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Older adults are an inherently heterogeneous population with various underlying pathologies, medication use, and habits. In this study, the variability of this population was studied for the gastric and duodenal fluid volumes, as the amount of gastrointestinal volumes could play an essential role in the dissolution of drugs. The fluid volumes were retrospectively quantified by using magnetic resonance imaging (MRI). In 265 included fasted older individuals, the gastric fluid volume was 28.9 ± 21.1 mL (arithmetic mean ± standard deviation). No significant covariate-effect on stomach fluid volume was observed for various medication use, pathologies, and habits (e.g. hypertension, smoking, proton-pump inhibitors (PPIs), and aspirin). The gastric fluid volume remained constant with increasing age and had a high variability. The volumes and the variability were, however, not higher than the gastric values reported in healthy younger adults. The duodenal fluid volume was 16.6 ± 10.0 mL and a slight but statistically significant decrease with age was seen. In addition, cystic pancreas, obesity, diuretics, and PPI use demonstrated a moderate but significant correlation with the duodenal fluid volume. The findings of this study could be considered when developing and testing new drug candidates for the older adult population. For example, the volumes including their variability could be used as an input in physiologically based pharmacokinetic (PBPK) modelling approaches to predict drug exposure in this population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cleo Demeester reports financial support was provided by Horizon 2020 research and innovation programme. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest that are directly relevant to the content of this article., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cardiac amyloidosis (CA) is often overlooked or misdiagnosed. Effects of growing disease awareness, diagnostic ameliorations and novel treatment options on CA diagnosis and management are scarcely reported., Objective: To report trends in diagnosis, referral routes, clinical presentation, early onset diagnostic red flags and outcome in de novo CA subjects., Methods: An unselected cohort of 139 de novo CA patients over an 8-year period in a tertiary referral hospital was recruited., Results: Transthyretin (ATTR, 82%, n  = 114) was the most common CA form; Light-chain (AL, 15%, n  = 21) and secondary (AA, 3%, n  = 4) are less prevalent. Increased awareness over time led to a marked ATTR diagnostic surge, steep non-invasive diagnostic approach increment and increased nuclear medicine and external cardiologist referrals (all p  < 0.001). A total of 41% ( n  = 57/139) of patients were referred by non-cardiology specialist disciplines. Specific referral to rule out CA (24-36%) and diagnostic time lag from symptom onset (9 ± 12 to 8 ± 14 months), however, did not improve (all p  > 0.050). Multiple early red flag events preceded CA diagnose several years in ATTR: Left ventricular hypertrophy (LVH, 60%, 4.9 ± 4.3 y), heart failure (54%, 2.5 ± 3.5 y), atrial fibrillation (47%, 5.9 ± 6.7 y), bilateral carpal tunnel syndrome (43%, 9.5 ± 5.7 y) and spinal stenosis (40%, 7.4 ± 6.5 y). LVH ≥ 12 mm was absent in 11% ATTR ( n  = 13/114) and 5% AL ( n  = 1/21) patients. Hypertension was common in both ATTR ( n  = 70/114, 62%) and AL ( n  = 10/21, 48%). 56% ( n  = 78/139) of CA presented with heart failure. Cumulative 1 and 5-year mortality of 10%/66%, 40%/52% and 75%/75% for ATTR, AL, and AA, respectively, remains high., Conclusions: Although CA diagnostic uptake and referral improve, specialist-specific disease and diagnostic red flag ignorance result in non-timely diagnosis and unfavourable outcome.

Background: The optimal duration of antithrombotic therapy (ATT) after patent foramen ovale (PFO) closure remains under debate. This study sought to compare the clinical outcome of patients receiving antithrombotic agents for a short (6 months) versus extended (>6 months) period after the procedure., Methods: This was a retrospective cohort study using a propensity score matching analysis on 259 consecutive patients (131 males, 43 ± 10 years) undergoing PFO closure due to cryptogenic stroke, with complete follow-up (median duration of 10 [4-13] years). The outcome was compared between patients receiving short-term (Group short, N  = 88) versus extended ATT (Group long, N  = 171)., Results: The PFO closure device was successfully implanted in all cases, with 3% of minor complications. After propensity score matching, there were no differences between Groups short and long in the rate of stroke (0.3 vs. 0.4% patient-year, p =1.00), bleeding (2 vs. 2% patient-year, p =0.17), and device thrombosis (0.3 vs. 0.1% patient-year; p =0.60). Univariate analysis showed that short-term ATT was not associated with an increased risk of recurrent stroke (HR: 1.271 [95% CI: 0.247-6.551], p =0.775) or prosthesis thrombus (HR: 0.50 [95% CI: 0.070-3.548], p =0.72). Kaplan-Meier analysis revealed similar overall survival in Group short and long (100 vs. 99 ± 1%, respectively; p =0.25)., Conclusions: Short-term (6 months) ATT after PFO closure did not impair the clinical outcome, with a preserved low rate of recurrent stroke (0.3% patient-year) and device thrombosis (0.2% patient-year) at 10-year follow-up., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Joelle Kefer et al.)

The labyrinthine fistula continues to be one of the most common complications in ears with cholesteatoma. Fifty-one patients with labyrinthine fistula were identified in a series of 1243 cases with cholesteatoma operated upon between 1989 and 1993 at the University ENT Clinic Wuerzburg. The surgical management concept comprised of removing the cholesteatoma matrix, categorizing the fistula type, and immediate covering of the labyrinthine capsule defect with bone dust, perichondrium and fibrin glue. The classification system of the fistulae used in the study used the depth of labyrinthine involvement as a criterion and also took into account the possibility of intentional or accidental damage to the labyrinth during surgical manipulation (Fig. 1). From 1991 on, patients were treated with 500 mg of Presnisolon 21 hydrogen succinate in a single intravenous dose, at the time the fistula was corrected. The postoperative hearing results were graded based on the extend of preservation of inner ear function at or near the preoperative level. None of the patients who had corticosteroid therapy suffered a profound sensory neural hearing loss (Fig. 2, 3), whereas five ears without steroids and a deep fistula lost function completely. The study concluded that corticosteroids have a beneficial impact on postoperative outcome in cases with severe injury to the membranous labyrinth.

Lipoprotein (a) (Lp[a]) is a cholesterol-rich lipoprotein resembling LDL but also containing a large polypeptide designated apolipoprotein (a) (apo[a]). Its levels are highly variable among individuals and, in a number of studies, are strongly correlated with the risk of coronary artery disease (CAD). In an effort to determine which genes control Lp(a) levels, we have studied 25 multiplex families (comprising 298 members) enriched for CAD. The apo(a) gene was genotyped among the families, using a highly informative pulse-field gel electrophoresis procedure. In addition, polymorphisms of the gene for the other major protein of Lp(a), apolipoprotein B (apoB), were examined. Quantitative sib-pair linkage analysis indicates that apo(a) is the major gene controlling Lp(a) levels in this CAD population (P = .001; 99 sib pairs), whereas the apoB gene demonstrated no significant quantitative linkage effect. We estimate that the apo(a) locus accounts for < or = 98% of variance of Lp(a) serum levels. Approximately 43% of this variation is explained by size polymorphisms within the apo(a) gene. These results indicate that the apo(a) gene is the major determinant of Lp(a) serum levels not only in the general population but also in a high-risk CAD population.

A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.

Subclinical involvement of the facial nerve by acoustic neuromas may be identified preoperatively using conventional electroneurography (ENoG). The clinical application of extratemporal stimulation distal to the stylomastoid foramen is limited in these cases by the more proximal site of the lesion. Transcranial magnetic coil stimulation (MCS) is a noninvasive means by which the facial nerve is stimulated at the level of the motor cortex or the brain stem, before it enters the internal auditory canal. Topographically such an assessment may have more diagnostic relevance than other forms of electrical stimulation in acoustic neuroma patients. To test this theory the facial nerves of 20 patients with acoustic neuromas were stimulated using ENoG and MCS preoperatively and 1 week postoperatively. Stimulation parameters were comparable and included threshold and suprathreshold levels of stimulation while compound action potential amplitudes and early and late response latencies were monitored. Facial nerve function was assessed clinically using the Stennert grading system. All the patients had clinically normal facial nerve function preoperatively. Normative data suggested a close correlation between threshold and suprathreshold amplitudes generated by both ENoG and MCS. To the contrary, in the pathologic ears there was a higher incidence of stimulus response abnormality determined by MCS than by ENoG. A comparison of these data, tumor size, and postoperative results promotes further evaluation of MCS as a prognostic index in acoustic neuroma patients.

Subclinical invasion of the facial nerve by acoustic neuromas may be identified preoperatively using conventional electroneurography (ENOG). The clinical application of extratemporal stimulation distal to the stylomastoid foramen is limited in these cases because of the more proximal site of the lesion. Transcranial magnetic coil stimulation (MCS) is a non-invasive means by which the facial nerve is stimulated at the level of the motor cortex or the brain stem before it enters the internal auditory canal. Topographically such an assessment may have more diagnostic relevance than other forms of electrical stimulation in acoustic neuroma patients. To test this theory the facial nerves of 20 patients with an acoustic neuroma were stimulated using ENOG and MCS before and 1 week after operation. Stimulation parameters were comparable and included threshold, double-threshold and supra-threshold levels of stimulation while compound action potential amplitudes and early and late response latencies were monitored. All the patients had clinically normal facial nerve function preoperatively. Using ENOG 65% of the patients showed amplitude reduction on the tumour side, whereas 70% of these patients had a reduction of amplitude to MCS. Combining both techniques, 88% of the patients had a significant amplitude reduction on the neuroma side. Comparison of the preoperative threshold measurements of both techniques showed that there was a significantly higher incidence of detection of lesions on the diseased side in neuromas larger than 2 cm by the use of MCS.

The prognostic value of the use of thrombolytic therapy (TL), the ejection fraction (EF) and the presence of late potentials (LP) in the signal-averaged ECG (filter less than 40 Hz) at the time of hospital discharge was assessed in a multicenter prospective study. This report presents the follow-up at 4 months of the first 263 patients. Thrombolytic therapy was given to 41%. The mean ejection fraction was 45%. The average duration of the high frequency QRS complex (HFQRS) was 104 ms. The mean duration of the terminal signal under 40 microV (D40) was 31 ms. The combination of both HFQRS greater than 110 ms and a D40 greater than 40 ms was considered as presence of LP. The cardiac mortality at 4 months was 5.7% (15 patients). Late ventricular tachycardia or fibrillation occurred in 2.3% (6 patients). The relative risk (RR) for cardiac death or late events was 5.14 with a 95% confidence interval (CI) of 1.2 to 22.0 when no thrombolytic therapy was used. The RR was 3.39 (CI: 1.4 to 8.4) for patients with an EF lower than 30%. The single most important electrocardiographic parameter was a D40 greater than 40 ms (RR: 3.14, CI: 1.3 to 7.8). The presence of LP had a RR of 4.28 (CI: 1.7 to 10.5). With stepwise regression analysis it was evident that cardiac function and information obtained by signal averaging offered independent prognostic information. The presence of LP at hospital discharge after acute infarction offers additional prognostic information to EF for the risk of later cardiac death, especially in patients without thrombolysis.