In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non–small-cell Lung Cancer

Introduction: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. Patients and methods: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. Results: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time.Conclusion: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.</p

Aortic stiffness as an independent predictor of cardiac function and cerebral white matter hyperintensities in diabetes mellitus assessed by Magnetic Resonance Imaging

ObjectivesTo evaluate the effect of local and/or systemic statin use as an adjunct to non-surgical and/or surgical periodontal therapy.Data Literature search according to PRISMA guidelines with the following eligibility criteria: (a) English or German language; (b) interventional studies; (c) statins as monotherapy or as an adjunct to non-surgical and/or surgical treatment of periodontitis; (d) clinical and/or radiographic treatment effect size of statin intake reported.Sources Medline (PubMed), Embase (Ovid), CENTRAL (Ovid). Study selectionThirteen clinical studies regarding local application and 2 with systemic administration of statins as an adjunct to non-surgical treatment (SRP) and 4 studies regarding intrasurgical statin application with a maximum follow-up of 9 months could be included; simvastatin, atorvastatin, and rosuvastatin were used. Local but not systemic statin application as an adjunct to SRP yielded significantly larger probing pocket depth (PD), radiographic defect depth (RDD), and bleeding index reduction, and larger clinical attachment level gain, and less residual PD and RDD (p≤0.016); rosuvastatin appeared as the most efficacious. Three of 4 studies reported a significant positive effect of intrasurgical statin application. No adverse events were reported after statin use. The vast majority of the included studies were from the same research group.ConclusionsSignificant additional clinical and radiographic improvements are obtained after local, but not systemic, statin use as an adjunct to SRP in deep pockets associated with intrabony defects and seemingly with furcation defects; intrasurgical statin application seems similarly beneficial. Confirmation of these results, and especially of the effect size, from other research groups is warranted

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

A non-linear field model of pattern formation with application to biological regulation

The study of complex physical systems promises inspiration, new conceptual approaches, and techniques for creating a theoretical foundation of biology. In particular, in the area of pattern formation, questions which are being explored from the physical point of view, such as the dynamics of growth, formation of pattern boundaries, occurrence of phase transitions, changes in symmetry, etc., may also be extended to the biological context. The multi-disciplinary seard1 is ongoing, not only for the solutions to dynamical equations, but even for appropriate basic models that capture the essence of pattern formation mechanisms. Useful insights into pattern formation problems in biological systems have been gained from the 'polar coordinate model' of positional information (French et al., 1976). On the other hand, the polar coordinate model lacks the formal structure to deal with global reorganization when an overall change in the size of the system occurs. To overcome this limitation and explore the insights offered into pattern formation by this established biological framework, we propose a morphogenetic field model of pattern formation, a physical model (Ginzburg Laundau theory) guided into particular form by biological phenomenology. We apply our model to pattern changes observed experimentally in Tetrahymena doublets, which show, in the conversion of two oral structures back to one, a surprising intermittent state with three oral structures. Our morphogenetic field model allows us to see 'why 3 is between 2 and 1', and to make detailed predictions on the location of pattern elements, novel cell configurations, and dynamical pathways of pattern formation. We conclude that the morphogenetic field approach has been very fruitful, in offering a 'simple' physical explanation for the enigmatic patterns of Tetrahymena, in suggesting new directions -both experimental and theoretical- for further studies of pattern formation, and in supporting the unification of the formalism, phenomenology and concepts of physical theory with the foundations of theory in biology.Ph.D