Treatment of External Auditory Canal Exostoses

Exostoses of the external auditory canal can occur in patients living in coastal, southern California communities with a history of cold-water aquatic activities such as ocean surfing and swimming. Although most canal exostoses are asymptomatic, patients with canal obstruction greater than 80% can have recurrent episodes of external otitis and a related conductive hearing loss. In most cases, medical treatment resolves the symptomatic external otitis and related hearing loss. Patients recalcitrant to medical treatment are candidates for surgical removal of the exostoses. This report reviews the authors' surgical experience with 18 patients (27 ears) who have undergone surgical removal of exostoses. Their preferred surgical technique of transmeatal removal of exostoses with a specialized mallet and thin chisel under local anesthesia is described.     

Recognition and management of neuropsychiatric complications in Parkinson's disease

Parkinson's disease is primarily considered a motor disease characterized by rest tremor, rigidity, bradykinesia and postural disturbances. However, neuropsychiatric complications, including mood and anxiety disorders, fatigue, apathy, psychosis, cognitive impairment, dementia, sleep disorders and addictions, frequently complicate the course of the illness. The pathophysiologic features of these complications are multifaceted and include neuropathophysiologic changes of a degenerative disease, exposure to antiparkinsonian treatments and emotional reactions to having a disabling chronic illness. Changes in mental status have profound implications for the well-being of patients with Parkinson's disease and of their caregivers. Treatment is often efficacious but becomes a challenge in advanced stages of Parkinson's disease. In this article, we review the key clinical features of neuropsychiatric complications in Parkinson's disease as well as what is known about their epidemiologic characteristics, risk factors, pathophysiologic features and management.     

Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients.

PURPOSE: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. EXPERIMENTAL DESIGN: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. RESULTS: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (V(D)), 30.3 liters; absorption constant rate, 5.8 h(-1); elimination half-time, 2.1 h; transfer rate from plasma to CSF (K(plasma-->CSF)), 7.2 x 10(-4)h(-1) and the backwards rate, 0.76 h(-1). Body surface area significantly influenced both clearance and V(D), and clearance was sex dependent. The AUC(CSF) corresponded to 20% of the AUC(plasma). A trend toward an increased K(plasma-->CSF) of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. CONCLUSIONS: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC(CSF)/AUC(plasma) ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.     

Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population‐based NutriNet‐Santé cohort

Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n = 696) were incident cancer cases diagnosed in the NutriNet‐Santé cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24‐hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=‐102.4 ± 79.8 g/d), dairy products (–93.9 ± 82.8 g/d), meat/offal (–35.5 ± 27.8/d), soy products (–85.8 ± 104.1 g/d), sweetened soft drinks (–77.9 ± 95.4 g/d), and alcoholic drinks (–92.9 ± 119.9 g/d), and an increase in broths (42.1 ± 34.9 g/d) and fats/sauces (18.0 ± 13.4 g/d). We observed a decrease in energy intake (–377.2 ± 243.5 kcal/d) and in intakes of alcohol (–7.6 ± 9.4 g/d) proteins (–17.4 ± 12.5 g/d), and several vitamins (p < 0.05) and micronutrients (p < 0.05). Conversely, lipid (19.4 ± 14.6 g/d), SFA (9.3 ± 7.0 g/d), MUFA (8.3 ± 6.3 g/d) and vitamin E (3.9 ± 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors.     

The clinical course of interstitial lung disease in an adult patient with an ABCA3 homozygous complex allele under hydroxychloroquine and a review of the literature

Objective: The gene mutations responsible for ABCA3 protein deficiency are involved in respiratory distress of the newborn and much more rarely in adult interstitial lung diseases (ILD). An adult patient homozygous for a complex allele encompassing the p.Ala1027Pro likely pathogenic mutation and the p.Gly974Asp variation was followed for a late-onset and fibrotic ILD. The evolution was marked by progressive clinical and functional degradation despite corticosteroid pulses. The patient, who was first registered on the list for lung transplantation, was improved quickly and persistently for at least 6.5 years with hydroxychloroquine treatment, allowing removal from the transplant list.     

Nutri-Score and NutrInform Battery: Effects on Performance and Preference in Italian Consumers

In May 2020, the European Commission announced a proposal for a mandatory front-of-pack label (FoPL) for all European Union (EU) countries. Indeed, FoPLs have been recognized by several public institutions as a cost-effective measure to guide consumers toward nutritionally favorable food products. The aim of this study was to compare the performance and consumer preference of two FoPLs currently proposed or implemented in EU countries, the interpretive format Nutri-Score and the non-interpretive format NutrInform Battery, among Italian consumers. The experimental study was conducted in 2021 on a representative sample of 1064 Italian adults (mean age = 46.5 ± 14.1 years; 48% men). Participants were randomized to either Nutri-Score or NutrInform and had to fill out an online questionnaire testing their objective understanding of the FoPL on three food categories (breakfast products, breakfast cereals and added fats) as well as purchase intention, subjective understanding and perception. Multivariable logistic regressions and t-tests were used to analyze the answers. In terms of the capacity of participants to identify the most nutritionally favorable products, Nutri-Score outperformed NutrInform in all food categories, with the highest odds ratio being observed for added fats (OR = 21.7 [15.3–31.1], p < 0.0001). Overall, with Nutri-Score, Italian participants were more likely to intend to purchase nutritionally favorable products than with NutrInform (OR = 5.29 [4.02–6.97], p < 0.0001). Focusing on olive oil, participants of the Nutri-Score group had higher purchase intention of olive oil compared to those in the NutrInform group (OR = 1.92 [1.42–2.60], p < 0.0001) after manipulating the label. The interpretive format Nutri-Score appears to be a more efficient tool than NutrInform for orienting Italian consumers towards more nutritionally favorable food choices.     

Effect of CSL112 (apolipoprotein A‐I [human]) on cholesterol efflux capacity in Japanese subjects: Findings from a phase I study and a cross‐study comparison

CSL112 (apolipoprotein A‐I [apoA‐I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA‐I increased in a dose‐dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline‐corrected area under the curve from 0 to 72 h (AUC_0–72) increased from 840 to 6490 mg h/dl, in the 2 and 6 g cohorts, respectively, followed by dose‐dependent increase of CEC. The plasma PK profile of apoA‐I and increases in total and ATP binding cassette transporter A1 dependent CEC were comparable in Japanese and White subjects. The geometric mean ratio (Japanese:White) for plasma apoA‐I AUC_0–72 and maximum plasma concentration (C_max) was 1.08 and 0.945, respectively. Cross‐study comparison analysis demonstrated similar CSL112 exposure and CEC enhancement in Japanese and non‐Japanese subjects (including patients with cardiovascular disease) and further confirmed consistent PKs/PDs of CSL112. This study suggests CSL112 acutely enhances CEC and is well‐tolerated with no differences between Japanese and White subjects.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Cholesterol efflux, mediated by apolipoprotein A‐I (apoA‐I), removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion; impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates. CSL112 (apoA‐I, human) has been shown to enhance cholesterol efflux capacity and is being investigated as a novel therapy to reduce the risk of early recurrent CV events. Japanese ethnicity is known to confer differences in lipoprotein metabolism. WHAT QUESTION DID THIS STUDY ADDRESS? This ethno‐bridging study characterized the pharmacokinetics (PKs), pharmacodynamics, safety and tolerability of CSL112 in healthy Japanese subjects compared with healthy White subjects to identify any ethnicity‐based differences in cholesterol efflux capacity (CEC) and safety issues and determine the appropriate dose in Japanese subjects prior to inclusion in future or ongoing studies. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Japanese ethnicity confers no clinically relevant difference in CSL112 exposure and CEC compared to White populations and safety profiles were comparable between populations. This study supports the inclusion of Japanese subjects in an ongoing phase III study, investigating the impact of CSL112 on CV risk reduction post‐myocardial infarction, with no dose adjustment needed. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study contributes to the discussion around PK differences between ethnic groups. It confirms similarity of apoA‐I exposure and CEC responses in Japanese and White populations, which warrants further investigation of this novel treatment approach to reduce the risk of early recurrent CV events.