Effect of Data Quality and Data Quantity on the Estimation of Intrinsic Solubility: Analysis Based on a Single-Source Data Set.

Aqueous solubility is one of the most important physicochemical properties of drug molecules and a major driving force for oral drug absorption. To date, the performance of in silico models for the estimation of solubility for novel chemical space is limited. To investigate possible reasons and remedies for this, the Johnson and Johnson in-house aqueous solubility data with over 40,000 compounds was leveraged. All data were generated through the same high-throughput assay, providing a unique opportunity to explore the relationship between data quality, quantity, and model estimations. Six intrinsic solubility data sets with different sizes and noise levels were generated by making use of three different approaches: (i) inclusion or exclusion of amorphous solid residue, (ii) measured or experimental log D to identify the intrinsic solubility, and (iii) adopting or omitting a quality check process in the data processing workflow. A random forest regressor was trained on the data sets with three different sets of descriptors calculated from RDKit, ADMET predictor, or Mordred, and the performances were evaluated with nested cross-validation as well as ten refined test sets. The models confirm, as expected, that with the same data set size, high-quality data leads to better model performance; however, also, models trained with larger data sets containing analytical variability can give equally accurate estimations compared to models trained with small, clean, and diverse data sets. However, noise introduced by including the presence of amorphous solid postsolubility measurement in the training data set cannot be overcome by increasing data size, as they are introducing a biased systematic positive error in the data set, confirming the importance of critical data review. Finally, two top-performing models were tested on the first test set from the second solubility challenge, achieving RMSE values of 0.74 and 0.72 and log S ± 0.5 of 46 and 48%, respectively. These results demonstrated improved performance compared to those reported in the findings of the competition, highlighting that a single-source curated data set can enhance the prediction of intrinsic solubility.

Patients' Experiences of Health After Surgical Treatment for Paraesophageal Hernia Grades III and IV: An Interview Based Study.

Surgery is the only available treatment for the longstanding chronic symptoms associated with large paraesophageal hernias except for reflux disease. The aim of this study was to illuminate how patients who previously suffered from grade III-IV hiatal hernia experience their life and health 2-6 months after surgery. The study is based on semi-structured interviews with 17 patients who received elective laparoscopic hernia repair for a large paraesophageal hernia. The data were analyzed using qualitative content analysis, resulting in three main themes: "Experiences of health," "Being unable to leave the disease behind," and "Still feeling unwell" and seven subthemes: "Escaping suffering"; "Learning to interpret bodily signals"; "Looking to the future with confidence"; "Finding oneself in a vicious circle of worry"; "The fear of relapse as a constant companion"; "Lingering disabling symptoms," and "New and frightening symptoms." Our study demonstrates large individual variations in the way patients experience their life and health after laparoscopic hernia repair. Central to the patients' descriptions is that simply feeling physically healthy is insufficient for achieving overall health. Health care personnel can benefit from learning about patients' experiences of health and suffering after surgery.

Ecological filtering drives rapid spatiotemporal dynamics in fish skin microbiomes.

Skin microbiomes provide vital functions, yet knowledge about the drivers and processes structuring their species assemblages is limited-especially for non-model organisms. In this study, fish skin microbiome was assessed by high throughput sequencing of amplicon sequence variants from metabarcoding of V3-V4 regions in the 16S rRNA gene on fish hosts subjected to the following experimental manipulations: (i) translocation between fresh and brackish water habitats to investigate the role of environment; (ii) treatment with an antibacterial disinfectant to reboot the microbiome and investigate community assembly and priority effects; and (iii) maintained alone or in pairs to study the role of social environment and inter-host dispersal of microbes. The results revealed that fish skin microbiomes harbour a highly dynamic microbial composition that was distinct from bacterioplankton communities in the ambient water. Microbiome composition first diverged as an effect of translocation to either the brackish or freshwater habitat. When the freshwater individuals were translocated back to brackish water, their microbiome composition converged towards the fish microbiomes in the brackish habitat. In summary, external environmental conditions and individual-specific factors jointly determined the community composition dynamics, whereas inter-host dispersal had negligible effects. The dynamics of the microbiome composition was seemingly non-affected by reboot treatment, pointing towards high resilience to disturbance. The results emphasised the role of inter-individual variability for the unexplained variation found in many host-microbiome systems, although the mechanistic underpinnings remain to be identified.

An Estimation of the Monetary Value of the Person-Sievert Useful for Occupational Radiological Protection within the Healthcare System of Sweden.

ABSTRACT: The As Low As Reasonably Achievable (ALARA) principle includes taking into account economic and societal factors. To consider these factors, decision-aiding techniques such as cost-benefit analysis were introduced by the International Commission on Radiological Protection (ICRP) 50 y ago. Over the years, developments in health economics have led to new ways of deriving the concept of a value of a statistical life (VSL), which now is influencing the monetary value assigned to a unit of collective dose for radiological protection purposes (the α value) used in cost-benefit analyses. The aim of the present study was to estimate an α value useful for occupational radiological protection within the healthcare system of Sweden. A survey based on the stated preference approach was developed and sent to staff who are exposed to ionizing radiation at their work in Region Västra Götaland (Sweden). The survey essentially contained two scenarios: the respondents' willingness to pay for measures against radon exposure at home and their willingness to accept compensation for x-ray exposure at work. Answers from 718 respondents were collected. In the sensitivity analysis of the survey, the overall median VSL based on the two scenarios was calculated to be $50 million (IQR $10 to 363 million). The corresponding α value was established to $1,600 person-mSv -1 ($2,100 person-mSv -1 if excess burden of taxes is excluded). The recommended α value is in the high end compared to other studies but within the interval of values being used by nuclear utilities today. The α value should be seen in the light of ICRP's recommendation about stakeholder involvement as an important part of the optimization process.

Drug solubilization in dog intestinal fluids with and without administration of lipid-based formulations.

The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.

Structure-properties relationships of defined CNF single-networks crosslinked by telechelic PEGs.

The high structural anisotropy and colloidal stability of cellulose nanofibrils' enable the creation of self-standing fibrillar hydrogel networks at very low solid contents. Adding methacrylate moieties on the surface of TEMPO oxidized CNFs allows the formation of more robust covalently crosslinked networks by free radical polymerization of acrylic monomers, exploiting the mechanical properties of these networks more efficiently. This technique yields strong and elastic networks but with an undefined network structure. In this work, we use acrylate-capped telechelic polymers derived from the step-growth polymerization of PEG diacrylate and dithiothreitol to crosslink methacrylated TEMPO-oxidized cellulose nanofibrils (MATO CNF). This combination resulted in flexible and strong hydrogels, as observed through rheological studies, compression and tensile loading. The structure and mechanical properties of these hydrogel networks were found to depend on the dimensions of the CNFs and polymer crosslinkers. The structure of the networks and the role of individual components were evaluated with SAXS (Small-Angle X-ray Scattering) and photo-rheology. A thorough understanding of hybrid CNF/polymer networks and how to best exploit the capacity of these networks enable further advancement of cellulose-based materials for applications in packaging, soft robotics, and biomedical engineering.

Corrigendum: Dose-dependent stimulation of human follicular steroidogenesis by a novel rhCG during ovarian stimulation with fixed rFSH dosing.

[This corrects the article DOI: 10.3389/fendo.2022.1004596.].

Analysis of stabilization mechanisms in ß-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches.

Our previous work shows that ß-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high Tg of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %.

Effects of environmental translocation and host characteristics on skin microbiomes of sun-basking fish.

Variation in the composition of skin-associated microbiomes has been attributed to host species, geographical location and habitat, but the role of intraspecific phenotypic variation among host individuals remains elusive. We explored if and how host environment and different phenotypic traits were associated with microbiome composition. We conducted repeated sampling of dorsal and ventral skin microbiomes of carp individuals (Cyprinus carpio) before and after translocation from laboratory conditions to a semi-natural environment. Both alpha and beta diversity of skin-associated microbiomes increased substantially within and among individuals following translocation, particularly on dorsal body sites. The variation in microbiome composition among hosts was significantly associated with body site, sun-basking, habitat switch and growth, but not temperature gain while basking, sex, personality nor colour morph. We suggest that the overall increase in the alpha and beta diversity estimates among hosts were induced by individuals expressing greater variation in behaviours and thus exposure to potential colonizers in the pond environment compared with the laboratory. Our results exemplify how biological diversity at one level of organization (phenotypic variation among and within fish host individuals) together with the external environment impacts biological diversity at a higher hierarchical level of organization (richness and composition of fish-associated microbial communities).

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison.

Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles. All-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.

Exhaled breath particles as a novel tool to study lipid composition of epithelial lining fluid from the distal lung.

BACKGROUND: Surfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges. METHODS: PEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry. RESULTS: The overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx. CONCLUSION: Our data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition. TRIAL REGISTRATION: NCT03044327, first posted 07/02/2017.

Revealing the interaction between peptide drugs and permeation enhancers in the presence of intestinal bile salts.

Permeability enhancer-based formulations offer a promising approach to enhance the oral bioavailability of peptides. We used all-atom molecular dynamics simulations to investigate the interaction between two permeability enhancers (sodium caprate, and SNAC), and four different peptides (octreotide, hexarelin, degarelix, and insulin), in the presence of taurocholate, an intestinal bile salt. The permeability enhancers exhibited distinct effects on peptide release based on their properties, promoting hydrophobic peptide release while inhibiting water-soluble peptide release. Lowering peptide concentrations in the simulations reduced peptide-peptide interactions but increased their interactions with the enhancers and taurocholates. Introducing peptides randomly with enhancer and taurocholate molecules yielded dynamic molecular aggregation, and reduced peptide-peptide interactions and hydrogen bond formation compared to peptide-only systems. The simulations provided insights into molecular-level interactions, highlighting the specific contacts between peptide residues responsible for aggregation, and the interactions between peptide residues and permeability enhancers/taurocholates that are crucial within the mixed colloids. Therefore, our results can provide insights into how modifications of these critical contacts can be made to alter drug release profiles from peptide-only or mixed peptide-PE-taurocholate aggregates. To further probe the molecular nature of permeability enhancers and peptide interactions, we also analyzed insulin secondary structures using Fourier transform infrared spectroscopy. The presence of SNAC led to an increase in ß-sheet formation in insulin. In contrast, both in the absence and presence of caprate, α-helices, and random structures dominated. These molecular-level insights can guide the design of improved permeability enhancer-based dosage forms, allowing for precise control of peptide release profiles near the intended absorption site.

Lead aprons and thyroid collars: to be, or not to be?

Wearing lead aprons and thyroid collars for long periods of time has a subjective component: to balance the effective dose reduction with the effort of carrying a heavy load. Occupational radiation exposure has decreased dramatically in the last century within the health care system. During the same period the use of lead aprons and thyroid collars has also gone up. Therefore, a question that may be raised is: how safe is safe enough? In order to promote stakeholder involvement, the aim of the present study was to investigate staff's experience of discomforts associated with wearing lead aprons and thyroid collars for long periods of time, and also to investigate staff's willingness to tolerate personal dose equivalent (expressed as radiation dose) and the corresponding increase in future cancer risk to avoid wearing these protective tools. A questionnaire was developed and given to staff working in operating or angiography rooms at Skaraborg Hospital in Sweden. The results from the 245 respondents showed that 51% experienced bothersome warmth, 36% experienced fatigue and 26% experienced ache or pain that they believed was associated with wearing lead aprons. One third of the respondents would tolerate a personal dose equivalent of 1 mSv per year to avoid wearing lead aprons, but only a fifth would tolerate the corresponding increase in future cancer risk (from 43% to 43.2%). In conclusion, discomforts associated with wearing lead aprons and thyroid collars for long periods of time are common for the staff using them. At the same time, only a minority of the staff would tolerate a small increase in future cancer risk to avoid wearing them. The present study gives an example of stakeholder involvement and points at the difficulties in making reasonable decisions about the use of these protective tools.

Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis.

OBJECTIVE: To investigate whether digital activity fluorescence optical imaging (FOI) patterns of inflammation can identify distinct rheumatoid arthritis (RA) phenotypes. METHODS: The hands of newly diagnosed patients with RA were evaluated by clinical examination, musculoskeletal ultrasound, and FOI. Inflammation on FOI was defined when capillary leakage and/or fluorophore perfusion was present. The FOI composite image was quantified into a digital disease activity (DACT) score, using novel computerized algorithms. Unsupervised clustering on FOI inflammatory patterns was used to identify subgroups of patients relative to anticyclic citrullinated peptides (ACPA) and/or rheumatoid factor (RF). RESULTS: Of 1326 examined hand joints in 39 patients with RA (72% female; 56% ever-smokers; 54% RF positive and 69% ACPA positive), 400 (30%) showed inflammation by FOI, and 95% (37 of 39) of patients had DACT-FOI scores greater than 1. Unsupervised analysis on FOI patterns revealed two patient clusters, cluster 1 (n = 29) and cluster 2 (n = 10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (90%, 26 of 29 vs. 30%, 3 of 10; P < 0.01), whereas C-reactive-protein levels (minimum-maximum) were significantly higher in cluster 2 (20 mg/l [1-102]) versus cluster 1 (2 mg/l [0-119]; P = 0.01). A wider variety and proportion of inflamed joints emerged for patients with RA in cluster 2 versus cluster 1, in which inflammation was more concentrated around the wrists and the right metacarpophalangeal 2 (MCP2), bilateral MCP3, and, to a lesser degree, left MCP2 and proximal interphalangeal joint and tendon regions. Cluster 1 displayed lower mean (±SD) DACT scores compared with cluster 2 (3.6 ± 2.1 vs. 5.4 ± 2.1; P = 0.03). CONCLUSION: FOI-based digital quantification of hand joint inflammation revealed two distinct RA subpopulations with and without ACPA and RF related autoantibodies.

Being Caught in a Vicious Circle: An Interview Study of Individuals Suffering From Grade II-IV Hiatal Hernia.

Large paraesophageal hernias are related to life-threatening complications that warrant immediate surgery. Whether the long-standing chronic symptoms related to the disease in individuals without hernia incarceration motivate surgical treatment is still a subject for discussion. The aim of this study was to explore how individuals suffering from Grade II-IV hiatal hernia describe their symptoms and health, as well as how the disease affects their life. Semistructured interviews were performed with 22 individuals planning to undergo surgery for a large paraesophageal hernia. The data were analyzed using qualitative content analysis and resulted in one main theme "Being caught in a vicious circle" and six subthemes "Distressing and uncertain times," "The symptoms have seized control over my health," "Loss of energy and strength," "Strategies for managing daily life," "Loss of social life," and "Moments of hope despite failing health." Central to the participants' descriptions is their commitment to strategies for managing the ever-present and unpredictable symptoms that have seized control over their health. They were trapped in a hopeless and isolated existence, that is, a vicious circle, from which they were unable to escape. Despite the low incidence of volvulus and incarceration, the symptom burden and effect on general health motivate treatment in these individuals.

Hornification of cellulose-rich materials - A kinetically trapped state.

The fundamental understanding concerning cellulose-cellulose interactions under wet and dry conditions remains unclear. This is especially true regarding the drying-induced association of cellulose, commonly described as an irreversible phenomenon called hornification. A fundamental understanding of the mechanisms behind hornification would contribute to new drying techniques for cellulose-based materials in the pulp and paper industry while at the same time enhancing material properties and facilitating the recyclability of cellulose-rich materials. In the present work, the irreversible joining of cellulose-rich surfaces has been studied by subjecting cellulose nanofibril (CNF) films to different heat treatments to establish a link between reswelling properties, structural characteristics as well as chemical and mechanical analyses. A heating time/temperature dependence was observed for the reswelling of the CNF films, which is related to the extent of hornification and is different for different chemical compositions of the fibrils. Further, the results indicate that hornification is related to a diffusion process and that the reswellability increases very slowly over long time, indicating that equilibrium is not reached. Hence, hornification is suggested to be a kinetically limited phenomenon governed by non-covalent reversible interactions and a time/temperature dependence on their forming and breaking.

Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial.

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.

Conventional outcome reporting per IVF cycle/embryo transfer may systematically underestimate chances of success for women undergoing ART: relevant biases in registries, epidemiological studies, and guidelines.

Pre-conception counselling and management of expectations about chance of success of IVF/ICSI treatments is an integral part of fertility care. Registry data are usually used to inform patients about expected success rates of IVF/ICSI treatment, as these data should best represent real-world populations and clinical practice. In registries, the success rate of IVF/ICSI treatments is conventionally reported per treatment cycle or per embryo transfer and estimated from data for which several treatment attempts per subject have been pooled (e.g. repetitive IVF/ICSI attempts or repetitive attempts of cryotransfer). This, however, may underestimate the true mean chance of success per treatment attempt, because treatment attempts of women with a poor prognosis will usually be over-represented in a pool of treatment cycle data compared to treatment events of women with a good prognosis. Of note, this phenomenon is also a source of potential bias when comparing outcomes between fresh transfers and cryotransfers, since women can undergo a maximum of only one fresh transfer after each IVF/ICSI treatment, but potentially several cryotransfers. Herein, we use a trial dataset from 619 women, who underwent one cycle of ovarian stimulation and ICSI, a Day 5 fresh transfer and/or subsequent cryotransfers (follow-up of all cryotransfers up to 1 year after the start of stimulation), to exemplify the underestimation of the live birth rate, when not accounting for repeated transfers in the same woman. Using mixed-effect logistic regression modelling, we show that the mean live birth rate per transfer per woman in cryocycles is underestimated by the factor 0.69 (e.g. live birth rate per cryotransfer of 36% after adjustment versus 25% unadjusted). We conclude that the average chance of success of treatment cycles of women of a given age, treated in a given centre, etc., when conventionally calculated per cycle or per embryo transfer from a pool of treatment events, do not apply to an individual woman. We suggest that patients are, especially at the outset of treatment, systematically confronted with mean estimates of success per attempt that are too low. Live birth rates per transfer from datasets encompassing multiple transfers from single individuals could be more accurately reported using statistical models accounting for the correlation between cycle outcomes within women.

Molecular Dynamics Simulations of Cellulose and Dialcohol Cellulose under Dry and Moist Conditions.

The development of wood-based thermoplastic polymers that can replace synthetic plastics is of high environmental importance, and previous studies have indicated that cellulose-rich fiber containing dialcohol cellulose (ring-opened cellulose) is a very promising candidate material. In this study, molecular dynamics simulations, complemented with experiments, were used to investigate how and why the degree of ring opening influences the properties of dialcohol cellulose, and how temperature and presence of water affect the material properties. Mechanical tensile properties, diffusion/mobility-related properties, densities, glass-transition temperatures, potential energies, hydrogen bonds, and free volumes were simulated for amorphous cellulosic materials with 0-100% ring opening, at ambient and high (150 °C) temperatures, with and without water. The simulations showed that the impact of ring openings, with respect to providing molecular mobility, was higher at high temperatures. This was also observed experimentally. Hence, the ring opening had the strongest beneficial effect on "processability" (reduced stiffness and strength) above the glass-transition temperature and in wet conditions. It also had the effect of lowering the glass-transition temperature. The results here showed that molecular dynamics is a valuable tool in the development of wood-based materials with optimal thermoplastic properties.

Live birth rates following individualized dosing algorithm of follitropin delta in a long GnRH agonist protocol.

PURPOSE: To explore the efficacy and safety of individualized follitropin delta dosing, based on serum anti-Müllerian hormone (AMH) concentration and bodyweight, in a long gonadotropin-releasing hormone (GnRH) agonist protocol. METHODS: Clinical outcomes after one treatment cycle are reported in women with AMH: 5-35 pmol/L. Oocytes were inseminated by intracytoplasmic sperm injection, blastocyst transfer was on Day 5 and remaining blastocysts were cryopreserved. Data collection included live births and neonatal health follow-up for all fresh/frozen transfers performed within one year after treatment allocation. RESULTS: In total, 104 women started stimulation, of whom 101 had oocyte recovery and 92 had blastocyst transfer. The average daily dose of follitropin delta was 11.0 ± 1.6 µg and the duration of stimulation was 10.3 ± 1.6 days. The mean number of oocytes was 12.5 ± 6.4, the mean number of blastocysts was 5.1 ± 3.4, and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate was 43%, the live-birth rate was 43%, and the cumulative live-birth rate was 58% per started stimulation. There were 6 cases of early OHSS (5.8%) graded as mild (n = 3) and moderate (n = 3) and 6 cases of late OHSS (5.8%) graded as moderate (n = 3) and severe (n = 3). CONCLUSION: In this first evaluation of the individualized follitropin delta dosing in a long GnRH agonist protocol, the cumulative live-birth rate was high. A randomized trial comparing follitropin delta in a long GnRH agonist protocol versus in a GnRH antagonist protocol should provide further insight into the efficacy and safety of this treatment option. TRIAL REGISTRATION NUMBER: NCT03564509; June 21, 2018.