Tunable Neuromorphic Switching Dynamics via Porosity Control in Mesoporous Silica Diffusive Memristors.

In response to the growing need for efficient processing of temporal information, neuromorphic computing systems are placing increased emphasis on the switching dynamics of memristors. While the switching dynamics can be regulated by the properties of input signals, the ability of controlling it via electrolyte properties of a memristor is essential to further enrich the switching states and improve data processing capability. This study presents the synthesis of mesoporous silica (mSiO2) films using a sol-gel process, which enables the creation of films with controllable porosities. These films can serve as electrolyte layers in the diffusive memristors and lead to tunable neuromorphic switching dynamics. The mSiO2 memristors demonstrate short-term plasticity, which is essential for temporal signal processing. As porosity increases, discernible changes in operating currents, facilitation ratios, and relaxation times are observed. The underlying mechanism of such systematic control was investigated and attributed to the modulation of hydrogen-bonded networks within the porous structure of the silica layer, which significantly influences both anodic oxidation and ion migration processes during switching events. The result of this work presents mesoporous silica as a unique platform for precise control of neuromorphic switching dynamics in diffusive memristors.

Treatment with liraglutide or naltrexone-bupropion in patients with genetic obesity: a real-world study.

Background: Rare genetic obesity commonly features early-onset obesity, hyperphagia, and therapy-resistance to lifestyle interventions. Pharmacotherapy is often required to treat hyperphagia and induce weight loss. We describe clinical outcomes of glucagon-like peptide-1 analogue liraglutide or naltrexone-bupropion treatment in adults with molecularly confirmed genetic obesity (MCGO) or highly suspected for genetic obesity without definite diagnosis (HSGO). Methods: We conducted a real-world cohort study at the Obesity Center CGG at Erasmus University Center, Rotterdam, Netherlands, between March 19, 2019, and August 14, 2023. All patients with MCGO and HSGO who were treated with either liraglutide or naltrexone-bupropion were included. Liraglutide 3 mg and naltrexone-bupropion were administered according to the manufacturer's protocol. Treatment evaluation occurred short-term, after 12 weeks on maximum or highest-tolerated dose, preceded by the 4-5 week dose escalation phase. Differences in anthropometrics, body composition, metabolic markers, self-reported appetite, eating behaviour, and quality of life (QoL) were evaluated. Findings: Ninety-eight adults were included in the analysis: 23 patients with MCGO and 75 patients with HSGO, with median BMI of 42.0 kg/m2 (IQR 38.7-48.2) and 43.7 kg/m2 (IQR 38.0-48.7), respectively. After liraglutide treatment, median weight at evaluation significantly decreased compared to baseline in both groups: -4.7% (IQR -6.0 to -1.5) in patients with MCGO and -5.2% (IQR -8.1 to -3.5) in patients with HSGO. Additionally, improvements were observed in appetite, fat mass, fasting glucose, and HbA1c in both patients with MCGO and with HSGO. Patients with HSGO also reported significant improvements in several domains of QoL and eating behaviour. In patients with MCGO and HSGO treated with naltrexone-bupropion, mean weight at evaluation significantly differed from baseline: -5.2% ± 5.8 in patients with MCGO and -4.4% ± 4.7 in patients with HSGO. Appetite, fat mass, and waist circumference significantly decreased in both groups. Obesity-related comorbidities improved in significant proportions of patients treated with liraglutide or naltrexone-bupropion. Interpretation: In conclusion, our short-term findings show potential of liraglutide and naltrexone-bupropion as treatment options for adults with (a clinical phenotype of) genetic obesity. Funding: MB, EvdA, and EvR are supported by the Elisabeth Foundation, a non-profit foundation supporting academic obesity research.

Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

OBJECTIVE: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. METHODS: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. RESULTS: A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patients with CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001). CONCLUSIONS: We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.

Improved Physical and Mental Health After a Combined Lifestyle Intervention with Cognitive Behavioural Therapy for Obesity.

Background: Obesity is a multifactorial, chronic, progressive disease associated with decreased health-related quality of life, comorbidities, and increased mortality risk. Lifestyle interventions, focusing on dietetics, physical exercise, and behavioral therapy, are a cornerstone of therapy. Despite this very multidisciplinary treatment approach, the definition of treatment success is often based only on a weight loss of ≥ 5%. However, the heterogeneous nature of obesity may necessitate a more comprehensive approach to assessing treatment effects. Objectives: Here, we describe changes in physiological, psychological, and behavioral health after a multidisciplinary combined lifestyle intervention (CLI). Additionally, we investigated whether these changes were related to weight loss. Methods: This prospective observational longitudinal study comprised 96 adults with obesity (73 women, 81 Caucasian) participating in a CLI at the Obesity Center CGG, Erasmus University Medical Center, Rotterdam, the Netherlands. The 1.5-year intervention comprised multidisciplinary professional guidance towards a healthy diet, increased physical activity, and included cognitive behavioral therapy. Physiological health outcomes, psychological well-being, eating behavior, and physical activity were assessed after ten weeks and 1.5 years and compared to baseline. Results: An average of 5.2% weight loss (-6.0 kg) was accompanied by a mean 9.8% decrease in fat mass (-5.9 kg; both P < 0.001) and significant improvements in metabolism, hormonal status, and immune parameters (all P < 0.05). Moreover, we observed decreased psychopathology, increased quality of life, and decreased disordered eating (all P < 0.05). Weight loss correlated with most metabolic changes (all P < 0.05) but not with most psychological/behavioral changes. Conclusions: Combined lifestyle intervention in patients with obesity was accompanied by significant improvements in body weight and body composition along with cardiometabolic, endocrine, immunological, psychological, and behavioral improvements. Interestingly, most changes in psychological and behavioral health occurred independently of weight loss. Obesity treatment success should be evaluated based on a combination of physical and patient-reported outcomes rather than weight loss alone.

Resting Energy Expenditure and Body Composition in Children and Adolescents With Genetic, Hypothalamic, Medication-Induced or Multifactorial Severe Obesity.

Background: Pediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure. Aim: To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with or without underlying medical causes. Methods: This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression. Results: We included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p<0.01). In 9 children with pseudohypoparathyroidism type 1a, mean REE% was similar (100.4 ± 5.1). Across all patients, mREE was decreased in 60 (21%) patients and elevated in 69 (24%) patients. After adjustment for FFM, mREE did not differ between patients within each of the subgroups of underlying medical causes compared to multifactorial obesity (all p>0.05). Conclusions: In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE.

Effects of glucagon-like peptide-1 analogue treatment in genetic obesity: A case series.

Obesity is highly prevalent and comes with serious health burden. In a minority, a genetic cause is present which often results in therapy-resistant obesity. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue, which has beneficial effects on satiety and weight in common obesity. We present the effects of GLP-1 analogues in adults with a molecularly proven genetic cause of their overweight or obesity. All patients were treated with liraglutide 3.0 mg daily, in addition to intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Two patients with 16p11.2 deletion syndrome and two patients with heterozygous pathogenic melanocortin-4 receptor variants were treated. At baseline, their age ranged between 21 and 32 years and body mass index (BMI) ranged between 28.1 and 55.7 kg/m2 . At follow-up (ranges 43 weeks-12 years), a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients achieved ≥5% weight loss, three of them lost ≥10% of their body weight. All patients reported improved quality of life and three of them reported ameliorated satiety. Moreover, improvement of glycaemic control and dyslipidaemia were seen. In two patients, REE before and during treatment was measured, which either increased (+26% of predicted REE) or decreased (-18% of predicted REE). Two patients experienced mild side effects for a brief period. In conclusion, our case series shows beneficial effects of GLP-1 analogues on weight, metabolic parameters and quality of life in all four patients with genetic obesity.

Clinical management of patients with genetic obesity during COVID-19 pandemic: position paper of the ESE Growth & Genetic Obesity COVID-19 Study Group and Rare Endo-ERN main thematic group on Growth and Obesity.

This article aims to provide guidance on prevention and treatment of COVID-19 in patients with genetic obesity. Key principals of the management of patients with genetic obesity during COVID-19 pandemic for patients that have contracted COVID-19 are to be aware of: possible adrenal insufficiency (e.g., POMC deficiency, PWS); a more severe course in patients with concomitant immunodeficiency (e.g., LEP and LEPR deficiency), although defective leptin signalling could also be protective against the pro-inflammatory phenotype of COVID-19; disease severity being masked by insufficient awareness of symptoms in syndromic obesity patients with intellectual deficit (in particular PWS); to adjust medication dose to increased body size, preferably use dosing in m2; the high risk of malnutrition in patients with Sars-Cov2 infection, even in case of obesity. Key principals of the obesity management during the pandemic are to strive for optimal obesity management and a healthy lifestyle within the possibilities of the regulations to prevent weight (re)gain and to address anxiety within consultations, since prevalence of anxiety for COVID-19 is underestimated.

Ethnic variation in infant-feeding practices in the Netherlands and weight gain at 4 months.

This prospective study of 4438 infants (0-4 months) examined differences in infant-feeding patterns in relation to the ethnic origin of their mothers, based on the mother's native language: Dutch (87%), Turkish (4%), Moroccan (3%), other European languages (3%), and various other languages (4%). Breastfeeding at birth varied between 75% and 94%. Dutch and Moroccan mothers breastfed for a shorter period (32% and 37% at 4 months, respectively) than did Turkish mothers and mothers with a native European language other than Dutch (47% and 51% at 4 months, respectively; P < .001). Of all mothers, 71% started exclusive breastfeeding at birth, and 21% continued exclusive breastfeeding for at least 4 months. The reasons why mothers discontinued breastfeeding (both exclusive breastfeeding and breastfeeding) were generally infant related. The average weight gain between birth and day 133 was 3.45, 3.87, and 3.69 kg for Dutch, Turkish, and Moroccan infants, respectively. Weight gain was influenced by ethnicity of the mothers and exclusive breastfeeding.

Determinants of Advanced Bone Age in Childhood Obesity
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BACKGROUND: Childhood obesity is associated with advanced bone age (BA). Previous studies suggest that androgens, oestrogens, sex hormone-binding globulin, and insulin are responsible for this phenomenon, but results are contradictory and might be biased by confounders. We aim to elucidate this matter by applying a multivariate approach. METHOD: We performed a correlation analysis of BA standard deviation score (SDS) with age- and sex-specific SDS for androgens, oestrogens, and with indicators of insulin secretion derived from oral glucose tolerance testing, in a group of obese children. A multivariate analysis was performed to investigate which parameters were independently predictive of BA SDS. RESULTS: In this cohort (n = 101; mean age 10.9 years; mean BA 11.8 years; mean BMI SDS 3.3), BMI SDS was significantly correlated to BA SDS (r = 0.55, p < 0.001). In a regression analysis in the total cohort (B = 0.27, p < 0.001) as well as in females (B = 0.34, p = 0.042), males (B = 0.31, p = 0.006), and pubertal children (B = 0.32, p = 0.046), dehydroepiandrosterone sulphate (DHEAS) showed a positive, independent association with BA SDS. No association with indicators of insulin secretion was found. CONCLUSION: BMI SDS is highly correlated to BA SDS in obese children. Increased DHEAS has a central role in advanced BA in obese children.
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Lysosomal destabilization contributes to apoptosis of germinal center B-lymphocytes.

During germinal center (GC) reactions, B-lymphocytes with high-affinity B-cell receptors are selected. Regulation of apoptosis is a key process in selecting such wanted B-cells and in eliminating B-cells with unwanted specificities. In this paper, we show that apoptosis in human GC B-cells involves lysosomal destabilization, which is strictly controlled by caspase-8 activity, but not by caspase-9 activity. Ligation of CD40 provides resistance to lysosomal destabilization. Experimental lysosomal rupture by the lysosomotropic drug O-methyl-l-serine dodecylamide hydrochloride (MSDH) induces apoptosis in GC B-cells, including phosphatidyl serine exposure, mitochondrial inactivation, and DNA fragmentation. These apoptotic features occur in the absence of caspase-3 activity. Follicular dendritic cells (FDCs) protect binding B-lymphocytes from lysosomal destabilization, in both the absence and the presence of MSDH. Our study demonstrates that lysosomal leakage induces apoptosis of GC B-cells in a caspase-3-independent manner and that high-affinity binding to FDCsprevents lysosomal leakage and apoptosis in GC B-cells.

Proteinases and their inhibitors in the immune system.

The most important roles of proteinases in the immune system are found in apoptosis and major histocompatibility complex (MHC) class II-mediated antigen presentation. A variety of cysteine proteinases, serine proteinases, and aspartic proteinases as well as their inhibitors are involved in the regulation of apoptosis in neutrophils, monocytes, and dendritic cells, in selection of specific B and T lymphocytes, and in killing of target cells by cytotoxic T cells and natural killer cells. In antigen presentation, endocytosed antigens are digested into antigenic peptides by both aspartic and cysteine proteinases. In parallel, MHC class II molecules are processed by aspartic and cysteine proteinases to degrade the invariant chain that occupies the peptide-binding site. Proteinase activity in these processes is highly regulated, particularly by posttranslational activation and the balance between active proteinases and specific endogenous inhibitors such as cystatins, thyropins, and serpins. This article discusses the regulation of proteolytic processes in apoptosis and antigen presentation in immune cells and the consequences of therapeutic interference in the balance of proteinases and their inhibitors.

Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor.

PURPOSE: For the last decade chromogranin-A (CgA) has been a well-established marker for neuroendocrine tumor (NET), and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been a useful marker for left ventricular dysfunction. This study examined the diagnostic value of CgA and NT-proBNP for carcinoid heart disease (CHD), and their prognostic value for overall survival in NET patients. PATIENTS AND METHODS: Serum samples were obtained and cardiac ultrasound studies performed in 102 NET patients. The criterion for mild and severe CHD was tricuspid regurgitation stage I/II and III/IV, respectively. Proportional odds and Cox proportional hazards models were constructed respectively to identify the association between CHD and overall survival with patient characteristics and the two markers. RESULTS: Severe CHD was found in 15 (15%) of 102 patients, 13 of whom had elevated NT-proBNP levels. In the univariate proportional odds model CHD was correlated with age (P = .007), CgA (P = .002), and NT-proBNP (P < .001), whereas in the multivariate model NT-proBNP and CgA were significantly associated with CHD (P < .001 and P = .01). In the univariate Cox models, age (P = .04), sex (P = .03), CgA (P = .003), and NT-proBNP (P = .04) were related to overall survival, and in the multivariate model CgA and NT-proBNP remained significantly related to overall survival (P = .002 and P = .04, respectively). CONCLUSION: NT-proBNP and CgA are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.

Human follicular dendritic cells: function, origin and development.

Follicular dendritic cells (FDCs) have important functions in the selection of memory B lymphocytes during germinal center reactions (GCR). They present native antigens to potential memory cells, of which only B cells with high affinity B cell receptors (BCR) can bind. These B lymphocytes survive, whereas nonbinding B cells undergo apoptotic cell death. FDCs are present in follicles of any secondary lymphoid organ and belong to the stromal cells of these organs. Ectopic FDC-formation can be found in a number of autoimmune diseases and/or chronic inflammatory situations. This indicates that the development of FDCs is not restricted to secondary lymphoid organs, but that it is rather a matter of local conditions that drives a precursor cell type into FDC-maturation. A precursor of FDCs has presently not been identified, but phenotypic marker studies, in vitro experiments with fibroblast-like cell lines, and recent data on mesenchymal precursor cells from the peripheral blood suggest a close relation to fibroblast-like cells.

Therapeutic efficacy of IL-2-loaded hydrogels in a mouse tumor model.

Interleukin-2 (IL-2) is a highly effective anticancer drug if it is applied locally for 5 consecutive days. In most cases this requires 5 invasive treatments, which is not usually acceptable for either the patient or the clinician. For this reason we have developed dextran-based hydrogels from which the required amount of encapsulated IL-2 (1-4 x 10(6) IU of IL-2) is gradually released during 5-10 days. Initially IL-2-containing macroscopic cylinder-shaped gels (implants), and later IL-2-containing injectable microspheres, were developed. These preparations were characterized in vitro, and the therapeutic activity was tested in DBA/2 mice with SL2 lymphosarcoma. The therapy was given to mice with a large and extensively metastasized tumor load (at least 5% of the body weight). If 1-4 x 10(6) IU of IL-2 was slowly released from the hydrogels over a period of 5-10 days, the therapeutic effects were very good and comparable to the effects of free IL-2 injections for 5 consecutive days. In conclusion, dextran-based hydrogels are promising systems for the controlled release of IL-2.

Weight and weight gain at 4 months (The Netherlands 1998): influences of nutritional practices, socio-economic and ethnic factors.

We describe the determinants of weight gain in the first 4 months of life in a cohort of 3256 infants. The study was designed as a survey with follow-up. In the period 1 April to 1 July 1998, all infants, usually 4 weeks old but not older than 4 months, brought to a well-baby clinic for the first time were included. Nutritional practices, demographic data on mother and child, birthweight and a second weight measured between days 118 and 147 were recorded. Simple and multiple linear regression analyses were performed. The average weight gain over 4 months was 27.7 g/day for boys and 24.5 g/day for girls. Weight gain was lower with high parity and if the mother was a native Dutch speaker. Nutritional practices affected weight gain only slightly: exclusive breast feeding for 4 months lowered the weight gain by 0.06 g/day. However, because of their higher birthweight, breast-fed infants weighed a little more than formula-fed infants at 4 months. In addition, we compared the median weight at the age of 4 months with the median weight at the same age in previous Dutch growth studies. The median weight, adjusted to day 133, was higher in 1998 than in 1965, 1980 and 1997 (boys 7.15 vs. 6.85, 6.77 and 6.95 kg; girls 6.59 vs. 6.49, 6.39 and 6.45 kg respectively).