain tissue from diabetes-induced neuroinflammation and memory deterioration. These results suggested that CLNPs could be a promising drug delivery system for encapsulating PP and thus can be used as an adjuvant therapy in the management of high-risk diabetic cognitive impairment conditions.

The effect of HIV and mpox co-infection on clinical outcomes: Systematic review and meta-analysis.

INTRODUCTION: Co-infection with HIV and mpox is a significant issue for public health because of the potential combined impact on clinical outcomes. However, the existing literature lacks a comprehensive synthesis of the available evidence. The purpose of this meta-analysis is to provide insight into the impact of HIV and mpox co-infection on clinical outcomes. METHODS: We systematically searched major electronic databases (PubMed, Embase, Cochrane Central, and Web of Science) for pertinent studies published up to June 2023. Included were studies that described the clinical outcomes of people who had both mpox and HIV. We performed the analysis using OpenMeta and STATA 17 software. RESULTS: With an overall number of participants of 35 207, 21 studies that met the inclusion criteria were considered. The greatest number of the studies (n = 10) were cohort designs, with three being cross-sectional and eight being case series studies. The meta-analysis found that people who had both HIV and mpox had a higher hospitalization rate than those who only had mpox (odds ratio [OR] 1.848; 95% confidence interval [CI] 0.918-3.719, p = 0.085, I2 = 60.19%, p = 0.020). Furthermore, co-infected patients had higher mortality rates than those who did not have HIV co-infection (OR 3.887; 95% CI 2.272-6.650, p < 0.001). Meta-regression analysis showed that CD4 levels can significantly predict the risk of hospitalization (p = 0.016) and death (p = 0.031). DISCUSSION: HIV causes immunosuppression, making it difficult for the body to mount an effective immune response against pathogens such as mpox. Individuals who are co-infected are at a higher risk of severe disease and death, according to our findings. Although hospitalization rates did not differ significantly between the two groups, it is critical to prioritize interventions and improve management strategies tailored specifically for people living with HIV. CONCLUSION: This meta-analysis provides substantial evidence that HIV and mpox co-infection has a negative impact on clinical outcomes. Co-infected individuals had higher hospitalization and significantly higher mortality rates. These findings highlight the significance of early diagnosis, prompt treatment initiation, and effective management strategies for people living with HIV and mpox.

Clinical and microbiological efficacy of intra-pocket application of diode laser in grade C periodontitis: a randomized controlled clinical trial.

BACKGROUND: Periodontitis is a microbially induced disease destroying structures anchoring teeth to jaw bones. Although metronidazole in combination with spiramycin is the effective conventional treatment of stage III grade C periodontitis, it has several systemic side effects. Laser therapy is widely used nowadays as an adjunct to scaling and root planing (SRP) to modulate inflammatory host response and eradicate microbes, due to bactericidal and detoxifying effects. Since microbiological analysis is one of the diagnostic methods identifying periodontal risk; our research aimed to investigate the efficacy of intra-pocket application of diode laser (980 nm) versus antibiotic therapy in enhancing clinical and microbiological parameters in stage III grade C periodontitis. METHODS: A randomized controlled clinical trial was conducted on fifty patients with stage III grade C periodontitis, divided equally into two groups. We managed test group by SRP with intra-pocket application of diode laser (980 nm) and the control group by SRP with systemic antibiotic administration (spiramycin and metronidazole). Then, we measured periodontal pocket depth (PPD) and clinical attachment loss (CAL) for both groups, before treatment (baseline), four and twelve weeks after. Moreover, we collected gingival crevicular fluid from both groups at baseline, four and twelve weeks after treatment and analyzed by real-time polymerase chain reaction to detect the relative count of Aggregatibacter actinomycetemcomitans and Porhyromonas gingivalis. RESULTS: Compared to baseline, all assessed clinical and microbiological parameters attested improvement at the end of the study period in each group individually with no significant difference between the two studied groups. Although, at twelve weeks, flare up of bacterial levels was detected with systemic antibiotic administration. CONCLUSION: Laser therapy can be considered as an effective treatment modality in stage III grade C periodontitis, avoiding the systemic antibiotic side effects and solving the recurrence problems due to bacterial resistance by long term usage. TRIAL REGISTRATION: NCT05222737 retrospectively on 03/02/2022, Clinicaltrial.gov.

Impact of Chlorella vulgaris, Nannochloropsis salina, and Arthrospira platensis as bio-stimulants on common bean plant growth, yield and antioxidant capacity.

The use of bio-stimulants in agriculture has emerged as a promising strategy to improve crop growth and yield. One type of bio-stimulant that has gained attention is microalgae extracts, which are known for their high metabolic activity, bioactive compounds, and ability to enhance plant growth and development. To investigate their effectiveness, a pot experiment was conducted at the Experimental Farm of Helwan University in Egypt during the 2022 season. The experiment aimed to evaluate the efficacy of Chlorella vulgaris, Nannochloropsis salina, and Arthrospira platensis (Spirulina platensis) extracts as bio-stimulants, applied through foliar spray at concentrations ranging from 0.25 to 2.0%, on common bean plants. Analysis of algal extract showed that . N. salina had the highest content of promotive growth hormones gibberellins (GA3) (74.85 ± 2.7mg100 g-1 d.wt). and auxins (IAA) (34.57 ± 2.7µg 100 g-1 d.wt.) compared to Chlorella and Arthrospira..The results revealed that the application of C. vulgaris, N. salina, and A. platensis extracts at concentrations up to 1.0% significantly improved various growth parameters, such as root, and shoot length, number of leaves and flowers per plant, leaf area, and total fresh and dry weight per plant. These extracts also positively affected yield attributes, including the number and fresh weight of pods per plant, seed index, seed yield per plant, and per feddan [a unit of land area]. Furthermore, the application of these extracts increased the chlorophyll content index with the maximum values of CCI (17.95. and 17.81%) was obtained at 0.50% N. salina, followed by 0.50% C.vulgaris. In addition to increase in the capacity of both non-enzymatic antioxidants [such as total antioxidant capacity, phenolics, and flavonoids] and enzymatic antioxidants [including catalase and ascorbic oxidase]. The most promising results were observed with the application of N. salina, and C. vulgaris extracts at a concentration of 0.5%. Additionally, the extracts significantly reduced the content of oxidative stress markers, such as malondialdehyde, percentage of electrolyte leakage, and hydrogen peroxide, in common bean plants compared to the control group. Contrarily, the measured parameters were reduced, while the levels of oxidative stress markers and some antioxidants including peroxidase, ascorbic peroxidase, superoxide dismutase, glutathione peroxidase, and glutathione transferase were increased by three algal extracts at a concentration of 2.0%, compared to control plants. Additionally, the application of these microalgae extracts improved the quality parameters, proximate composition, seed energy, and mineral contents of the harvested seeds, with the most significant positive impact was observed at 0.5% concentration of algal extract. These findings demonstrate the successful and safe utilization of extracts from C. vulgaris, N. salina, and A. platensis at concentrations up to 1.0% as bio-stimulants to enhance common bean yields and improve the nutritional quality of dried beans for consumers.

The diagnostic utility of heparin-binding protein among patients with bacterial infections: a systematic review and meta-analysis.

BACKGROUND: Bacterial infections are considered a leading cause of hospitalization and death globally. There is still a need for a rapid and feasible biomarker for bacterial infections. Heparin-binding protein (HBP) was shown to be related to bacterial infections. The objective of the study is to investigate the diagnostic accuracy of HBP in bacterial infections. METHODS: Articles were screened in PubMed, SCOPUS, Web of Science, and Cochrane to recognize eligible studies. We included studies investigating the diagnostic accuracy of HBP and reported the necessary data to construct 2 × 2 tables. A univariate analysis was conducted to determine the pooled sensitivity and specificity, and a bivariate diagnostic random-effects model was used to calculate the optimal cut-off point. RESULTS: The analysis comprised sixteen studies in total. Plasma HBP showed a sensitivity of 0.90 (95% CI: [0.79, 0.96]) and a specificity of 0.87 (95% CI: [0.66, 0.96]) in diagnosing bacterial infections using blood samples. Pooling data from seven studies revealed that HBP in cerebrospinal fluid (CSF) has sensitivity and specificity of 96% (95% CI: [0.85, 0.99]), and 95% (95% CI: [0.89, 0.97]), respectively, for the diagnosis of bacterial meningitis. In urinary tract infections (UTI), urine-HBP was revealed to have a high diagnostic value in discriminating bacterial from non-bacterial UTI infection at a cut-off value of 32.868 ng/ml with sensitivity and specificity of 87%. CONCLUSION: HBP has shown a high diagnostic accuracy of bacterial infections, including UTI and meningitis. Further studies are needed to determine its prognostic value and whether it could guide antibiotic therapy.

Role of cytokines and Th17/Tregs imbalance in the pathogenesis of otitis media with effusion. Modulation of Notch1/Hes1/mTORC1/S6k1 signalling pathway underlies the protective effect of astaxanthin.

Otitis media with effusion (OME) is a recurrent middle ear inflammatory condition. It may be complicated by acquired hearing loss and speech impairment especially in children. Accordingly, the current study aimed to assess the role of cytokines and the imbalance of Th17/Tregs in the pathogenesis of OME. Additionally, the protective effect of astaxanthin and its mechanisms related to Notch1/ Hes1/mTORC1/S6K1 signalling were investigated. METHODS: Forty-eight children were grouped as follow: G1: control healthy group G2: acute otitis media (AOM) group, G3: OME group. In the lipopolysaccharide (LPS) induced OME rat model, 15 rats were randomised into: G1: normal control group, G2: LPS group, and G3: astaxanthin treated group. RESULTS: Biochemical analysis of the children's peripheral blood samples showed that IL1ß, IL-2, IL-4, IL-6, IL-17, and IL-23 were significantly elevated, while TGF-ß was significantly decreased in AOM and OME patients (group 2 and 3). In the LPS- induced OME rat model, astaxanthin treatment resulted in suppression of IL-17, IL-6, TNF-α, Muc5A, TFF3, NICD, Hes1, mTORC1, and S6K1 in rat middle ear mucosa. Furthermore, astaxanthin significantly downregulated RORγ while upregulating FoxP3 and restored the balance between Th17/Tregs. Moreover, astaxanthin improved the histopathological picture of the inflamed middle ear mucosa. CONCLUSIONS: Proinflammatory cytokines as well as Th17/Tregs imbalance play a crucial role in the pathogenesis of AOM and OME. Additionally, astaxanthin alleviated LPS- induced OME in rats through suppression of Notch1/ Hes1/mTORC1/S6K1 pathway, and regulation of Th17/Tregs.

Melatonin enhances captopril mediated cardioprotective effects and improves mitochondrial dynamics in male Wistar rats with chronic heart failure.

Mitochondrial dysfunction is a recent emerging research scope that proved to be involved in many cardiovascular diseases culminating in chronic heart failure (CHF), which remains one of the primary causes of morbidity and mortality. This study investigated the added cardio-protective effects of exogenous melatonin administration to conventional captopril therapy in isoproterenol (ISO) exposed rats with CHF. Five groups of Wistar rats were recruited; (I): Control group, (II): (ISO group), (III): (ISO + captopril group), (IV): (ISO + melatonin group) and (V): (ISO + melatonin/captopril group). Cardiac function parameters and some oxidant, inflammatory and fibrotic markers were investigated. Moreover; mRNA expression of mitochondrial mitophagy [parkin & PTEN induced kinase 1 (PINK1)], biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)], fusion [mitofusin 2 (Mfn2)] and fission [dynamin-related protein 1 (DRP-1)] parameters in rat's myocardium were evaluated. Rats' myocardium was histo-pathologically and immunohistochemically evaluated for Beclin1 and Sirt3 expression. The present study revealed that captopril and melatonin ameliorated cardiac injury, oxidative stress biomarkers, and pro-inflammatory cytokines in ISO-exposed rats. These protective effects could be attributed to mitochondrial dynamic proteins control (i.e. enhanced the mRNA expression of parkin, PINK1, PGC-1α and Mfn2, while reduced DRP-1 mRNA expression). Also, Beclin1 and Sirt3 cardiac immunoreactivity were improved. Combined captopril and melatonin therapy showed a better response than either agent alone. Melatonin enhanced myocardial mitochondrial dynamics and Sirt3 expression in CHF rats and may represent a promising upcoming therapy added to conventional heart failure treatment.

Virtual and augmented reality in cardiovascular care in low and middle income country.

The global health sector has witnessed an escalating integration of Virtual Reality (VR) and Augmented Reality (AR) technologies, particularly in high-income countries. The application of these cutting-edge technologies is gradually extending to Low- and Middle-Income Countries (LMICs), notably in the domain of cardiovascular care. AR and VR technologies are revolutionizing cardiovascular care by offering solutions for diagnosis, medical training, and surgical planning. AR and VR provide detailed and immersive visualizations of cardiac structures, aiding in diagnosis and intervention planning. In cardiovascular care, VR reduces patient-reported pain, eases anxiety, and accelerates post-procedural recovery. AR and VR are also valuable for life support training, creating immersive and controlled learning environments. AR and VR have the potential to significantly impact healthcare in low- and middle-income countries with enhanced accessibility and affordability. This review outlines the existing spectrum of VR and AR adoption and its burgeoning utility in the cardiovascular domain within LMICs.

Implantable cardioverter defibrillators for primary prevention in patients with ischemic and non-ischemic cardiomyopathy: A meta-analysis.

BACKGROUND: Ischemic and nonischemic cardiomyopathy (NICM) are one of the leading causes of sudden cardiac death (SCD). Evidence supporting Implantable Cardioverter Defibrillator (ICD) for the prevention of SCD and mortality has shown conflicting results to date. OBJECTIVE: We aim to evaluate the impact of ICD therapy with conventional care for the primary prevention of death of various causes in adults with ICM and NICM. METHODS: We performed a systematic literature search on the electronic database for relevant articles from inception until 30th May 2023. Pooled odds ratios (OR) were calculated using a random effect model, and a p-value of <0.05 was considered statistically significant. RESULTS: A total of 13 randomized controlled trials involving 7857 patients were included in the study. Pooled analysis showed that ICD therapy was associated with a significant reduction in the incidence of all-cause mortality (OR, 0.69 (95%CI:0.55-0.87), P = 0.001), with a similar trend among ICM and NICM compared with the control group. ICD therapy also reduces the incidence of SCD (OR, 0.32(95%CI: 0.24-0.43), P<0.00001) with a similar trend in ICM and NICM, as well as death due to arrhythmia (OR, 0.35(95%CI: 0.19-0.64), P<0.001). However, the incidence of cardiovascular mortality in the ICD group (OR, 0.77(95%CI: 0.58-1.02), P=0.07) was comparable to the control group. CONCLUSION: ICD therapy was associated with a reduction in the incidence of all-cause mortality, sudden cardiac death, and death due to arrhythmia among ischemic and nonischemic cardiomyopathy patients.

Neuro-oncological research output in Africa: a scoping review of primary brain tumors.

BACKGROUND: There is evidence that individuals of African ancestry, particularly those residing in Africa, suffer from an unfortunate amount of under-representation in cancer research worldwide. AIM: We aimed to analyze current research output and potentially predict future trends in neuro-oncological research in Africa. Investigating deficits in the field will assist in identifying top-performing countries, which ones face challenges, and how to solve them. Therefore, targeted interventions can be applied to overcome these challenges. METHODS: We conducted a systematic computer-based search on the following databases (PubMed, Scopus, Web of Science, and Embase) for research articles related to the neuro-oncological field in Africa. We aimed to retrieve any article published in the period between 1 January 2000 and 10 January 2023. RESULTS: We included 200 eligible articles in our study. The output of neuro-oncological research has been increasing over the past two decades, peaking in 2019. Among the included articles, clinical practice issues constituted the majority (80%), while public health-related topics accounted for 20% of the publications. Regarding the type of neurological tumor, neuroblastoma was the most common, with 26 articles (13%), meningioma with 21 (10.5%), and glioma with 16 articles (8%). CONCLUSION: The interest in African neuro-oncological research is increasing. Hence, there is a need for ongoing efforts to address issues with clinical practice and public health related to neurological tumors in the continent. Future studies should concentrate on filling in knowledge gaps and investigating novel methods for neuro-oncological conditions that affect African populations in terms of prevention, diagnosis, treatment, and management strategies.

Ischemic heart disease in Africa: An overnight epidemiological transition.

Ischemic heart disease (IHD) falls among the leading causes of death, representing a major burden, ranking first in all regions of the world and eighth in Africa as a leading killer. Recent evidence suggests that Africa is having an epidemiological transition with higher rates of non-communicable diseases (NCDs). IHD contributed to 361 thousand deaths in the African region in 2005, and this number is expected to be more than double by 2030. IHD currently ranks as the leading cause of death for men and the second leading cause of death for women in the African region in patients older than 60 years. There are multiple risk factors related to lifestyle associated with IHD. Thus, strict measures are the key in terms of health promotion and disease prevention. Hurdles impeding the prevention and control of IHD in Africa include poor health care services, low income, and rising costs of cardiac interventions..

Attitudes towards Receiving Monkeypox Vaccination: A Systematic Review and Meta-Analysis.

BACKGROUND: The public's attitude towards Mpox vaccination is a critical factor in the success of immunisation programmes. Understanding the factors contributing to vaccine acceptance or hesitancy is critical for developing effective health communication strategies. This systematic review and meta-analysis aims to bring together evidence from observational studies on attitudes towards Mpox vaccination, including willingness and rejection. METHODS: From this review's inception until June 2023, a comprehensive search was conducted across four major electronic databases: PubMed, Web of Science, Scopus, and EBSCO. The inclusion criteria included studies investigating public attitudes towards Mpox vaccination, as defined by acceptance and willingness to be vaccinated versus rejection and unwillingness. RESULTS: Thirty studies met the inclusion criteria among the screened literature. An analysis of 27 studies involving 81,792 participants revealed that 45,926 (56.14%) were willing to receive the Mpox vaccination. In contrast, ten studies involving 7448 participants revealed that 2156 people (28.94%) were unwilling to receive the Mpox vaccination. Females were less willing to receive the vaccine than males, with an odds ratio (OR) of 0.61 (95% CI, 0.43-0.86). Furthermore, homosexuals were found to be more willing than heterosexuals, with an OR of 1.44 (95% CI, 1.14-1.80). CONCLUSION: Vaccination is emerging as a critical strategy for preventing Mpox infection and fostering herd immunity against potential outbreaks. Improving public awareness and acceptance of vaccination is critical to avoiding a situation similar to the COVID-19 pandemic. Targeted educational and outreach programmes could explain the benefits of vaccination, bridging the information gap and encouraging a proactive public health approach to emerging infectious diseases.