Severe cutaneous adverse reactions associated with the immune checkpoint inhibitors: A case/non-case analysis using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND/OBJECTIVES: The immune checkpoint inhibitors (ICIs) have been increasingly associated with severe cutaneous adverse reactions (SCARs). These reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are uncommon but potentially lethal. Despite the severity of these reactions and growing association with the ICIs, their specific risk and mortality rates have been largely unexplored. METHODS: A case/non-case analysis was performed using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to examine the reporting odds ratios (RORs) for ICI-associated SCARs cases under two conditions: (1) ICIs compared with all drugs in FAERS and (2) ICIs compared with a reference group of pooled anticancer drugs to control for underlying malignancy. RESULTS: A statistically significant ROR for SJS (ROR: 5.44), TEN (ROR: 5.81) and DRESS (ROR: 1.38) were identified under Condition 1. Under Condition 2, this significance was maintained for SJS (ROR: 7.31), TEN (ROR: 7.40) and DRESS (ROR: 3.90), and mild significance was identified for AGEP (ROR: 1.89). Mortality rates for the ICIs were increased compared with the anticancer medications (28.5% vs. 24.5% for SJS, 55.3% vs. 46% for TEN, 3.0% vs. 2.1% for AGEP and 7.1% vs. 6.1% for DRESS). CONCLUSIONS: Our results suggest an association between SCARs and the ICIs independent of cancer status.

Medication Associations With Severe Cutaneous Adverse Reactions: A Case/Non-Case Analysis Using the FDA Adverse Event Reporting System.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) are potentially life-threatening severe cutaneous adverse reactions (SCARs). Although the classical causal agents of SCARs (antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol) are well characterized, there has been little update to this list to account for newly marketed medications. OBJECTIVE: To provide an updated and stratified list of medications with significant reporting odds ratios (RORs) of SCARs. METHODS: A case/non-case analysis using the United States FDA Adverse Event Reporting System was performed. RESULTS: As expected, the prototypical medication classes made up the majority of reported cases of SJS, TEN, AGEP, and DRESS (77%, 64%, 75%, and 72%, respectively). In addition, several infrequently or previously undescribed classes/medications implicated in SCARs were identified to have significant ROR signals, including acetylcysteine, anticoagulants, diuretics, immunotherapies, proton pump inhibitors, antivirals, and antifungals. Among these reported for SJS were acetylcysteine (ROR: 64.38) and fluconazole (ROR: 17.13). For TEN, we identified furosemide (ROR: 26.32), spironolactone (ROR: 14.45), fluconazole (ROR: 30.21), amphotericin B (39.06), and acetylcysteine (ROR: 93.12). For AGEP, we identified acyclovir (ROR: 61.72), valacyclovir (ROR: 30.76), and enoxaparin (ROR: 27.37). For DRESS, we identified vemurafenib (ROR: 17.35), acyclovir (ROR: 30.63), abacavir (ROR: 26.62), raltegravir (ROR: 23.27), and valacyclovir (ROR: 21.77) to have strong reporting odds. CONCLUSION: Our analysis provides an updated tool for physicians to reference when identifying suspected SCARs and a basis for future studies to investigate atypical medication causality.

Circulating direct infusion MS and NMR metabolomic profiles of post-gonadectomy kittens with or without additional dietary choline supplementation.

Choline is beneficial for energy metabolism and growth in various species. Choline may work similarly in kittens at risk of obesity. Direct infusion MS (Di-MS) and NMR spectroscopy were used to investigate the metabolomic signatures of kittens supplemented with or without additional dietary choline for 12 weeks. Fifteen intact male kittens consumed a base diet (3310 mg choline/kg DM) to their daily metabolisable energy requirement (DER) over an 11-week acclimation. Kittens were gonadectomised and assigned, based on body weight, to the base diet (CONTROL, n 7) or the base diet with 300 mg/kgBW0·75 additional choline as choline chloride (CHOLINE, n 8) and offered three times their individual energy requirement divided into three meals. At weeks -1 and 12, fasted blood was sampled and serum analysed for 130 metabolites via Di-MS and fifty-one metabolites via NMR spectroscopy. Changes in fasted metabolites were assessed using a repeated-measures GLIMMIX procedure with time and group as fixed effects, and time as a repeated measure. Metabolites of one-carbon metabolism and lipids increased, and medium-chain acyl carnitines decreased from week -1 to 12 for CHOLINE (P < 0·05), but not CONTROL (P > 0·05). Increases in amino acid, biogenic amine and organic compound concentrations were observed in both groups (P < 0·05). The results suggest impacts of dietary choline at greater intakes than currently recommended on one-carbon metabolism and fatty acid oxidation, and these may promote healthy growth in post-gonadectomy kittens.

Trends in stroke admissions to a Tanzanian hospital over four decades: a retrospective audit.

AIMS: The aim of this study was to record stroke admissions to a tertiary referral hospital in Tanzania over four decades. METHODS: We audited the medical records held at a large teaching and tertiary referral hospital in northern Tanzania over four decades. We collected records for the years 1974-1976, 1984-1986, 1994-1995 and 2008. All patients admitted as inpatients with a primary diagnosis of stroke were included in the study. Data collected included age, sex, stroke subtype, predominant side of symptoms and survival to discharge. RESULTS: The number of stroke admissions rose from just four in the three-year period 1974-1976 (mean 1.3 cases annually) to 153 cases annually in 2008. The mean age of those admitted rose steadily during this period, as did the proportion of females admitted. CONCLUSIONS: The burden of stroke on health services in Tanzania appears to have increased rapidly. If this increase is to be slowed, then sustainable primary preventative measures to target known stroke risk factors will be required.

More than just dermatitis: The multifaceted nature of chronic itch through the historical perspective of Napoleon Bonaparte.

Derived from the survival advantage needed to eradicate harmful irritants from the skin's surface, itch, also known as pruritus, is an intriguing phenomenon and a key feature of many dermatologic diseases. The pathologic form, chronic itch, is a condition that precedes itself by its complex pathophysiology, numerous etiologies, and interplay of mechanisms that often make it difficult to diagnose and treat. One particular sufferer of this condition, the 18th-century French emperor Napoleon Bonaparte, makes for a compelling case study of the complexity of chronic itch. We delve into the many etiologies and mechanisms of chronic itch, using Napoleon's lifelong struggle with this condition as our model, identifying potential environmental, neurologic, psychiatric, and immunologic origins of his condition.

Identifying the target population and preventive strategies to combat feline obesity.

Feline obesity continues to be a priority health and welfare issue. Most research surrounding obesity currently focuses on obesity treatment. However, treatment for feline obesity is slow, often unsuccessful and not without consequences. Identifying high-risk populations for obesity onset is crucial for developing and implementing preventive strategies. This review identifies post-gonadectomy kittens aged 5-12 months as the primary target population for obesity prevention in domestic cats and highlights dietary and feeding management strategies to be implemented for obesity prevention.

Description of the fasted serum metabolomic signature of lean and obese cats at maintenance and of obese cats under energy restriction.

This study aimed to investigate the serum metabolomic profile of obese and lean cats as well as obese cats before and after energy restriction for weight loss. Thirty cats, 16 obese (body condition score 8 to 9/9) and 14 lean (body condition score 4 to 5/9), were fed a veterinary weight loss food during a 4-week period of weight maintenance (L-MAINT and O-MAINT). The 16 obese cats were then energy restricted by a 60% energy intake reduction with the same food for a 10-week period (O-RESTRICT). Fasted serum metabolites were measured using nuclear magnetic resonance and direct infusion mass spectrometry after the maintenance period for L-MAINT and O-MAINT cats and after the energy restriction period for O-RESTRICT and compared between groups using a two-sided t-test. Obese cats lost 672 g ± 303 g over the 10-week restriction period, representing a weight loss rate of 0.94 ± 0.28% per week. Glycine, l-alanine, l-histidine, l-glutamine, 2-hydroxybutyrate, isobutryric acid, citric acid, creatine, and methanol were greater in O-RESTRICT compared to O-MAINT. There was a greater concentration of long-chain acylcarnitines in O-RESTRICT compared to both O-MAINT and L-MAINT, and greater total amino acids compared to O-MAINT. Glycerol and 3-hydroxybutyric acid were greater in O-MAINT compared to L-MAINT, as were several lysophosphatidylcholines. Thus, energy restriction resulted in increased dispensable amino acids in feline serum which could indicate alterations in amino acid partitioning. An increase in lipolysis was not evident, though greater circulating acylcarnitines were observed, suggesting that fatty acid oxidation rates may have been greater under calorie restriction. More research is needed to elucidate energy metabolism and substrate utilization, specifically fatty acid oxidation and methyl status, during energy restriction in strict carnivorous cats to optimize weight loss.

Serum metabolomic analysis of the dose-response effect of dietary choline in overweight male cats fed at maintenance energy requirements.

Choline participates in methyl group metabolism and has been recognized for its roles in lipid metabolism, hepatic health and muscle function in various species. Data regarding the impacts of choline on feline metabolic pathways are scarce. The present study investigated how choline intake affects the metabolomic profile of overweight cats fed at maintenance energy. Overweight (n = 14; body condition score:6-8/9) male adult cats were supplemented with five doses of choline in a 5x5 Latin Square design. Cats received a daily dose of choline on extruded food (3620 mg choline/kg diet) for three weeks at maintenance energy requirements (130 kcal/kgBW0.4). Doses were based on body weight (BW) and the daily recommended allowance (RA) for choline for adult cats (63 mg/kg BW0.67). Treatment groups included: Control (no additional choline, 1.2 x NRC RA, 77 mg/kg BW0.67), 2 x NRC RA (126 mg/kg BW0.67), 4 x NRC RA (252 mg/kg BW0.67), 6 x RA (378 mg/kg BW0.67), and 8 x NRC RA (504 mg/kg BW0.67). Serum was collected after an overnight fast at the end of each treatment period and analyzed for metabolomic parameters through nuclear magnetic resonance (NMR) spectroscopy and direct infusion mass spectrometry (DI-MS). Data were analyzed using GLIMMIX, with group and period as random effects, and dose as the fixed effect. Choline up to 8 x NRC RA was well-tolerated. Choline at 6 and 8 x NRC RA resulted in greater concentrations of amino acids and one-carbon metabolites (P < 0.05) betaine, dimethylglycine and methionine. Choline at 6 x NRC RA also resulted in greater phosphatidylcholine and sphingomyelin concentrations (P < 0.05). Supplemental dietary choline may be beneficial for maintaining hepatic health in overweight cats, as it may increase hepatic fat mobilization and methyl donor status. Choline may also improve lean muscle mass in cats. More research is needed to quantify how choline impacts body composition.

Dose-response relationship between dietary choline and serum lipid profile, energy expenditure, and respiratory quotient in overweight adult cats fed at maintenance energy requirements.

Choline is an essential nutrient linked to hepatic lipid metabolism in many animal species, including cats. The current study investigated the serum lipid profiles, serum liver enzymes, respiratory quotients, and energy expenditures of overweight cats fed maintenance diets, in response to graded doses of supplemental dietary choline. Overweight (body condition score [BCS]: ≥6/9) adult male neutered cats (n = 14) were supplemented with five choline chloride doses for 3-wk periods, in a 5 × 5 Latin square design. Doses were based on individual body weight (BW) and the daily recommended allowance (RA) for choline (63 mg/kg BW0.67) according to the National Research Council. Doses were control (no additional choline: 1.2 × RA, 77 mg/kg BW0.67), 2 × RA (126 mg/kg BW0.67), 4 × RA (252 mg/kg BW0.67), 6 × RA (378 mg/kg BW0.67), and 8 × RA (504 mg/kg BW0.67). Choline was top-dressed over the commercial extruded cat food (3,620 mg choline/kg diet), fed once a day at maintenance energy requirements (130 kcal/kgBW0.4). Body weight and BCS were assessed weekly. Fasted blood samples were taken and indirect calorimetry was performed at the end of each 3-wk period. Serum was analyzed for cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, non-esterified fatty acids, glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), and alanine aminotransferase. Very low-density lipoprotein cholesterol (VLDL) and low-density lipoprotein cholesterol were calculated. Data were analyzed via SAS using proc GLIMMIX, with group and period as the random effects, and treatment as the fixed effect. Statistical significance was considered at P < 0.05. Body weight and BCS did not change (P > 0.05). Serum cholesterol, HDL-C, triglycerides, and VLDL increased with 6 × RA (P < 0.05). Serum ALP decreased with 8 × RA (P = 0.004). Choline at 4 × and 6 × RA decreased serum BUN (P = 0.006). Fed or fasted respiratory quotient and energy expenditure did not differ among dietary choline doses (P > 0.05). These results suggest that dietary choline supplementation at 6 × RA may increase hepatic fat mobilization through increased lipoprotein transport and beneficially support hepatic health in overweight cats. Future studies that combine these results with existing knowledge of feline weight loss and hepatic lipidosis are warranted.

Choline is an essential nutrient important for lipid metabolism in the liver of many mammals. In the present study, fourteen overweight cats had their commercial extruded cat food top-dressed with different amounts of choline chloride supplement. The amounts of choline were based on the individual body weights and the published recommended allowance (RA) for dietary choline intake in adult cats. The choline treatments were control (no additional choline added, 1.2 × RA), 2 × RA, 4 × RA, 6 × RA, and 8 × RA. The cats were separated into five groups. Each group received the choline treatments once daily for 3 wk per treatment. Choline at 6 × RA increased serum cholesterol, triglycerides, and lipoproteins. There were no significant differences in respiratory quotient or energy expenditure with choline intake. The results of this study suggest that choline at 6 × RA increases the transport of lipids from the liver. This may be beneficial in supporting liver health in overweight cats. Future studies should investigate supplementing choline to cats undergoing weight loss and those at risk of developing fatty liver.

Dietary choline in gonadectomized kittens improved food intake and body composition but not satiety, serum lipids, or energy expenditure.

Gonadectomy is a major risk factor for feline obesity. The lipotropic effects of choline have demonstrated benefits for growth and carcass composition in livestock. The consumption of supplemental choline on body weight (BW), body composition, lipid metabolism, energy expenditure (EE), and serum satiety hormones were evaluated in 15 gonadectomized male kittens. Kittens were offered a base diet formulated for growth (3310mg choline/kg dry matter [DM]) to daily energy requirements (DER) over an 11-week acclimation. Post-gonadectomy, kittens were assigned to a base diet (CONTROL, n = 7) or choline group (base diet with additional choline at 300mg/kg BW0.75 as a top dress) (CHOLINE, n = 8). For 12-weeks post-neuter, kittens were offered three times their DER over three meals to mimic ad libitum feeding. At week -1 and 12, body composition was assessed using dual energy x-ray absorptiometry (DXA), 24-hour indirect calorimetry was performed for EE and respiratory quotients (RQ), and fasted serum samples were analyzed for lipid compounds and satiety hormones. Daily food intake (FI) and weekly BW were measured. Data was analyzed as a repeated measures of variance (ANCOVA) using the GLIMMIX procedure with time and group as fixed effects. CHOLINE had lower mean daily FI and lower rates of BW accretion (P<0.05) in contrast to CONTROL. All absolute body composition data increased over time for both groups, with lower increases in total tissue mass (P = 0.031) and fat mass (P = 0.005) in CHOLINE. Serum satiety hormones and lipid compounds did not differ (P>0.05) between groups, but both groups experienced a decrease in low-density lipoproteins and increase in high-density lipoproteins (P<0.05). Primary substrate utilization showed lipid use when fasted and use of protein or mixed macronutrients in the fed state. Fed state EE decreased post-gonadectomy (P = 0.004), however, CHOLINE did not affect total EE or RQ. These results suggest that supplemental dietary choline reduces FI, BW, and fat mass and may help to reduce the propensity of weight gain and subsequent obesity in gonadectomized feline populations.

A functionalized heterobimetallic (99m)Tc/Re complex as a potential dual-modality imaging probe: synthesis, photophysical properties, cytotoxicity and cellular imaging investigations.

A novel bimodal fluorescent/radiolabelled probe based on a pyridyltriazole scaffold (known as pyta) is reported here. The final dual imaging agent combines carboxylate functionalization, for biomolecule conjugation, with two distinct metal chelating sites: a pyta-based tricarbonylrhenium moiety as a fluorescent probe and a (99m)Tc(CO3)(+) core through the tridentate chelating iminodiacetic acid (IDA) clamp as a SPECT reporter. The heterodinuclear (99m)Tc/Re complex , as well as its non-radioactive dirhenium analog , was prepared in six steps. The (99m)Tc/Re agent is water-soluble and stable against histidine challenge. Its structural characterization was achieved by HPLC comparison with the non-radioactive complex . Upon excitation in the MLCT band at 321 nm, the compound exhibits a bright green luminescence centered at 496 nm, with a quantum yield of 0.86% in Tris buffer, pH 7.4. Additionally, the influence of this compound on cell viability was tested on malignant cell lines (A549, HT29 and MCF-7 human lung, colon and breast carcinomas, respectively). Cell viability after 72 h incubation at 37 °C with 300 µmol of complex was >60% for all cell lines. Finally, cellular uptake studies of compound were performed by fluorescent microscopy, showing that the complex was clearly detected at the cellular level in A549 cells and to a lesser extent in HT29 cells. Taking into consideration the luminescent properties, the good radiochemical purity and the promising biological data (in vitro stability, non-toxicity, and cell tracking in two cell lines), the functionalized (99m)Tc/Re dinuclear compound can be considered a potential pre- and intraoperative diagnostic probe.