Occurrence Of Serious Adverse Effects Research Articles

Review of the Efficacy and Safety of Gadopiclenol: A Newly Emerging Gadolinium-Based Contrast Agent.

Gadolinium-based contrast agents (GBCAs) are one of the most commonly used agents in magnetic resonance imaging. Gadopiclenol is a new GBCA aimed at providing improved diagnostic efficacy with a favorable safety profile. The proposed advantages are due to its specific pharmacological properties, one of which is high relaxivity values. The aim of this review is to assess the efficacy, diagnostic accuracy, and safety of gadopiclenol in comparison to other currently used gadolinium-based contrast agents. PubMed and other database systems were used to identify relevant studies. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed, resulting in 10 articles that were included in the review. The outcomes were reviewed according to several factors regarding efficacy and accuracy in terms of qualitative and quantitative descriptors relative to properties of enhancement provided by the contrast agent. In terms of safety profile, a number of outcomes were assessed such as the occurrence of serious adverse effects, severe kidney injury, and organ-based contrast retention. Gadopiclenol was found to provide outcomes comparable to other commonly used GBCAs at lower doses with further favorable results at higher doses while maintaining an acceptable safety profile. However, it was found to have high rates of retention within the liver and can cause nonsignificant QT prolongation in healthy individuals, which arguably creates the need for further research regarding more long-term implications of these possible adverse effects.

Pharmacological interventions for prophylaxis of vestibular migraine.

Vestibular migraine is a form of migraine where one of the main features is recurrent attacks of vertigo. These episodes are often associated with other features of migraine, including headache and sensitivity to light or sound. These unpredictable and severe attacks of vertigo can lead to a considerable reduction in quality of life. The condition is estimated to affect just under 1% of the population, although many people remain undiagnosed. A number of pharmacological interventions have been used or proposed to be used as prophylaxis for this condition, to help reduce the frequency of the attacks. These are predominantly based on treatments that are in use for headache migraine, with the belief that the underlying pathophysiology of these conditions is similar. To assess the benefits and harms of pharmacological treatments used for prophylaxis of vestibular migraine. The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 September 2022. We included randomised controlled trials (RCTs) and quasi-RCTs in adults with definite or probable vestibular migraine comparing beta-blockers, calcium channel blockers, antiepileptics, antidepressants, diuretics, monoclonal antibodies against calcitonin gene-related peptide (or its receptor), botulinum toxin or hormonal modification with either placebo or no treatment. We excluded studies with a cross-over design, unless data from the first phase of the study could be identified. We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) improvement in headache, 6) improvement in other migrainous symptoms and 7) other adverse effects. We considered outcomes reported at three time points: < 3 months, 3 to < 6 months, > 6 to 12 months. We used GRADE to assess the certainty of evidence for each outcome. We included three studies with a total of 209 participants. One evaluated beta-blockers and the other two evaluated calcium channel blockers. We did not identify any evidence for the remaining interventions of interest. Beta-blockers versus placebo One study (including 130 participants, 61% female) evaluated the use of 95 mg metoprolol once daily for six months, compared to placebo. The proportion of people who reported improvement in vertigo was not assessed in this study. Some data were reported on the frequency of vertigo attacks at six months and the occurrence of serious adverse effects. However, this is a single, small study and for all outcomes the certainty of evidence was low or very low. We are unable to draw meaningful conclusions from the numerical results. Calcium channel blockers versus no treatment Two studies, which included a total of 79 participants (72% female), assessed the use of 10 mg flunarizine once daily for three months, compared to no intervention. All of the evidence for this comparison was of very low certainty. Most of our outcomes were only reported by a single study, therefore we were unable to conduct any meta-analysis. Some data were reported on improvement in vertigo and change in vertigo, but no information was available regarding serious adverse events. We are unable to draw meaningful conclusions from the numerical results, as these data come from single, small studies and the certainty of the evidence was very low. There is very limited evidence from placebo-controlled randomised trials regarding the efficacy and potential harms of pharmacological interventions for prophylaxis of vestibular migraine. We only identified evidence for two of our interventions of interest (beta-blockers and calcium channel blockers) and all evidence was of low or very low certainty. Further research is necessary to identify whether these treatments are effective at improving symptoms and whether there are any harms associated with their use.

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia-Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability.

Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. In a retrospective database review (1994-2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%-35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%-19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%-90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5-28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene ( RYR1 ) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3-30.9; P = .013). Dantrolene median dose was 50 (25-400) and 200 (25-400) mg·day -1 in responders and nonresponders, respectively. We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

Subcutaneous Testosterone Is Effective and Safe as Gender-Affirming Hormone Therapy in Transmasculine and Gender-Diverse Adolescents and Young Adults: A Single Center's 8-Year Experience.

Purpose: To describe our Center's 8-year experience with subcutaneous testosterone (SC-T) as gender-affirming hormone therapy (GAHT) in transmasculine and gender-diverse (TM/GD) youth.Methods: An Institutional Review Board (IRB)-approved retrospective study for 119 TM/GD subjects who started SC-T at age 13–19 and received SC-T for >6 months between 2012 and 2020.Results: SC-T was typically started at 25–50 mg biweekly and dose was escalated at provider's discretion. Over 96% of subjects were on 100–320 mg monthly (divided weekly or biweekly) at last follow-up. There was an overall increase in mean total and free testosterone (T) over the dose range (p=0.003), with mean total and free T levels of 460 ng/dL and 92 pg/mL, respectively, at a monthly SC-T dose of 200 mg. For subjects on SC-T without additional menstrual suppression, 54% had cessation of menses at 140 mg monthly and 97% at 200 mg monthly. On average, menses stopped 4.7 (standard deviation 3.0) months after starting SC-T. There was a decrease in high-density lipoprotein and increase in hematocrit from baseline to follow-up. Body mass index Z-scores did not change significantly with treatment. Mild acne was common; severe acne and significant injection site reactions were uncommon. Sustained hypertension, transaminitis, and dyslipidemia were infrequent.Conclusions: SC-T is well tolerated and effective in reaching recommended T levels and stopping menses in TM/GD youth. Occurrence of serious adverse effects is low and inability to tolerate injections is very uncommon. SC-T is a safe and effective alternative to intramuscular testosterone in initiation and maintenance of GAHT in TM/GD youth.

Disulfiram repurposing in the combined chemotherapy of Chagas disease

Abstract Background: Chagas disease (CD) has high morbimortality and the available trypanocidal treatment, including benznidazole (BZ), has limited efficacy in chronic patients. Furthermore, BZ causes adverse effects (AE) that prevent treatment completion in up to 30% of patients. The use of repositioned drugs or drug combination may provide an effective trypanocidal treatment. Disulfiram (DF) may enhance BZ activity and decrease BZ related AE. This study aims to assess the safety of a new combination of drugs for CD therapy, assuming BZ as the drug of choice plus DF as repositioned drug. Methods: This single-centre, open-label, phase I/II clinical trial was designed to evaluate the safety of the combined use of BZ plus DF for CD therapy. Participants are adults with indeterminate form of chronic CD, both sexes, aged from 18 to 70 years old and Trypanosoma cruzi polymerase chain reaction-positive. The primary outcome will be the occurrence of serious AE. The secondary outcome will be post-treatment Trypanosoma cruzi polymerase chain reaction negativization. Six groups of 9 patients will be sequentially tested. The first group will be allocated to receive BZ 100 mg/d + DF 250 mg/d for 60 days. Upon safety confirmation (&lt;1/3 of participants with serious AE), the combination dose will be gradually increased and dispensed to 5 groups (group II:BZ 200 mg/day+DF 250 mg/d; group III:BZ 300 mg/d + DF 250 mg/d; group IV:BZ 100 mg/d + DF 500 mg/d; group V:BZ 200 mg/d + DF 500 mg/d; group VI: BZ 300 mg/d + DF 500 mg/d) for 60 days in order to determine the maximum tolerated dose. Discussion: Our hypothesis is that the drug combination will be well tolerated and allow the proposal of phase II trials in larger scale to test the efficacy of the new drug combination in CD. We expect that the studied combination will have less AEs with an efficacy similar or superior to the current treatment. This will allow the successful treatment of a greater number of patients while decreasing the treatment cost as less patients will need treatment for AEs. Trial registration: This study was registered on the Brazilian Clinical Trials Database - REBEC (RBR-5n4htp). Registered 7 January 2020. UTN Number: U1111-1246-1293. http://www.ensaiosclinicos.gov.br/rg/RBR-5n4htp/

Comparison of the Effect of Classical Ketogenic Diet and Modified Atkins Diet on Lipid Profile in Patients with Intractable Epilepsy

Abstract Objectives This study aimed to shed light on the differences between the effect of classical ketogenic diet (KD) and modified Atkins diet (MAD) on lipid profile in children and adolescents with intractable epilepsy. Methods The study was a non-randomized controlled clinical trial, conducted in the period of 2015 to 2017 (ClinicalTrials.gov, NCT03014752). Inclusion criteria included patients aged 1–18 years old, resistance to at least two antiepileptic drugs and no history of metabolic diseases that KD is contraindicated. The exclusion criteria included the occurrence of serious adverse effects and reluctance to adhere to the diet. Patients received the interventions for three months. Classical KD was initiated with 4:1 ketogenic ratio. MAD was initiated with a ketogenic ratio of 1:1 to 2:1 according to the John Hopkins protocol. The blood sample was obtained for measurement of the lipid profile, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). A repeated measures ANOVA was performed to compare the differences between groups. Results Twenty-six patients were allocated to classical KD and 26 were allocated to MAD. Fourteen patients remained at the end of the study in each group. In the classical KD group, the serum levels of TC, TG and LDL increased significantly before and after three months. In the MAD group, the serum levels of TC and LDL increased significantly before and after the study. After three months, there was a significant difference in the serum levels of TG and LDL between classical KD and MAD groups (P &amp;lt; 0.05); however, no significant difference was observed in the serum levels of TC and HDL in both groups (P &amp;gt; 0.05). Conclusions Patients who were on the MAD had significantly higher levels of TG and LDL than those who were on classical KD. Funding Sources Tehran University of Medical Sciences.

Pioglitazone attenuates kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats

Gentamicin, belonging to the aminoglycosides, possesses the greatest nephrotoxic effect of all other antibiotics from this group. On the other hand, pioglitazone, which represents peroxisome proliferator-activated receptor γ (PPARγ) agonist recently showed antiinflamatory, antioxidative effects, amelioration of endothelial dysfunction etc. Therefore, the goal of our study was to investigate the effects of pioglitazone on kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats. These effects were observed by following values of biochemical (serum urea and creatinine) parametars, total histological kidney score, urine level of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) as well as parametars of oxidative stress (malondialdehyde, superoxide dismutase, catalase, total oxidant status, total antioxidant status, oxidative stress index and advanced oxidation protein products). It seems that pioglitazone protects the injured rat kidney in a U-shaped manner. Medium dose of pioglitazone (1 mg/kg, i.p.) was protective regarding biochemical (serum urea and creatinine), total histological score and the values of kidney injury molecule-1 (KIM-1) (P < 0.05 vs. control group, i.e. rats injected with gentamicin only). This finding could be of great importance for the wider use of aminoglycosides, with therapy that would reduce the occurrence of serious adverse effects, such as nephrotoxicity and acute renal failure.

The Use of Human Mesenchymal Stem Cells as Therapeutic Agents for the in vivo Treatment of Immune-Related Diseases: A Systematic Review.

Background: One of the greatest challenges for medicine is to find a safe and effective treatment for immune-related diseases. However, due to the low efficacy of the treatment available and the occurrence of serious adverse effects, many groups are currently searching for alternatives to the traditional therapy. In this regard, the use of human mesenchymal stem cells (hMSCs) represents a great promise for the treatment of a variety of immune-related diseases due to their potent immunomodulatory properties. The main objective of this study is, therefore, to present and summarize, through a systematic review of the literature, in vivo studies in which the efficacy of the administration of hMSCs for the treatment of immune-related diseases was evaluated.Methods: The article search was conducted in PubMed/MEDLINE, Scopus and Web of Science databases. Original research articles assessing the therapeutic potential of hMSCs administration for the in vivo treatment immune-related diseases, published from 1984 to December 2017, were selected and evaluated.Results: A total of 132 manuscripts formed the basis of this systematic review. Most of the studies analyzed reported positive results after hMSCs administration. Clinical effects commonly observed include an increase in the survival rates and a reduction in the severity and incidence of the immune-related diseases studied. In addition, hMSCs administration resulted in an inhibition in the proliferation and activation of CD19+ B cells, CD4+ Th1 and Th17 cells, CD8+ T cells, NK cells, macrophages, monocytes, and neutrophils. The clonal expansion of both Bregs and Tregs cells, however, was stimulated. Administration of hMSCs also resulted in a reduction in the levels of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, IL-2, IL-12, and IL-17 and in an increase in the levels of immunoregulatory cytokines such as IL-4, IL-10, and IL-13.Conclusions: The results obtained in this study open new avenues for the treatment of immune-related diseases through the administration of hMSCs and emphasize the importance of the conduction of further studies in this area.

Toxicity and Safety Concerns in Orlistat Therapy for Obesity: A Critical Evaluation

Orlistat is a selective inhibitor of gastric and pancreatic lipase indicated for the treatment of obesity. It is also known to significantly reduce risk of associated co-morbidities such as heart attack, type-2 diabetes mellitus, hypertension and stroke. Recent reports have raised concerns on the possible occurrence of serious adverse effects with prolonged use. Orlistat has been shown to inhibit carboxylesterase-2, a major detoxification enzyme, predisposing to severe liver, pancreatic and kidney damage. Orlistat alters the pharmacodynamic response of some drugs when co-administered leading to severe toxicity and reduced efficacy. Safety is a major concern considering the widespread use of this drug both as a prescription and over-the-counter medication. There is need for large-scale observation studies on orlistat use to generate appropriate data that will guide the regulatory agencies in taking relevant decision on continued use of orlistat as anti-obesity drug.

The effect of intravenous immunoglobulin on neuromyelitis optica

ObjectiveEvaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). MethodsEight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7g/kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). ResultsAll 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis (LETM). The mean age of onset was 20.5 years (range, 7–31 years) and 87.5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3–17 years). Following 83 infusions (range, 4–21 per patient) and a mean follow-up time of 19.3 months (range, 6–39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z=−2.5, P=.01). The EDSS score fell from 3.3 [SD 1.3] to 2.6 [SD 1.5] (z=−2.0, P=.04). ConclusionsTreatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders.

Estudio del efecto del tratamiento con inmunoglobulinas por vía intravenosa en la neuromielitis óptica

ObjectiveEvaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). MethodsEight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7 g per kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). ResultsAll 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis. The mean age of onset was 20.5 years (range, 7-31 years) and 87,5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z=2,5, P=.01). The EDSS score fell from 3.3±1.3 to 2.6±1.5 (z=−2.0, P=.04). ConclusionsTreatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders.

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia.

The efficacy of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) patients has significantly increased in the last 20 years; as a result, the focus of research is slowly shifting from trying to increase survival rates to reduce chemotherapy-related toxicity. At the present time, the cornerstone of therapy for ALL is still formed by a reduced number of drugs with a highly toxic profile. In recent years, a number of genetic polymorphisms have been identified that can play a significant role in modifying the pharmacokinetics and pharmacodynamics of these drugs. The best example is that of the TPMT gene, whose genotyping is being incorporated to clinical practice in order to individualize doses of mercaptopurine. However, there are additional genes that are relevant for the metabolism, activity, and/or transport of other chemotherapy drugs that are widely use in ALL, such as methotrexate, cyclophosphamide, vincristine, L-asparaginase, etoposide, cytarabine, or cytotoxic antibiotics. These genes can also be affected by genetic alterations that could therefore have clinical consequences. In this review we will discuss recent data on this field, with special focus on those polymorphisms that could be used in clinical practice to tailor chemotherapy for ALL in order to reduce the occurrence of serious adverse effects.

Estimating absolute risks in the presence of nonadherence: an application to a follow-up study with baseline randomization.

The intention-to-treat (ITT) analysis provides a valid test of the null hypothesis and naturally results in both absolute and relative measures of risk. However, this analytic approach may miss the occurrence of serious adverse effects that would have been detected under full adherence to the assigned treatment. Inverse probability weighting of marginal structural models has been used to adjust for nonadherence, but most studies have provided only relative measures of risk. In this study, we used inverse probability weighting to estimate both absolute and relative measures of risk of invasive breast cancer under full adherence to the assigned treatment in the Women's Health Initiative estrogen-plus-progestin trial. In contrast to an ITT hazard ratio (HR) of 1.25 (95% confidence interval [CI] = 1.01 to 1.54), the HR for 8-year continuous estrogen-plus-progestin use versus no use was 1.68 (1.24 to 2.28). The estimated risk difference (cases/100 women) at year 8 was 0.83 (-0.03 to 1.69) in the ITT analysis, compared with 1.44 (0.52 to 2.37) in the adherence-adjusted analysis. Results were robust across various dose-response models. We also compared the dynamic treatment regimen "take hormone therapy until certain adverse events become apparent, then stop taking hormone therapy" with no use (HR = 1.64; 95% CI = 1.24 to 2.18). The methods described here are also applicable to observational studies with time-varying treatments.

The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development

The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development

The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development

The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development

Immunoglobulins in chronic inflammatory demyelinating polyneuropathy.

This article reviews the efficacy and tolerability of intravenous immunoglobulins (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), including those forms associated with monoclonal gammopathy (paraproteinemic demyelinating neuropathy, PDN). Class I trials demonstrated that IVIg are effective in CIDP. About two-thirds of patients respond to initial treatment; however, most of them require repeated drug doses to maintain improvement. For PDN there are some evidences that IVIg are efficacious; however, it seems that less than 50% of the patients respond to this treatment and the persistence of the response over time has not been thoroughly investigated. The safety profile of immunoglobulins is generally good; however, the possibility of the occurrence of serious adverse effects should always be considered before starting treatment.

渥美病院における定期的に検査を要する薬剤の臨床検査実施状況について

There are many medical supplies, which are required to undergo periodical laboratory tests to prevent the occurrence of serious adverse effects. However, it is uncertain as to whether or not such laboratory tests are actually carried out routinely at hospitals. In order to prevent serious adverse effects, it is important to clarify the current performance of the laboratory tests in hospitals and to perform such laboratory tests properly. In this study, we surveyed the current performance of laboratory tests on Flutamide, Ticlopidine, Benzbromarone, Acarbose, and Thiamazole, which have all been recently required to undergo laboratory tests to prevent potential adverse effects.The present study showed the performance rate of proper laboratory tests, based on package inserts, to be 60, 33.3 and 46.2% for Ticlopidine, Acarbose, and Thiamazole, respectively. Surprisingly, the performance rate of proper laboratory tests for Flutamide was zero, in spite of the fact that it is well known to cause serious liver dysfunction.Our findings suggest a poor recognition by medical staff members of the importance of laboratory tests in or-der to prevent adverse effects. It is therefore important to promote the implementation of periodical laboratory tests, and pharmacists should play a significant role in appropriately conducting such needed laboratory tests to avoid the occurrence of serious adverse effects.