Adverse Effects Of Treatment Research Articles

Omega-3 fatty acids as adjuvant therapy in the adverse effects of antineoplastic treatment for breast cancer: a systematic review

Omega-3 fatty acids as adjuvant therapy in the adverse effects of antineoplastic treatment for breast cancer: a systematic review

The anti-allergic potential of stingless bee honey from different botanical sources via modulation of mast cell degranulation

BackgroundAllergy is an inflammatory disorder affecting around 20% of the global population. The adverse effects of current conventional treatments give rise to the increased popularity of using natural food products as complementary and alternative medicine against allergic diseases. Stingless bee honey, commonly known as Kelulut honey (KH) in Malaysia, has been used locally as a traditional remedy to relieve cough and asthma. This study evaluated the anti-allergic potential of KH collected from four different botanical sources on phorbol ester 12-myristate-3-acetate and calcium ionophore-activated human mast cells.MethodsThe present study examined the inhibitory effects of all collected honey on the release of selected inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, IL-8, histamine, and β-hexosaminidase in an activated HMC. Besides that, all honey's total phenolic content (TPC) was also examined, followed by using liquid chromatography with tandem mass spectrometry (LC–MS/MS) to identify the phytochemicals in the honey. Further examination of the identified phytochemicals on their potential interaction with selected signaling molecules in an activated mast cell was conducted using computational methods.ResultsThe results indicated that there were significant inhibitory effects on all selected inflammatory mediators’ release by KH sourced from bamboo (BH) and rubber tree (RH) at 0.5% and 1%, but not KH sourced from mango (AH) and noni (EH). BH and RH were found to have higher TPC values and were rich in their phytochemical profiles based on the LC–MS/MS results. Computational studies were employed to determine the possible molecular target of KH through molecular docking using HADDOCK and PRODIGY web servers.ConclusionsIn short, the results indicated that KH possesses anti-allergic effects towards an activated HMC, possibly by targeting downstream MAPKs. However, their anti-allergic effects may vary according to their botanical sources. Nevertheless, the present study has provided insight into the potential application of stingless bee honey as a complementary and alternative medicine to treat various allergic diseases.

Cancer patients in the emergency department

A growing number of patients are living with cancer or have a history of cancer leading to increasing adverse effects of treatment or disease necessitating emergency department (ED) consultation. Long-term cancer survivors are at higher risk of comorbidities causing a substantial increase in health care resource utilization. The most frequent reasons for cancer-related ED visits are dyspnea, fever, pain, gastrointestinal or neurological symptoms leading to high hospital and intensive care unit admission rates. Acute respiratory failure in cancer patients necessitates timely diagnostic testing, whereby computed tomography is superior to chest X‑ray. Delay in intensive care unit (ICU) admission or mechanical ventilation increases mortality. Febrile neutropenia is an emergency with urgent need for antibiotic treatment. Treatment of neutropenic and nonneutropenic patients with sepsis does not differ. Cardiovascular disease is now the second leading cause of long-term morbidity and mortality among cancer survivors. Immunotherapy can lead to substantial and in some patients life-threatening complications that may not easily be recognized in the ED. Cancer-specific emergencies such as leukostasis, tumorlysis or hypercalcemia rarely present to ED and require interdisciplinary care. The constantly growing cancer population is likely to increase ED utilization. Knowledge about cancer treatment and disease-associated complications is crucial for emergency physicians. Palliative care education should secure appropriate end-of-life care avoiding futile interventions.

Interventions for the treatment of oral cavity and oropharyngeal cancers: surgical treatment.

Interventions for the treatment of oral cavity and oropharyngeal cancers: surgical treatment.

Lasers in Medicine: The Changing Role of Therapeutic Laser-Induced Retinal Damage—From de rigeuer to Nevermore

For over five decades, laser-induced retinal damage (LIRD) was thought to be the necessary cost of all therapeutic effects of laser treatment for the most important causes of irreversible visual loss, the chronic progressive retinopathies (CPRs). The development of modern retinal laser therapy with the discovery of “low-intensity/high-density subthreshold micropulse” laser (SDM) showed that the supposed need for LIRD represented a case of confusing association with causation. This revealed that LIRD was unnecessary and detrimental to clinical outcomes, and thus, contraindicated as the most severe complication of retinal laser treatment. SDM allowed for an understanding of the mechanism of retinal laser treatment as a physiologic reset effect, triggered by heat-shock protein (HSP) activation upregulating the unfolded protein response and restoring proteostasis by increasing protein repair by 35% in dysfunctional cells via a thermally sensitive conformational change in the K10 step of HSP activation kinetics. Because HSP activation kinetics are catalytic, even low levels (the “reset” threshold) of HSP activation result in a maximal treatment response. SDM and the study of HSP activation kinetics in the retina show that the therapeutic effects of retinal laser treatment can be fully realized without any degree of LIRD. Besides LIRD, all effects of retinal laser treatment are restorative and therapeutic, without any known adverse treatment effects. Without LIRD, the benefits of retinal laser treatment are infinitely renewable and direct treatment of the fovea is possible. Elimination of LIRD from retinal laser treatment has revolutionized the clinical potential of retinal laser treatment to broaden treatment indications to permit, for the first time, effective early and preventive treatment to reduce visual loss from the most frequent causes of irreversible visual loss worldwide, the CPRs.

Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension.

Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.

Beyond Conventional Meat Preservation: Saddling the Control of Bacteriocin and Lactic Acid Bacteria for Clean Label and Functional Meat Products.

Advancements in food science and technology have paved the way for the development of natural antimicrobial compounds to ensure the safety and quality of meat and meat products. Among these compounds, bacteriocin produced by lactic acid bacteria has gained considerable scientific attention for its ability to preserve the healthy properties of meat while preventing spoilage. This natural preservative is seen as a pioneering tool and a potent alternative to chemical preservatives and heat treatment, which can have harmful effects on the nutritional and sensory qualities of meat. Bacteriocin produced by lactic acid bacteria can be used in various forms, including as starter/protective cultures for fermented meats, purified or partially purified forms, loaded in active films/coatings, or established in encapsulate systems. This review delves into the downstream purification schemes of LAB bacteriocin, the elucidation of their characteristics, and their modes of action. Additionally, the application of LAB bacteriocins in meat and meat products is examined in detail. Overall, the use of LAB bacteriocins holds immense potential to inspire innovation in the meat industry, reducing the dependence on harmful chemical additives and minimizing the adverse effects of heat treatment on nutritional and sensory qualities. This review provides a comprehensive understanding of the potential of bacteriocin produced by lactic acid bacteria as a natural and effective meat preservative.

Effect of Nitric Oxide Donors on Uterine and Subendometrial Blood Flow in Patients with Unexplained Infertility: A Randomized Controlled Trial

Unexplained infertility has been defined, by the Practice Committee of the American Society of Reproductive Medicine (ASRM), as inability of a couple to conceive for at least 12 months, with unremarkable standard infertility evaluation ((ASRM), 2006). Although estimates vary, the prevalence of unexplained infertility is approximately 15–30% Aim of the Work to evaluate the effect of nitroglycerine transdermal patches on uterine and subendometrial blood flow in women with unexplained infertility. Patients and Methods Transdermal nitroglycerine patch was administered to the allocated group from the 2nd day of cycle till maturation of the follicles ≥ 18 mm just for one cycle. Results The relatively underdeveloped endometrial thickness did not change significantly after treatment of women with unexplained infertility with nitroglycerin and remained significantly lower than women of the fertile group. Also, nitroglycerin treatment did not result in significant change in uterine artery Doppler indices. However, uterine artery indices of nitroglycerin-treated women did not also show a significant difference (P > 0.05) from fertile women. On the contrary, nitroglycerin treatment in women with unexplained infertility significantly increased subendometrial 3D power Doppler indices to mean values that did not differ significantly from the fertile women. According to the results of the current study, biochemical pregnancy was more commonly achieved in the nitroglycerin group compared to the control group (6.67% vs 3.33%), Yet this difference failed to prove statistical significance. Although adverse effects of nitroglycerin treatment in the current study, namely headache, blurring of vision and hypotension, were more common on the nitroglycerin group compared to the control and fertile groups; this difference couldn’t reach statistical significance (P > 0.05). Conclusion Doppler study of uterine hemodynamics can be considered in infertility work-up. Although still lacking evidence, women with suboptimal uterine perfusion may be offered therapies improving uterine blood flow, such as nitroglycerin.

Agranulocytosis: a rare complication of the thionamides

Agranulocytosis is a rare and life-threatening side effect of antithyroid drugs (ATD); it has been reported in < 0.2% of patients, usually within the first 3 months after starting ATD. We present a 62-year-old Libyan female patient who developed agranulocytosis 3 months after starting treatment with methimazole for hyperthyroidism. After 1 month of doubling her ATD dose, she developed a fever, sore throat, and generalized weakness for several days. Laboratory examinations revealed agranulocytosis (total leukocyte count was 1.14 × 103/µL, with granulocytes at 2.99% and lymphocytes at 93.21%). She was hospitalized, ATD was discontinued, and empirical antibiotic treatment was given. She was started on granulocyte colony-stimulating factor. Her cell counts improved, and she was discharged. The present case report aims to increase awareness of this potentially lethal adverse effect of ATD treatment. Patient education and close monitoring of high-risk patients are the key to reduce its morbidity and mortality.

Myasthenia gravis treatment in the elderly presents with a significant iatrogenic risk: a multicentric retrospective study.

Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. We retrospectively analysed the files of all MG patients with disease onset after age 70years in four French University Hospitals, including clinical, electrophysiological, biological, and treatment data, with an emphasis on TAE. MG outcomes were assessed using the Myasthenia Gravis Foundation of America (MGFA) status scale. We included 138 patients (59% of men) with a mean follow-up of 4.5years (range 1-19). Mean age at diagnosis was 78years (70-93). Anti-acetylcholine receptor antibodies were found in 87% of cases, electrophysiological abnormalities in 82%, and thymoma in 10%. MG outcome was good in a majority of cases, with 76% of treated patients presenting with alleviated symptoms at follow-up. TAE were observed in 41% of patients, including severe TAE in 14% of cases. Seven patients (5.1%) died, including four (2.9%) from MG-related respiratory failure, and three (2.2%) from MG treatment-related complications, i.e., sepsis in 2 cases and brain toxoplasmosis in 1 case. TAE were observed in 53% of patients treated with azathioprine, 23% of patients treated with corticosteroids, and 15% of patients treated with mycophenolate mofetil. This retrospective study demonstrates MG in the elderly presents with a significant iatrogenic risk, including fatal immunosuppressant-related infections.

The Effect of Low-Dose Glucocorticoids Over Two Years on Weight and Blood Pressure in Rheumatoid Arthritis: Individual Patient Data From Five Randomized Trials.

Weight gain and hypertension are well known adverse effects of treatment with high-dose glucocorticoids. To evaluate the effects of 2 years of low-dose glucocorticoid treatment in rheumatoid arthritis (RA). Pooled analysis of 5 randomized controlled trials with 2-year interventions allowing concomitant treatment with disease-modifying antirheumatic drugs. 12 countries in Europe. Early and established RA. Glucocorticoids at 7.5 mg or less prednisone equivalent per day. Coprimary end points were differences in change from baseline in body weight and mean arterial pressure after 2 years in intention-to-treat analyses. Difference in the change of number of antihypertensive drugs after 2 years was a secondary end point. Subgroup and sensitivity analyses were done to assess the robustness of primary findings. A total of 1112 participants were included (mean age, 61.4 years [SD, 14.5]; 68% women). Both groups gained weight in 2 years, but glucocorticoids led, on average, to 1.1 kg (95% CI, 0.4 to 1.8 kg; P<0.001) more weight gain than the control treatment. Mean arterial pressure increased by about 2 mm Hg in both groups, with a between-group difference of -0.4 mm Hg (CI, -3.0 to 2.2 mm Hg; P= 0.187). These results were consistent in sensitivity and subgroup analyses. Most patients did not change the number of antihypertensive drugs, and there was no evidence of differences between groups. Body composition was not assessed, and generalizability to non-European regions may be limited. This study provides robust evidence that low-dose glucocorticoids, received over 2 years for the treatment of RA, increase weight by about 1 kg but do not increase blood pressure. None.

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β=0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

Effects of supervised exercise and self-managed psychosexual therapy on sexual health in men with prostate cancer: A randomized clinical trial.

71 Background: Sexual dysfunction is a common, distressing, and persistent adverse effect of prostate cancer treatment and current management strategies do not adequately address physical and psychological effects. Exercise is emerging as potential therapy in the management of sexual health. The purpose of this study was to investigate the effects of supervised, clinic-based, resistance and aerobic exercise with and without psychosexual therapy self-management on sexual health in men with prostate cancer. Methods: A 3-arm, parallel group, multi-center randomized clinical trial was undertaken between 2014 and 2018. The study was conducted at university-affiliated exercise clinics. Eligible participants were men with prostate cancer who had previously or were currently undergoing treatment and concerned about sexual dysfunction. One-hundred and twelve participants were randomized to: 1) 6 months of supervised, group-based resistance and aerobic exercise (n=39), 2) the same exercise program plus psychosexual therapy (n=36), or 3) usual care (n=37). Exercise was undertaken 3 days per week at university-affiliated exercise clinics. Psychosexual therapy consisted of a brief self-management intervention that addressed psychological and sexual wellbeing. The primary outcome was sexual health assessed with the International Index of Erectile Function. Secondary outcomes included body composition, physical function, and muscle strength. Analyses were undertaken using an intention-to-treat approach. Results: Erectile function increased by 5.1 points (exceeds MICD) with exercise and 1.0 point with usual care (P interaction=.010) while intercourse satisfaction increased by 2.2 points with exercise and 0.2 points with usual care (P interaction=.026). Self-managed psychosexual therapy did not result in additional improvements. Compared with usual care, exercise prevented an increase in fat mass (P interaction=.028) and improved physical function outcomes, as well as upper and lower body muscle strength. Conclusions: Supervised resistance and aerobic exercise improved erectile function and intercourse satisfaction in men with prostate cancer; however, self-managed psychosexual therapy resulted in no additional improvements. Men with prostate cancer concerned about sexual dysfunction should be encouraged to undertake exercise as a potential countermeasure. Clinical trial information: ACTRN12613001179729 .

Efficacy and Safety of Flumatinib in Treatment of Patients with Chronic Myeloid Leukemia

To analyze the efficacy and safety of flumatinib in the treatment of patients with chronic myeloid leukemia (CML). The clinical data of 56 CML patients treated with flumatinib from January 2020 to December 2021 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. Patients were divided into three groups: 35 new diagnosed CML patients treated with flumatinib (group A), 10 patients with imatinib/dasatinib intolerance (group B) and 11 patients with imatinib/dasatinib resistance (group C) switched to flumatinib treatment, respectively. The molecular response and adverse effects of flumatinib treatment were evaluated. In group A, the early molecular response (EMR) at 3 months was 40.0%, and the major molecular response (MMR) at 6 and 12 months was 43.7% and 46.2%, respectively. In group B, the EMR was 50.0% at 3 months, and the MMR was 70.0% and 66.2% at 6 and 12 months, respectively. Among evaluable patients, 6 cases in group B achieved molecular response of 4.5 (MR4.5) at 12 months after switching to flumatinib treatment. In group C, 3 cases who switched from imatinib resistance to flumatinib achieved MR4.5 at 12 months, but 2 cases who switched from dasatinib resistance to flumatinib failed. Subgroup analysis showed significant differences in EUTOS long-term survival (ELTS) scores for patients in the medium-risk/high-risk group compared with those in the low-risk group for 3-month EMR (18.8% vs 57.9%), 6-month MMR (15.4% vs 63.2%) and 12-month MR4.5 (15.4% vs 69.2%) (P =0.036, P =0.012,P =0.015). The most common adverse effect in group A was thrombocytopenia, accounting for 54.5%, and 22.8% (8/35) patients discontinued the drug due to haematological adverse effects. Compared with patients who did not discontinue the drug or whose recovery time from discontinuation due to haematological toxicity was <1 month, patients whose recovery time from discontinuation was ≥1 month had a significantly worse 3-month EMR, 6-month MMR and 12-month MR4.5 (P =0.028, P =0.021, P =0.002). Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.

Formulation and evaluation of solid lipid nanoparticles loaded with papaya seed chloroform extract for long-term antifertility effects on the male rat, Bandicota bengalensis

The study is the first to formulate and investigate potential of papaya seed chloroform extract based solid lipid nanoparticles (PSCEN) as antifertility agents on male Bandicota bengalensis. The prepared nanoparticles were spherical of size 300–600 nm. The release kinetics showed a controlled release of the drug with major release over 48 h. To assess the antifertility effects of PSCEN, adult male rats were fed a diet containing two different concentrations of PSCEN (5% and 10%) for 15 days under bi-choice conditions. The mean total active ingredient ingestion of the rats in the two treated groups ranged from 2.13–3.31 and 3.92–5.87 g/100g body weight, respectively. No adverse effects of treatment on body weight were observed. Also, no mortality of rats was observed. The treatment had a significant effect on the weight of the testis and the epididymis, but not on the other organs. Sperm motility (%), sperm viability (%), sperm count (millions/ml), sperm mitochondrial activity (%), sperm nuclear chromatin de-condensation (%) and sperm hypo-osmotic swelling (%) were significantly decreased, and sperm abnormality (%) significantly increased compared to the vehicle control group. The reproductive success rates of male rats treated with 5% and 10% PSCEN and mated with untreated female rats were 20.00–66.67% and 16.67%, respectively, while in untreated female rats mated with male rats of vehicle control group, reproductive success rate was 33.33 to 80%. The study found a maximal antifertility effect of the 10% PSCEN containing bait, which was irreversible up to 105 days after stopping treatment, suggesting long-term efficacy.

Early-life prophylactic antibiotic treatment disturbs the stability of the gut microbiota and increases susceptibility to H9N2 AIV in chicks

BackgroundAntibiotics are widely used for prophylactic therapy and for improving the growth performance of chicken. The problem of bacterial drug resistance caused by antibiotic abuse has previously attracted extensive attention; however, the influence of early-day use of prophylactic antibiotics on the gut microflora and on the disease resistance ability in chicks has not been explored. Here, we comprehensively evaluate the growth performance, gut microbial dynamics, level of antibiotic resistance genes (ARGs) in the gut microbial community, and resistance to H9N2 avian influenza virus (AIV) in chickens following long-term and short-term early-day prophylactic antibiotic treatment.ResultsUnexpectedly, long-term prophylactic enrofloxacin treatment slowed the growth rate of chickens, whereas short-term antibiotics treatments were found to increase the growth rate, but these changes were not statistically significant. Strikingly, expansions of Escherichia-Shigella populations were observed in early-life prophylactic antibiotics-treated groups of chickens, which is in contrast to the general perception that antibiotics should control their pathogenicity in chicks. The gut microbiota composition of chickens treated long term with antibiotics or received early-day antibiotics treatment tend to be more dramatically disturbed compared to the gut microbiome of chickens treated with antibiotics for a short term at a later date, especially after H9N2 AIV infection.ConclusionsOur data provide evidence that early-day and long-term antibiotic treatments have a more adverse effect on the intestinal microbiome of chickens, compared to short-term late age antibiotic treatment. Furthermore, our metagenomic data reveal that both long-term and short-term antibiotic treatment increase the relative abundance of ARGs. Our findings highlight the adverse effects of prophylactic antibiotic treatment and provide a theoretical basis for the cautious administration of antibiotics in food-producing animal management.Ao91n5eHkkQPyDkUXXsk_bVideo

BDNF/TrkB pathway activation in D1 receptor-expressing striatal projection neurons plays a protective role against L-DOPA-induced dyskinesia

L-DOPA-induced dyskinesia (LID) is a frequent adverse side effect of L-DOPA treatment in Parkinson's disease (PD). Understanding the mechanisms underlying the development of these motor disorders is needed to reduce or prevent them. We investigated the role of TrkB receptor in LID, in hemiparkinsonian mice treated by chronic L-DOPA administration. Repeated L-DOPA treatment for 10 days specifically increased full-length TrkB receptor mRNA and protein levels in the dopamine-depleted dorsal striatum (DS) compared to the contralateral non-lesioned DS or to the DS of sham-operated animals. Dopamine depletion alone or acute L-DOPA treatment did not significantly increase TrkB protein levels. In addition to increasing TrkB protein levels, chronic L-DOPA treatment activated the TrkB receptor as evidenced by its increased tyrosine phosphorylation. Using specific agonists for the D1 or D2 receptors, we found that TrkB increase is D1 receptor-dependent. To determine the consequences of these effects, the TrkB gene was selectively deleted in striatal neurons expressing the D1 receptor. Mice with TrkB floxed gene were injected with Cre-expressing adeno-associated viruses or crossed with Drd1-Cre transgenic mice. After unilateral lesion of dopamine neurons in these mice, we found an aggravation of axial LID compared to the control groups. In contrast, no change was found when TrkB deletion was induced in the indirect pathway D2 receptor-expressing neurons. Our study suggests that BDNF/TrkB signaling plays a protective role against the development of LID and that agonists specifically activating TrkB could reduce the severity of LID.

Medical treatment of eosinophilic esophagitis.

Medical treatment of eosinophilic esophagitis.

The Association of Oxaliplatin-Containing Adjuvant Chemotherapy Duration with Overall and Cancer-Specific Mortality in Individuals with Stage III Colon Cancer: A Population-Based Retrospective Cohort Study.

Few studies have examined the relationship between duration of oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer and mortality in routine practice. We examined the association between treatment with 50% versus >85% of a maximal course of adjuvant therapy (eight cycles of CAPOX, twelve cycles of FOLFOX) and mortality in stage III colon cancer. Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019. In the primary comparison, we compared patients who received 50% or >85% of a maximal course of adjuvant therapy; in a secondary comparison, we evaluated a dose effect across patients who received FOLFOX in one-cycle increments from six to ten cycles against >85% (more than ten cycles) of a maximal course of FOLFOX. The main outcomes were overall and cancer-specific mortality. Follow-up began 270 days after adjuvant treatment initiation and terminated at the first of the outcome of interest, loss of eligibility for Ontario's Health Insurance Program, or study end. Overlap propensity score weights accounted for baseline between-group differences. We determined the hazard ratio, estimating the association between mortality and treatment. Non-inferiority was concluded in the primary comparison for either outcome if the upper limit of the two-sided 95% CI was ≤1.11, which is the margin used in the International Duration Evaluation of Adjuvant Chemotherapy Collaboration. We included 3546 patients in the analysis of overall mortality; 486 (13.7%) received 50% and 3060 (86.3%) received >85% of a maximal course of therapy. Median follow-up was 5.4 years, and total follow-up was 20,510 person-years. There were 833 deaths. Treatment with 50% of a maximal course of adjuvant therapy was associated with a hazard ratio of 1.13 (95% CI 0.88 to 1.47) for overall mortality and a subdistribution hazard ratio of 1.31 (95% CI 0.91 to 1.87) for cancer-specific mortality versus >85% of a maximal course of therapy. In the secondary comparison, there was a trend toward higher overall mortality in patients treated with shorter durations of therapy, though confidence intervals overlapped considerably. We could not conclude that treatment with 50% of a maximal course is non-inferior to >85% of a maximal course of adjuvant therapy for mortality in stage III colon cancer. Clinicians and patients engaging in decision-making around treatment duration in this context should carefully consider the trade-off between treatment effectiveness and adverse effects of treatment.

Amiodarone accumulates two cholesterol precursors in myocardium: A controlled clinical study.

Amiodarone is an effective antiarrhythmic drug, which interferes with cholesterol synthesis. In the human body, it inhibits two enzymes in the cholesterol-synthesis pathway, followed by increases especially in serum desmosterol and zymostenol concentrations and a decrease in that of serum lathosterol. We explored whether desmosterol and zymostenol accumulate also in myocardial tissue during amiodarone treatment. Thirty-three patients admitted for cardiac transplantation volunteered for the study. Ten patients were on amiodarone treatment (AD group) and 23 were not (control group). The groups were matched as regards demographic and clinical variables. Myocardial samples were obtained from the removed hearts from 31 patients. Cholesterol, non-cholesterol sterols and squalene were quantified by means of gas-liquid chromatography. In serum and myocardium, desmosterol was 19- and 18-fold higher and zymostenol 4- and 2-fold higher in the AD group versus the control group (p<0.001 for all). In contrast, myocardial cholesterol, squalene and lathosterol levels were lower in the AD group than in the control group (p<0.05 for all). Levels of phytosterols and cholestanol were similar in the serum and myocardium in the two groups. Levels of myocardial and serum desmosterol, zymostenol, lathosterol and phytosterols correlated with each other in both groups (p<0.05 for all). Amiodarone treatment caused the accumulation of desmosterol and zymostenol in myocardium. In particular, myocardial desmosterol concentrations were substantially elevated, which may play a part in some of the therapeutic and adverse effects of amiodarone treatment.