Targeted linked-read sequencing for direct haplotype phasing of parental GJB2/SLC26A4 alleles: A universal and dependable noninvasive prenatal diagnosis method applied to autosomal recessive nonsyndromic hearing loss in at-risk families.

Noninvasive prenatal diagnosis (NIPD) for autosomal recessive nonsyndromic hearing loss (ARNSHL) has been rarely reported until recent years. However, the previous method could not be performed on challenging genome loci (e.g. CNVs, deletions, inversions, or gene recombinants) or on families without proband genotype. Here, this study assesses the performance of relative haplotype dosage analysis (RHDO)-based NIPD for identifying fetal genotyping in pregnancies at risk of ARNSHL. Fifty couples carrying pathogenic variants associated with ARNSHL in either GJB2 or SLC26A4 were recruited. The RHDO-based targeted linked-read sequencing combined with whole gene coverage probes was used to genotype the fetal cell-free DNA (cfDNA) of 49 families that met the quality control standard.. Fetal amniocyte samples were genotyped using invasive prenatal diagnosis (IPD) to assess the performance of NIPD. The NIPD results showed 100%(49/49) concordance with those obtained through IPD. Two families with copy number variation and recombination were also successfully identified. Sufficient specific informative SNPs for haplotyping, as well as the fetal cfDNA concentration and sequencing depth, are prerequisites for RHDO-based NIPD. This method has the merits of covering the entire genes of GJB2 and SLC26A4, qualifying for copy number variation and recombination analysis with remarkable sensitivity and specificity. Therefore, it has clinical potential as an alternative to traditional IPD for ARNSHL.

Patient-reported outcomes after personalised dose-escalation for stage II-III non-small-cell lung cancer patients: Results from the randomised ARTFORCE PET-Boost trial.

BACKGROUND AND PURPOSE: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy. MATERIALS AND METHODS: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes. RESULTS: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months. CONCLUSION: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue.

Developmental trajectories of GABAergic cortical interneurons are sequentially modulated by dynamic FoxG1 expression levels.

GABAergic inhibitory interneurons, originating from the embryonic ventral forebrain territories, traverse a convoluted migratory path to reach the neocortex. These interneuron precursors undergo sequential phases of tangential and radial migration before settling into specific laminae during differentiation. Here, we show that the developmental trajectory of FoxG1 expression is dynamically controlled in these interneuron precursors at critical junctures of migration. By utilizing mouse genetic strategies, we elucidate the pivotal role of precise changes in FoxG1 expression levels during interneuron specification and migration. Our findings underscore the gene dosage-dependent function of FoxG1, aligning with clinical observations of FOXG1 haploinsufficiency and duplication in syndromic forms of autism spectrum disorders. In conclusion, our results reveal the finely tuned developmental clock governing cortical interneuron development, driven by temporal dynamics and the dose-dependent actions of FoxG1.

Noninvasive Prenatal Diagnosis of SEA-Thalassemia by Combining 1000 Genomes Database and Relative Haplotype Dosage.

To explore a noninvasive method for diagnosis of SEA-thalassemia and to investigate whether the regional factors affect the accuracy of this method. The method involved using a public database and bioinformatics software to construct parental haplotypes for proband and predicting fetal genotypes using relative haplotype dosage. We screened and downloaded sequencing data of couples who were both SEA-thalassemia carriers from the China National Genebank public data platform, and matched the sequencing data format with that of the reference panel using Ubuntu system tools. We then used Beagle software to construct parental haplotypes, predicted fetal haplotypes by relative haplotype dosage. Finally, we used Hidden Markov Model and Viterbi algorithm to determine fetal pathogenic haplotypes. All noninvasive fetal genotype diagnosis results were compared with gold standard gap-PCR electrophoresis results. Our method was successful in diagnosing 13 families with SEA-thalassemia carriers. The best diagnostic results were obtained when Southern Chinese Han was used as the reference panel, and 10 families showed full agreement between our noninvasive diagnostic results and the gap-PCR electrophoresis results. The accuracy of our method was higher when using a Chinese Han as the reference panel for haplotype construction in the Southern Chinese Han region as opposed to Beijing Chinese region. The combined use of public databases and relative haplotype dosage for diagnosing SEA-thalassemia is a feasible approach. Our method produces the best noninvasive diagnostic results when the test samples and population reference panel are closely matched in both ethnicity and geography. When constructing parental haplotypes with our method, it is important to consider the effect of region in addition to population background alone.

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model.

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains' growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.

Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.

The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.

Corrigendum: Effect of intravenous immunoglobulin therapy on the prognosis of patients with severe fever with thrombocytopenia syndrome and neurological complications.

[This corrects the article DOI: 10.3389/fimmu.2023.1118039.].

Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

A self-management program increases the dosage of inpatient rehabilitation by 26 minutes per day: a process evaluation.

PURPOSE: To evaluate the implementation of a self-management program, My Therapy, designed to increase inpatient rehabilitation therapy dosage via independent practice. MATERIALS AND METHODS: A process evaluation of My Therapy for adult patients admitted for rehabilitation for any condition supervised by physiotherapists and occupational therapists across eight rehabilitation wards compared usual care. Outcomes included reach, dosage, fidelity and adaptation. RESULTS: The mean (SD) age of the process evaluation sample (n = 123) was 73 (11) years with a mean (SD) length of stay of 14.0 (6.6) days. The My Therapy program reached 68% of participants (n = 632/928), and resulted in an average increase in therapy dosage of 26 (95% CI 12 to 40) minutes/day of independent practice. All My Therapy audited programs (n = 28) included body function/structure impairment-based exercises, and half (n = 13/28) included activity/participation-based exercises. On average, participants completed programs 1.8 (SD 1.2) times/day, which were prescribed in accordance with the My Therapy criteria, demonstrating fidelity. There were no between-group differences in daily steps or standing time, however, My Therapy participants spent more time sitting (p ≤ 0.05). Implementation adaptations were minimal. CONCLUSION: A self-management rehabilitation program was implemented with fidelity for two in three rehabilitation patients, resulting in increased therapy dosage with minimal adaptations.

The My Therapy self-management program was implemented with good reach (68% of participants received My Therapy) across four public and private inpatient rehabilitation services.Under My Therapy conditions, the dosage of inpatient rehabilitation therapy participation increased by an average of 26 minutes per day, which will help close the evidence-practice gap between the current rehabilitation dosage of about 1-hour per day, and the recommended rehabilitation dosage of 3-hours per day.My Therapy programs most frequently included impairment-based exercises that were completed in sitting, and did not increase time spent standing and walking.Consideration should be given to prescribing My Therapy (content and dosage) at an optimal level to promote patient functional independence, while maintaining safety.

Effectiveness of a nonweight-based daily dosage of ready-to-use therapeutic food in children suffering from uncomplicated severe acute malnutrition: A nonrandomized, noninferiority analysis of programme data in Afghanistan.

Severe acute malnutrition (SAM) remains a major global public health problem. SAM cases are treated using ready-to-use therapeutic food (RUTF) at a dosage of ∼200 kcal/kg/day per the standard treatment protocol (STD). Emerging evidence on simplifications to the standard protocol, which among other adaptations, includes reducing the daily RUTF dosage, indicates that it is effective and safe for treating children with SAM. In response to a foreseen stock shortage of RUTF, the government of Afghanistan endorsed the temporary use of a modified treatment protocol in which the daily RUTF dosage was prescribed at 1000 kcal/day (irrespective of body weight) until the child achieved moderate acute malnutrition status (weight-for-height z-score ≥ -3 or mid-upper arm circumference [MUAC] ≥ 115 mm), at which point 500 kcal/day was prescribed until cured (modified treatment protocol [MTP]). In this paper, we report the results of this nonweight-based daily RUTF dosage experience. Data of 2042 children with SAM, treated using either the STD protocol (n = 269) or the MTP protocol (n = 1773) from August 2019 to March 2021 in five provinces, were analyzed. The per-protocol analyses confirmed noninferiority of MTP protocol when compared to STD protocol for recovery rate [93.3% vs. 90.2%; ∆ (95% confidence interval, CI) = 3.1 (-0.9; 7.2) %] and length-of-stay [82.6 vs. 75.6 days; ∆ (95% CI) = 6.9 (3.3; 10.5) days], considering the margin of noninferiority of -10% and +14 days, respectively. Weight gain velocity was smaller in the MTP protocol group than in the STD protocol group [3.7 (1.7) vs. 5.2 (2.9) g/kg/day; ∆ (95% CI) = -1.5 (-1.8, -1.2); p < 0.001]. The STD group had a significantly higher mean than the MTP group for absolute MUAC gain [∆ (95% CI) = 1.7 (1.0; 2.3) mm; p < 0.001] and the MUAC velocity [∆ (95% CI) = 0.29 (0.20; 0.37) mm/week; p < 0.001]. Our results confirm the noninferiority of a nonweight-based daily dosage and support the endorsement of this modification as an alternative to the standard protocol in resource-constrained contexts.

Tabletized Nanomedicine: From the Current Scenario to Developing Future Medicine.

The limitations of conventional therapeutic treatments prevailed in the development of nanotechnology-based medical formulations, termed nanomedicine. Nanomedicine is an advanced medicine that often consists of therapeutic agent(s) embedded in biodegradable or biocompatible nanomaterial-based formulations. Among nanomedicine approaches, tablet (oral) nanomedicine is still under development. In tabletized nanomedicine, the dynamic interplay between nanoformulations and the intricate milieu of the gastrointestinal tract simulates a pivotal role, particularly accentuating the influence exerted upon the luminal, mucosal, and epithelial cells. In this work, we document the perspectives and opportunities of nanoformulations toward the development of tabletized nanomedicine. This review also unveils the notion of integrating nanomedicine within a tablet formulation, which facilitates the controlled release of drugs, biomolecules, and agent(s) from the formulation to achieve a better therapeutic response. Finally, an attempt was made to explore current trends in nanomedicine technology such as bacteriophage, probiotic, and oligonucleotide tabletized nanomedicine and the combination of nanomedicine with imaging agents, i.e., nanotheranostics.

Modeling of Styl'One Evolution Correction Factors for Multicomponent Mixtures Scaling-up to Roller Compaction.

Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet.

A Comprehensive Analysis of Biopharmaceutical Products Listed in the FDA's Purple Book.

Although biopharmaceuticals constitute around 10% of the drug landscape, eight of the ten top-selling products were biopharmaceuticals in 2023. This study did a comprehensive analysis of the FDA's Purple Book database. Firstly, our research uncovered market trends and provided insights into biologics distributions. According to the investigation, although biotechnology has advanced and legislative shifts have made the approval process faster, there are still challenges to overcome, such as molecular instability and formulation design. Moreover, our research comprehensively analyzed biological formulations, pointing out significant strategies regarding administration routes, dosage forms, product packaging, and excipients. In conjunction with biologics, the widespread integration of innovative delivery strategies will be implemented to confront the evolving challenges in healthcare and meet an expanding array of treatment needs.

3D printing processes in precise drug delivery for personalized medicine.

With the advent of personalized medicine, the drug delivery system will be changed significantly. The development of personalized medicine needs the support of many technologies, among which three-dimensional printing (3DP) technology is a novel formulation-preparing process that creates 3D objects by depositing printing materials layer-by-layer based on the computer-aided design method. Compared with traditional pharmaceutical processes, 3DP produces complex drug combinations, personalized dosage, and flexible shape and structure of dosage forms (DFs) on demand. In the future, personalized 3DP drugs may supplement and even replace their traditional counterpart. We systematically introduce the applications of 3DP technologies in the pharmaceutical industry and summarize the virtues and shortcomings of each technique. The release behaviors and control mechanisms of the pharmaceutical DFs with desired structures are also analyzed. Finally, the benefits, challenges, and prospects of 3DP technology to the pharmaceutical industry are discussed.

Patients' Preference for Pharmaceutical Dosage Forms: Does It Affect Medication Adherence? A Cross-Sectional Study in Community Pharmacies.

Background: Dosage forms (DF), which are primarily divided into solid, semisolid, liquid, and gaseous, are among the different factors that influence drug adherence. Thus, the purpose of this study was to evaluate how patients' preferences for pharmaceutical DF affected their adherence to medication in community pharmacies in Gondar town. Methods: A cross-sectional study on community pharmacies was carried out from June 25 to July 27, 2023. The statistical package for social sciences, version 26, was used for data analysis. Factors associated with patient medication discontinuation were found using both bivariate and multivariate logistic regressions. Results: According to our study, the majority of respondents (42.4%) preferred tablet DF. Most respondents (63.9%) DF preference was affected by the size of the medication, in which small-sized were most preferable (59.6%). The oral route of administration was the most preferable (71.2%). The majority of the respondents (59.9%) had a history of discontinuation of medicines. Being male (AOR=2.21, 95% CI: 1.29, 3.79), living in rural areas (AOR=1.98, 95% CI: 1.03, 3.83), types of DF (AOR=4.59, 95% CI: 1.28, 16.52), high frequency of administration (AOR=2.22, 95% CI: 1.08, 4.57), high cost of medication (AOR=3.09, 95% CI: 1.69, 5.68), getting some improvement from illness (AOR=3.29, 95% CI: 1.10, 9.87), and high number of drugs (AOR=3.29, 95% CI: 1.67, 13.85) were significantly associated with medication discontinuation. Conclusion: Our findings showed that tablet dosage forms, oral routes of administration, and once-daily taking of medicines were the most preferred by our respondents. Being male, living in rural areas, types of DF, high frequency of administration, high cost of medication, getting some improvement from illness, and high number of drugs were significantly associated with medication discontinuation. This provides an insight into what to consider when prescribing medicine to enhance patients' adherence and overall therapeutic outcomes.

Sentinel lymph node identification using NIR-II ultrabright Raman nanotags on preclinical models.

Surface-enhanced Raman spectroscopy (SERS) nanotags have garnered much attention as promising bioimaging contrast agent with ultrahigh sensitivity, but their clinical translation faces challenges including biological and laser safety. As breast sentinel lymph node (SLN) imaging agents, SERS nanotags used by local injection and only accumulation in SLNs, which were removed during surgery, greatly reduce biological safety concerns. But their clinical translation lacks pilot demonstration on large animals close to humans. The laser safety requires irradiance below the maximum permissible exposure threshold, which is currently not achievable in most SERS applications. Here we report the invention of the core-shell SERS nanotags with ultrahigh brightness (1 pM limit of detection) at the second near-infrared (NIR-II) window for SLN identification on pre-clinical animal models including rabbits and non-human primate. We for the first time realize the intraoperative SERS-guided SLN navigation under a clinically safe laser (1.73 J/cm2) and identify multiple axillary SLNs on a non-human primate. No evidence of biosafety issues was observed in systematic examinations of these nanotags. Our study unveils the potential of NIR-II SERS nanotags as appropriate SLN tracers, making significant advances toward the accurate positioning of lesions using the SERS-based tracer technique.

Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug-resistant focal seizures.

OBJECTIVE: Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate. METHODS: A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration. RESULTS: The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period. SIGNIFICANCE: Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load. PLAIN LANGUAGE SUMMARY: Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.

Exploring gonadotropin dosing effects on MII oocyte retrieval in ovarian stimulation.

PURPOSE: Ovarian stimulation with gonadotropins is crucial for obtaining mature oocytes for in vitro fertilization (IVF). Determining the optimal gonadotropin dosage is essential for maximizing its effectiveness. Our study aimed to develop a machine learning (ML) model to predict oocyte counts in IVF patients and retrospectively analyze whether higher gonadotropin doses improve ovarian stimulation outcomes. METHODS: We analyzed the data from 9598 ovarian stimulations. An ML model was employed to predict the number of mature metaphase II (MII) oocytes based on clinical parameters. These predictions were compared with the actual counts of retrieved MII oocytes at different gonadotropin dosages. RESULTS: The ML model provided precise predictions of MII counts, with the AMH and AFC being the most important, and the previous stimulation outcome and age, the less important features for the prediction. Our findings revealed that increasing gonadotropin dosage did not result in a higher number of retrieved MII oocytes. Specifically, for patients predicted to produce 4-8 MII oocytes, a decline in oocyte count was observed as gonadotropin dosage increased. Patients with low (1-3) and high (9-12) MII predictions achieved the best results when administered a daily dose of 225 IU; lower and higher doses proved to be less effective. CONCLUSIONS: Our study suggests that high gonadotropin doses do not enhance MII oocyte retrieval. Our ML model can offer clinicians a novel tool for the precise prediction of MII to guide gonadotropin dosing.

Non canonical bases differentially represented in the sex chromosomes of the dioecious plant Silene latifolia.

The oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), known as oxi-mCs, garners significant interest in plants as potential epigenetic marks. While research in mammals has established a role in cell reprogramming, carcinogenesis and gene regulation, their functions in plants remain unclear. In rice, 5hmC has been associated with transposable elements and heterochromatin. This study utilizes Silene latifolia, a dioecious plant with heteromorphic sex chromosomes and a genome with a large proportion of transposable elements, which provides a favourable environment for the study of oxi-mCs in individual sexes. Notably, we detected surprisingly high levels of oxi-mCs in S. latifolia comparable to mammals. Nuclei showed enrichment in heterochromatic regions, except for 5hmC which signal was homogeneously distributed. Intriguingly, the same X chromosome in females displayed overall enrichment of 5hmC and 5fC regarding its counterpart. This fact is shared with 5mC resembling dosage compensation. Colocalization showed higher correlation between 5mC and 5fC than with 5hmC, suggesting no potential relationship between 5hmC and 5fC. Additionally, the promoter of several sex-linked genes and sex biased TEs gathered on a clear sex-dependent clustering. Together, these findings unveil a hypothetical role of oxi-mCs in S. latifolia sex chromosome development, warranting further exploration.

Flexible modelling of the dissolution performance of directly compressed tablets.

In this study, a compartmental disintegration and dissolution model is proposed for the prediction and evaluation of the dissolution performance of directly compressed tablets. This dissolution model uses three compartments (Bound, Disintegrated, and Dissolved) to describe the state of each particle of active pharmaceutical ingredient. The disintegration of the tablet is captured by three fitting parameters. Two disintegration parameters, ß0 and ßt,0, describe the initial disintegration rate and the change in disintegration rate, respectively. A third parameter, α, describes the effect of the volume of dissolved drug on the disintegration process. As the tablet disintegrates, particles become available for dissolution. The dissolution rate is determined by the Nernst-Brunner equation, whilst taking into account the hydrodynamic effects within the vessel of a USP II (paddle) apparatus. This model uses the raw material properties of the active pharmaceutical ingredient (solubility, particle size distribution, true density), lending it towards early development activities during which time the amount of drug substance available may be limited. Additionally, the strong correlations between the fitting parameters and the tablet porosity indicate the potential to isolate the manufacturing effects and thus implement the model as part of a real-time release testing strategy for a continuous direct compression line.