Precision Medicine for More Oxygen (P4O2)-Study Design and First Results of the Long COVID-19 Extension.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies.

Boronic acid and diol-containing polymers: how to choose the correct couple to form "strong" hydrogels at physiological pH.

Dynamic covalent hydrogels crosslinked by boronate ester bonds are promising materials for biomedical applications. However, little is known about the impact of the crosslink structure on the mechanical behaviour of the resulting network. Herein, we provide a mechanistic study on boronate ester crosslinking upon mixing hyaluronic acid (HA) backbones modified, on the one hand, with two different arylboronic acids, and on the other hand, with three different saccharide units. Combining rheology, NMR and computational analysis, we demonstrate that carefully selecting the arylboronic-polyol couple allows for tuning the thermodynamics and molecular exchange kinetics of the boronate ester bond, thereby controlling the rheological properties of the gel. In particular, we report the formation of "strong" gels (i.e. featuring slow relaxation dynamics) through the formation of original complex structures (tridentate or bidentate complexes). These findings offer new prospects for the rational design of hydrogel scaffolds with tailored mechanical response.

Injectable Self-Healing Hydrogels Based on Boronate Ester Formation between Hyaluronic Acid Partners Modified with Benzoxaborin Derivatives and Saccharides.

We demonstrate here, for the first time, formation of injectable dynamic covalent hydrogels at physiological pH using benzoxaborin-saccharide complexation as a reversible cross-linking method. The gels were prepared by simply mixing hyaluronic acid modified with an original boronic acid derivative, 3,4-dihydro-2H-benzo[e][1,2]oxaborinin-2-ol (1,2-ABORIN), and HA functionalized with 1-amino-1-deoxy-d-fructose. Dynamic rheological experiments confirmed the gel-like behavior (storage modulus (G') > loss modulus (G″) in the frequency window explored) for the designed HA-1,2-ABORIN/HA-fructose network. Furthermore, this hydrogel exhibited excellent self-healing and injectability behaviors in aqueous conditions and was found to be responsive to pH. Additionally, fibroblast cells encapsulated in the HA network showed high viability (>80% after 7 days of cell culture), as monitored by Live/Dead staining. Taken together, this new class of boronate ester cross-linked hydrogel provides promising future for diverse biomedical applications.

The Dividing Line Between Wildlife Research and Management-Implications for Animal Welfare.

Wild animals are used for research and management purposes in Sweden and throughout the world. Animals are often subjected to similar procedures and risks of compromised welfare from capture, anesthesia, handling, sampling, marking, and sometimes selective removal. The interpretation of the protection of animals used for scientific purposes in Sweden is based on the EU Directive 2010/63/EU. The purpose of animal use, irrespective if the animal is suffering or not, decides the classification as a research animal, according to Swedish legislation. In Sweden, like in several other European countries, the legislation differs between research and management. Whereas, animal research is generally well-defined and covered in the legislation, wildlife management is not. The protection of wild animals differs depending on the procedure they are subjected to, and how they are classified. In contrast to wildlife management activities, research projects have to implement the 3Rs and must undergo ethical reviews and official animal welfare controls. It is often difficult to define the dividing line between the two categories, e.g., when marking for identification purposes. This gray area creates uncertainty and problems beyond animal welfare, e.g., in Sweden, information that has been collected during management without ethical approval should not be published. The legislation therefore needs to be harmonized. To ensure consistent ethical and welfare assessments for wild animals at the hands of humans, and for the benefit of science and management, we suggest that both research and management procedures are assessed by one single Animal Ethics Committee with expertise in the 3Rs, animal welfare, wildlife population health and One Health. We emphasize the need for increased and improved official animal welfare control, facilitated by compatible legislation and a similar ethical authorization process for all wild animal procedures.

Fluoride-promoted esterification with imidazolide-activated compounds: a modular and sustainable approach to dendrimers.

Based on the growing demand for facile and sustainable synthetic methods to structurally perfect polymers, we herein describe a significant improvement of esterification reactions capitalizing on 1,1'-carbonyldiimidazole (CDI). Cesium fluoride was shown to be an essential catalyst for these reactions to reach completion. This approach was successfully applied to the synthesis of structurally flawless and highly functional polyester dendrimers employing traditional and accelerated growth strategies. A sixth generation bis-MPA dendrimer with a molecular weight of 22.080 Da and 192 peripheral hydroxy groups was isolated in less than one day of total reaction time. Large quantities of dendrimers were obtained in high yields (>90%) using simple purification steps under sustainable conditions. The fluoride-promoted esterification (FPE) via imidazolide-activated compounds is wide in scope and constitutes a potentially new approach toward functional polymers and other materials.

Postprandial lipid and insulin responses among healthy, overweight men to mixed meals served with baked herring, pickled herring or baked, minced beef.

PURPOSE: The aim was to compare postprandial lipid, insulin and vitamin D responses after consumption of three otherwise identical meals served either with baked herring, pickled herring or with baked, minced beef. METHODS: Seventeen healthy, overweight men (mean age 58 years, BMI 26.4-29.5 kg/m(2)) consumed standardized lunches together with baked herring, pickled herring or baked, minced beef on three occasions in a crossover design. Blood samples were taken just before and up to 7 h after the meal. The postprandial response was measured as serum concentrations of triglycerides (TG), total cholesterol and lipoproteins (LDL, HDL and VLDL), insulin, 25-OH vitamin D and plasma fatty acid composition. RESULTS: There was no difference in postprandial lipid responses between the two herring meals, whereas a slower TG clearance was observed after the baked, minced beef meal. The 150 g servings of baked and pickled herring provided 3.3 and 2.8 g of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), respectively, which was reflected in a substantial postprandial increase in plasma LC n-3 PUFA levels. The pickled herring contained 22% sugar and consequently gave a higher insulin response compared with the other two meals. CONCLUSIONS: Both pickled and baked herring are good sources of LC n-3 PUFA in the diet, but the presence of sugar in pickled herring should be taken into consideration, especially if large amounts are consumed. The faster postprandial TG clearance after a meal with baked herring compared with baked beef supports previous studies on the beneficial effects of herring on cardiovascular health.

Low doses of eicosapentaenoic acid and docosahexaenoic acid from fish oil dose-dependently decrease serum triglyceride concentrations in the presence of plant sterols in hypercholesterolemic men and women.

Plant sterols (PSs) lower LDL cholesterol (LDL-C) concentrations, whereas the n-3 (ω-3) fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglyceride (TG) concentrations. Incorporating both PSs and EPA+DHA from fish oil (FO) in a single food format was expected to beneficially affect 2 blood lipid risk factors. The aim of this study was to investigate the dose-response relation between low doses (<2 g/d) of EPA+DHA from FO, incorporated in a low-fat PS-enriched spread, and TG concentrations. In addition, effects on LDL-C were investigated. The study was designed as a randomized, double-blind, placebo-controlled parallel study. After a 4-wk run-in period, subjects were randomly assigned to consume either a control (C) spread (no PSs, no FO) or 1 of 4 intervention spreads containing a fixed amount of PSs (2.5 g/d) and varying amounts of FO (0.0, 0.9, 1.3, and 1.8 g/d of EPA+DHA) for 4 wk. Before and after the intervention, fasting blood samples were drawn for measuring serum lipids and EPA and DHA in erythrocyte membranes. In total, 85 hypercholesterolemic men and 247 women with a mean age of 57.9 y (range: 25-74 y) were included. Eighteen subjects dropped out during the study. At baseline, mean TG and LDL-C concentrations were 1.09 and 4.00 mmol/L, respectively. After the intervention, a significant dose-response relation for the TG-lowering effect of EPA+DHA [ßln (TG) = -0.07 mmol/L per gram of EPA+DHA; P < 0.01] was found. Compared with the C group, TG concentrations were 9.3-16.2% lower in the different FO groups (P < 0.05 for all groups). LDL-C concentrations were 11.5-14.7% lower in the different PS groups than in the C group (P < 0.01 for all groups). EPA and DHA in erythrocyte membranes were dose-dependently higher after FO intake than after the C spread, indicating good compliance. Consumption of a low-fat spread enriched with PSs and different low doses of n-3 fatty acids from FO decreased TG concentrations in a dose-dependent manner and decreased LDL-C concentrations. This trial was registered at clinicaltrials.gov as NCT01313988.

Low-Fat Nondairy Minidrink Containing Plant Stanol Ester Effectively Reduces LDL Cholesterol in Subjects with Mild to Moderate Hypercholesterolemia as Part of a Western Diet.

The cholesterol-lowering efficacy of plant stanol ester (STAEST) added to fat- or milk-based products is well documented. However, their efficacy when added to nondairy liquid drinks is less certain. Therefore, we have investigated the cholesterol-lowering efficacy of STAEST added to a soymilk-based minidrink in the hypercholesterolemic subjects. In a randomized, double-blind, placebo-controlled parallel study, the intervention group (n = 27) consumed 2.7 g/d of plant stanols as the ester in soymilk-based minidrink (65 mL/d) with the control group (n = 29) receiving the same drink without added plant stanols once a day with a meal for 4 weeks. Serum total, LDL, and non-HDL cholesterol concentrations were reduced by 8.0, 11.1, and 10.2% compared with controls (P < 0.05 for all). Serum plant sterol concentrations and their ratios to cholesterol declined by 12-25% from baseline in the STAEST group while the ratio of campesterol to cholesterol was increased by 10% in the controls (P < 0.05 for all). Serum precursors of cholesterol remained unchanged in both groups. In conclusion, STAEST-containing soymilk-based low-fat minidrink consumed once a day with a meal lowered LDL and non-HDL cholesterol concentrations without evoking any side effects in subjects consuming normal Western diet. The clinical trial registration number is NCT01716390.

Chemoselective Pd-catalyzed oxidation of polyols: synthetic scope and mechanistic studies.

The regio- and chemoselective oxidation of unprotected vicinal polyols with [(neocuproine)Pd(OAc)]2(OTf)2 (1) (neocuproine = 2,9-dimethyl-1,10-phenanthroline) occurs readily under mild reaction conditions to generate α-hydroxy ketones. The oxidation of vicinal diols is both faster and more selective than the oxidation of primary and secondary alcohols; vicinal 1,2-diols are oxidized selectively to hydroxy ketones, whereas primary alcohols are oxidized in preference to secondary alcohols. Oxidative lactonization of 1,5-diols yields cyclic lactones. Catalyst loadings as low as 0.12 mol % in oxidation reactions on a 10 g scale can be used. The exquisite selectivity of this catalyst system is evident in the chemoselective and stereospecific oxidation of the polyol (S,S)-1,2,3,4-tetrahydroxybutane [(S,S)-threitol] to (S)-erythrulose. Mechanistic, kinetic, and theoretical studies revealed that the rate laws for the oxidation of primary and secondary alcohols differ from those of diols. Density functional theory calculations support the conclusion that ß-hydride elimination to give hydroxy ketones is product-determining for the oxidation of vicinal diols, whereas for primary and secondary alcohols, pre-equilibria favoring primary alkoxides are product-determining. In situ desorption electrospray ionization mass spectrometry (DESI-MS) revealed several key intermediates in the proposed catalytic cycle.

Structural Sampling of Glycan Interaction Profiles Reveals Mucosal Receptors for Fimbrial Adhesins of Enterotoxigenic Escherichia coli.

Fimbriae are long, proteinaceous adhesion organelles expressed on the bacterial envelope, evolutionarily adapted by Escherichia coli strains for the colonization of epithelial linings. Using glycan arrays of the Consortium for Functional Glycomics (CFG), the lectin domains were screened of the fimbrial adhesins F17G and FedF from enterotoxigenic E. coli (ETEC) and of the FimH adhesin from uropathogenic E. coli. This has led to the discovery of a more specific receptor for F17G, GlcNAcb1,3Gal. No significant differences emerged from the glycan binding profiles of the F17G lectin domains from five different E. coli strains. However, strain-dependent amino acid variations, predominantly towards the positively charged arginine, were indicated by sulfate binding in FedF and F17G crystal structures. For FedF, no significant binders could be observed on the CFG glycan array. Hence, a shotgun array was generated from microvilli scrapings of the distal jejunum of a 3-week old piglet about to be weaned. On this array, the blood group A type 1 hexasaccharide emerged as a receptor for the FedF lectin domain and remarkably also for F18-fimbriated E. coli. F17G was found to selectively recognize glycan species with a terminal GlcNAc, typifying intestinal mucins. In conclusion, F17G and FedF recognize long glycan sequences that could only be identified using the shotgun approach. Interestingly, ETEC strains display a large capacity to adapt their fimbrial adhesins to ecological niches via charge-driven interactions, congruent with binding to thick mucosal surfaces displaying an acidic gradient along the intestinal tract.

A longitudinal study of physical function in patients with early-onset dementia.

BACKGROUND: The aim of this study was to explore changes in mobility in terms of ambulation and transfer over 1 year in patients with early-onset Alzheimer's disease (EOAD), and to compare mobility in EOAD with patients with other types of early-onset dementia (EOOD). METHOD: Forty-two patients with EOAD and 30 patients with EOOD were included. All patients were home-dwelling and had mild or moderate degree of dementia. Mobility was assessed using the Timed Up and Go Test (TUG), a modified version of the Clinical Outcome Variables Scale, timed stair walking, and timed rise from the floor. RESULTS: The EOAD group performed significantly better than the EOOD group on all mobility tests. After 1 year, 25 persons with EOAD were tested again. The performance on TUG (p = 0.028) and stair walking (p = 0.02) had deteriorated at the 1-year follow-up in the EOAD group. CONCLUSION: Patients with EOAD performed better on mobility tasks than patients with EOOD, but their performance deteriorated at 1-year follow-up.

Facile Synthesis of Functionalized Lactones and Organocatalytic Ring-Opening Polymerization.

A facile one-step synthesis of functionalized valerolactones was carried out by the conjugate addition of thiols to the α,ß-unsaturated valerolactone 5,6-dihydro-2H-pyran-2-one. The resultant 3-mercaptovalerolactones undergo ring-opening polymerization in solution or in the melt to generate polyesters functionalized either with benzyl mercaptans or oligoethylene glycol pendant groups. The copolymerization of the 3-mercaptovalerolactones with ε-caprolactone generates random copolymers.

Whole grain rye breakfast - sustained satiety during three weeks of regular consumption.

Whole grain rye products have previously been shown to increase feelings of satiety for up to 8h after intake under standardized conditions. This study was set out to investigate the sustainability of the satiating effect after regular consumption of breakfast meals with whole grain rye porridge or refined wheat bread. The study was randomized, cross-over and double-blind. Healthy subjects (n=24) were randomly assigned to daily consumption of iso-caloric standardized breakfast meals with whole grain rye porridge or refined wheat bread for two 3-wk phases, separated by a wash out of 3-4weeks. Each intervention phase had 3 scheduled visit days (days 1, 8 and 22) when appetite ratings (hunger, satiety and desire to eat) were registered for 24h at standardized conditions. Orocecal transit time (salicylazosulfapyridine/sulfapyridine method) and breath hydrogen as an indicator of colonic fermentation were measured at day 8 of each 3-wk phase in a subgroup (n=16). To investigate effects of breakfast on free-living food intake, 3-day weighed food diaries were self-registered during both intervention phases. Whole grain rye porridge breakfast resulted in higher ratings of satiety and lower hunger and desire to eat during 4h post consumption compared to refined wheat bread breakfast (p<0.001). This effect was sustained throughout the 3-wk study phases. Unlike previous studies, the effects did not persist into the afternoon (4-8h). The orocecal transit times after consumption of both breakfasts were similar and in the range of 5-6h. The rye porridge resulted in high levels of breath hydrogen 4-8h after intake, showing extensive colonic fermentation. This was however not related to any changes in appetite during this time-period. There were no significant differences in self-reported macronutrient- and energy intake between diets. This study shows that the satiating effect of rye persists after repeated daily consumption for up to three weeks. Clinicaltrials.gov Identifier: NCT01117363.

Rye kernel breakfast increases satiety in the afternoon - an effect of food structure.

BACKGROUND: The structure of whole grain cereals is maintained to varying degrees during processing and preparation of foods. Food structure can influence metabolism, including perceived hunger and satiety. A diet that enhances satiety per calorie may help to prevent excessive calorie intake. The objective of this work was to compare subjective appetite ratings after consumption of intact and milled rye kernels. METHODS: Two studies were performed using a randomized, cross-over design. Ratings for appetite (hunger, satiety and desire to eat) were registered during an 8-h period after consumption of whole and milled rye kernels prepared as breads (study 1, n = 24) and porridges (study 2, n = 20). Sifted wheat bread was used as reference in both study parts and the products were eaten in iso-caloric portions with standardized additional breakfast foods. Breads and porridges were analyzed to determine whether structure (whole vs. milled kernels) effected dietary fibre content and composition after preparation of the products. Statistical evaluation of the appetite ratings after intake of the different breakfasts was done by paired t-tests for morning and afternoon ratings separately, with subjects as random effect and type of breakfast and time points as fixed effects. RESULTS: All rye breakfasts resulted in higher satiety ratings in the morning and afternoon compared with the iso-caloric reference breakfast with sifted wheat bread. Rye bread with milled or whole kernels affected appetite equally, so no effect of structure was observed. In contrast, after consumption of the rye kernel breakfast, satiety was increased and hunger suppressed in the afternoon compared with the milled rye kernel porridge breakfast. This effect could be related to structural differences alone, because the products were equal in nutritional content including dietary fibre content and composition. CONCLUSIONS: The study demonstrates that small changes in diet composition such as cereal grain structure have the potential to effect feelings of hunger and satiety. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT01042418.

Effects of probiotic fermented milk on symptoms and intestinal flora in patients with irritable bowel syndrome: a randomized, placebo-controlled trial.

OBJECTIVE: The effect of probiotics on IBS symptoms has been mixed, but remains an intriguing treatment option with appeal to the patient. MATERIAL AND METHODS: Patients fulfilling the Rome II criteria were randomized double-blind to a daily intake of 500 ml of fermented milk containing at least 5 × 10(7) CFU/ml of Lactobacillus paracasei ssp paracasei F19, Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 or an equal volume of acidified milk for 8 weeks. Symptoms were assessed at baseline and weekly using a disease-specific validated symptom rating scale (IBS-SSI). The predefined primary outcome measure was patient reported adequate symptom relief. Adherence to study protocol were assessed by performing stool samples at the of the treatment period. RESULTS: Eight-one patients were screened. Sixty-four patients were randomized; 18 patients did not complete the study due to protocol violations or withdrew due to lack of effect. Fifty-two patients (13 males) completed the study as per protocol; mean age was 51.3 years (range 29-67). The proportion of patients reporting adequate symptom relief increased in both patient groups, but there was not any statistical difference between the groups. IBS-SSI scores did not differ statistically between the groups at the end of the treatment period, but improved during the study period in both groups. CONCLUSIONS: During this 8-week trial gastrointestinal symptoms improved. However, there was no difference between treatment with fermented milk containing probiotics or acidified milk. The effect of probiotics on IBS symptoms remains uncertain and further studies are warranted.

Characterization and reduction of noise in dynamic PET data using masked volumewise principal component analysis.

UNLABELLED: Masked volumewise principal component (PC) analysis (PCA) is used in PET to distinguish structures that display different kinetic behaviors after administration of a tracer. When masked volumewise PCA was introduced, one article proposed noise prenormalization because of temporal and spatial variations of the noise between slices. However, the noise prenormalization proposed in that article was applicable only to datasets reconstructed using filtered backprojection (FBP). The study presented in this article aimed at developing a new noise prenormalization that is applicable to datasets regardless of whether they were reconstructed with FBP or an iterative reconstruction algorithm, such as ordered-subset expectation maximization (OSEM). METHODS: A phantom study was performed to investigate differences in the expectation values and SDs of datasets reconstructed with FBP and OSEM. A novel method, higher-order PC noise prenormalization, was suggested and evaluated against other prenormalization methods on clinical datasets. RESULTS: Masked volumewise PCA of data reconstructed with FBP was much more dependent on an appropriate prenormalization than was analysis of data reconstructed with OSEM. Higher-order PC noise prenormalization showed an overall good performance with both FBP and OSEM reconstructions, whereas the other prenormalization methods performed well with only 1 of the 2 methods. CONCLUSION: Higher-order PC noise prenormalization has potential for improving the results from masked volumewise PCA on dynamic PET datasets independent of the type of reconstruction algorithm.

Effect of a vegetable-oil emulsion on body composition; a 12-week study in overweight women on a meal replacement therapy after an initial weight loss: a randomized controlled trial.

PURPOSE: The maintenance of an obtained lower weight level is often found to be difficult. The aim of this study was to determine weight maintenance after an initial weight loss by consumption of a meal replacement with a vegetable-oil emulsion associated with prolonged satiety. METHODS: After a 6-week weight loss period with very low calorie diet (VLCD), subjects with >5% body weight (BW) loss were randomized to a 12-week weight maintenance follow-up period, comparing a partial meal replacement diet containing a vegetable-oil emulsion (test) or dairy fat (control). Anthropometric data and safety variables were collected at baseline and after 4, 8 and 12 weeks. RESULTS: A significant weight loss was observed during the 12-week weight maintenance diet in the test and control group, respectively; 1.0 ± 2.1 kg (p < 0.05) versus 1.3 ± 2.1 kg (p < 0.05) with no significant difference between the groups. Body fat mass (BFM) decreased significantly (p < 0.05) in the test group (--1.7%) compared to the control group (--0.8%). CONCLUSIONS: Addition of a vegetable-oil emulsion to a meal replacement weight maintenance program after an initial weight loss using VLCD was associated with decreased BFM by 0.9% without any change in BW between the two groups.