Lateral Quantum Confinement Effect on High-TC Superconducting FeSe Monolayer.

Despite decades of research in spatially confined superconducting systems to understand the modification of superconductivity from reduced length scales, the investigation of the quantum confinement effect on high-temperature superconductors remains an outstanding challenge. Here, we report scanning tunneling spectroscopy measurements on laterally confined FeSe monolayers on SrTiO3 substrates, which are formed by epitaxially growing FeSe films with a coverage less than one unit cell. Comparing to the uniform regions of FeSe monolayers, the peninsula regions at the monolayer boundary exhibit reduced Fermi energy and undiminished superconductivity, leading to a putative crossover from a Bardeen-Cooper-Schrieffer state to a Bose-Einstein condensate state. In isolated FeSe monolayer islands, superconductivity is shown to exist in samples of smaller volume in contrast to conventional superconductors, while the validity of Anderson's criterion remains fulfilled. Our work reveals lateral quantum confinement effects in unconventional superconductors to enrich the understanding of high-temperature superconductivity in low-dimensional systems.

Nanocrystal-Loaded Lipid Carriers for Improved Oral Absorption and Anticancer Efficacy of Etoposide: Formulation Development, Transport Mechanism, In Vitro and In Vivo Evaluation.

To improve the oral absorption and anticancer efficacy of the BCS-IV drug etoposide (ETO), oral nanocrystal-loaded lipid carriers (Lipo@NCs) were developed in this study by modifying the BCS-IV drug nanocrystal with the lipid bilayer. The ETO-Lipo@NCs were prepared by the thin film hydration high-pressure homogenization method, and the core of positively charged ETO nanocrystals was prepared by the sonoprecipitation-high pressure homogenization method. The optimized ETO-Lipo@NCs were spherical particles with an average particle size of 220.3 ± 14.2 nm and a zeta potential of -9.95 ± 0.81 mV, respectively. The successful coating of a lipid bilayer on the surface of nanocrystals in ETO-Lipo@NCs was confirmed by several characterization methods. Compared to nanocrystals, the release rate and degree of Lipo@NCs in SIF were significantly decreased, indicating that the lipid bilayer can effectively prevent the rapid dissolution of core nanocrystals. ETO-Lipo@NCs demonstrated a significant improvement in the intestinal permeability and absorption of ETO in a single intestinal perfusion experiment. In the cells, ETO-Lipo@NCs showed enhanced cellular uptake and transepithelial transport compared with ETO nanocrystals. Pharmacokinetic analysis indicated that ETO-Lipo@NCs had a longer plasma half-life than ETO solution, and the oral bioavailability of ETO-Lipo@NCs was 1.96- and 10.92-fold higher than that of ETO nanocrystals and ETO coarse crystals, respectively. Moreover, the ETO-Lipo@NCs orally dosed at 10 mg/kg exhibited an excellent inhibitory effect against tumors in a subcutaneous Lewis lung carcinoma (LLC) xenograft model compared with other preparations. These results indicate that the Lipo@NCs formulation has an oral absorption-promoting effect of the BCS-IV drug ETO, which could warrant further application in the oral delivery of other poorly bioavailable drugs.

Coupling Drug Dissolution with BCS.

PURPOSE: The purpose of this study is to develop a Temporal Biopharmaceutic Classification System (T-BCS), linking Finite Dissolution Time (F.D.T.) and Mean Dissolution Time (M.D.T.) for Class I/III drugs and Mean Dissolution Time for saturation (M.D.T.s.) for Class II/IV drugs. METHODS: These parameters are estimated graphically or by fitting dissolution models to experimental data and coupled with the dose-to-solubility ratio (q) for each drug normalized in terms of the actual volume of dissolution medium (900 mL). RESULTS: Class I/III drugs consistently exhibited q values less than 1, aligning with expectations based on their solubility, while some Class II/IV drugs presented a deviation from anticipated q values, with observations of q < 1. This irregularity was rendered to the dissolution volume of 250 mL used for biopharmaceutical classification purposes instead of 900 mL applied as well as the dual classification of some sparingly soluble drugs. Biowaivers were also analyzed in terms of M.D.T., F.D.T. estimates and the regulatory dissolution time limits for rapidly and very-rapidly dissolved drugs. CONCLUSIONS: The T-BCS is useful for establishing correlations and assessing the magnitude of M.D.T., F.D.T., or M.D.T.s. for inter- and intra-class comparisons of different drugs and provide relationships between these parameters across all the models that were utilized.

Life-course social participation and physical activity in midlife: longitudinal associations in the 1970 British Cohort Study (BCS70).

A hypothesized benefit of social participation is that it encourages people to be more physically active. However, limited evidence exists on the association between social participation over the life-course and physical activity in midlife. We sought to apply a life-course framework to examine the association of social participation and device measured physical activity in midlife in the UK. We used the 1970 British Birth Cohort Study (BCS70), which includes all people born in Britain during a single week in 1970. Social participation was assessed at ages 16, 30, 34 and 42. Physical activity was measured by accelerometery at age 46, as mean daily step count and time spent in moderate to vigorous physical activity (MVPA). The associations of social participation and physical activity were tested using two different life-course models: the sensitive period model and the accumulation model. Individuals with medium and high participation compared to no social participation over their life-course had higher mean daily step count and MVPA in midlife, supporting the accumulation model. In the sensitive period model, only those that actively participated at age 42 had higher mean daily steps and MVPA compared to those who did not participate. Our study provides empirical evidence on the importance of sustaining social participation at all ages over the life-course rather than at a particular timepoint of someone's life. If our findings reflect causal effects, interventions to promote social participation throughout the life-course could be an avenue to promote physical activity in middle life.

Effects of a physical exercise programme on bodyweight, body condition score and chest, abdominal and thigh circumferences in dogs.

BACKGROUND: Research on the effects of physical exercise on canine body composition is limited. The aim of this study was to investigate the effects of a physical exercise programme on bodyweight, body condition score (BCS) and chest, abdominal and thigh circumferences in dogs. Twenty-one healthy dogs of different breeds exercised together with their owners during an eight-week programme consisting of jogging and strength exercises. Standardised measurements were performed in triplicates with a measuring tape on standing dogs. Chest circumference was measured at three anatomical locations, abdomen at two and thigh at one. Data on bodyweight, BCS (9-point scale) and circumferences were analysed with mixed model repeated measures analyses to evaluate changes after the programme and effects of target distance. RESULTS: Seven dog owners choose a target distance of 2 km and 14 owners choose 5-10 km. Mean BCS decreased (P = 0.007) after the programme (5.1 ± 0.9 vs. 4.7 ± 0.6) but there was no effect of target distance. Almost all chest and abdominal circumference measurements decreased (P ≤ 0.007) with the 2 km group driving the reduction in chest circumference and the 5-10 km group driving the reduction in abdominal circumference. In contrast, thigh circumference (28.8 ± 0.4 vs. 30.2 ± 0.4) increased (P = 0.007) while bodyweight was maintained. There were positive correlations between BCS and abdominal/chest ratios before and after the programme (Pearson correlation; R square ≤ 0.43, P ≤ 0.0012) but the mean ratio remained constant. CONCLUSIONS: Results indicated a redistribution between total body fat and muscle mass in body composition of normal weight to slightly overweight dogs after the physical exercise programme. The use of bodyweight alone was not a reliable evaluation method to complement the BCS assessment. However, repeated measurements of chest, abdominal and thigh circumference might aid in the assessment of body composition in dogs performing physical exercise. Further research should include a control group and objective evaluations of total body fat and lean mass, in order to investigate the effectiveness of physical exercise as a freestanding method for decreasing BCS and increasing muscle mass in overweight dogs.

Qualification of In Vitro Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs.

This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.

A prospective cohort study of factors associated with the digital cushion thickness in dairy cattle.

Key factors such as stage of lactation, parity, and body fat reserves have been associated with the digital cushion thickness (DCT), however, there are discrepancies between the results of previously published studies. The objective of this study was to examine the association of stage of lactation, body fat reserves, parity, and lesion incidence with DCT in a large cohort of intensively monitored cows. Across 4 UK farms, 2,352 cows were prospectively enrolled and assessed at 4 time points: before calving (T1-Precalving), immediately after calving (T2-Calving), in early lactation (T3-Early), and in late lactation (T4-Late). At each time point, BCS was recorded, the presence of sole lesions (sole ulcers and sole hemorrhage) and white line lesions was assessed by veterinarians, and an ultrasound image was taken to retrospectively measure the backfat thickness (BFT) in the pelvic region and the digital cushion on the hind left lateral claw. Mixed effects multivariable linear regression models, with the cow as a random effect, were fit to examine the association between the explanatory variables and DCT. The explanatory variables tested were farm, parity, stage of lactation, BCS, BFT, height, the presence of a lesion at the time of measurement, the chronicity of a lesion during early lactation, the predicted maximum daily milk yield, and the rate of milk production rise in early lactation. Stage of lactation and farm were both associated with DCT; however, an interaction was present, and this DCT pattern of change was farm-dependent. Two distinct patterns emerged; one indicated the nadir to occur shortly after calving, the other indicated the nadir to occur during early lactation. Neither BFT nor BCS were significantly associated with DCT. Heifers displayed thinner digital cushions compared with multiparous cows; however, this effect was dependent on the stage of lactation, with heifers having a thinner digital cushion up until late lactation, by which time DCT was commensurate with multiparous animals. Sole lesions and white line lesions at the time of measurement were associated with DCT (sole lesion: estimate = -0.07 mm, 95% CI = -0.14-0.00; white line lesion: estimate = 0.28 mm, 95% CI = 0.15-0.42).

Factors influencing pregnancy rate and loss after laparoscopic artificial insemination with frozen-thawed semen in Lohi sheep under sub-tropical conditions.

This study evaluates factors influencing pregnancy rates per artificial insemination (P/AI) and pregnancy loss in Lohi ewes undergoing laparoscopic AI with frozen-thawed semen under sub-tropical conditions. Data from three experiments comprising ewes (n = 358) of mixed parity (nulliparous; NP and parous; P), various body condition score (BCS) and assigned to long-term (LTP, 11 days) and short-term (STP, 5 days) oestrus synchronization regimen across high breeding season (HBS) and low breeding season (LBS) were analysed. Laparoscopic insemination was conducted 54 h post-sponge removal. Pregnancy diagnosis and loss were evaluated on days 35 and 90 post-insemination via ultrasonography. Results showed parity significantly influenced P/AI, with nulliparous ewes achieving higher pregnancy ratios than parous ewes (p = .001). BCS significantly influenced P/AI (p < .05), with a quadratic relationship observed between BCS and season (BCS*BCS*Season; p = .07). Progestin treatment did not significantly influence the ratio of pregnant ewes (p = .07). Pregnancy losses were significantly higher during LBS than HBS (p < .05), irrespective of progestin treatment. In conclusion, parity and BCS significantly influenced P/AI, with BCS demonstrating a quadratic association with season. Ewes bred during LBS experienced higher pregnancy losses than HBS, irrespective of progestin treatment.

Radiofrequency as a method of localizing impalpable breast lesions.

BACKGROUND: The incidence of early stage breast cancer has risen as a result of increased detection of non-palpable tumors through the implementation of screening programs and greater public awareness. Performing breast-conserving surgery can be challenging due to the need for accurate localization of non-palpable breast lesions, particularly given the logistical difficulties associated with wire localization. After implementing a new technique for localizing non-palpable breast lesions (LOCalizerTM Radiofrequency identification TAG-Hologic®), a radiofrequency identification tag localization device manufactured by Hologic, Inc. in Marlborough, MA, was launched in 2017, our objective was to investigate its impact on surgical outcomes, whether there was an increase in re-excision rates for positive margins and whether the attainment of clear margins was dependent on the exact positioning of the RFID device. METHOD: A single-center single-arm interventional study, data were gathered both in a forward-looking manner for 1 year (prospectively) and by looking back at past records for 1 year (retrospectively) for a total period of two years. Individuals who were diagnosed with non-palpable breast lesions, as confirmed by histological analysis, or invasive breast cancer and who were scheduled to undergo breast-conserving surgery were eligible for inclusion in the study. The RFID (Radiofrequency Identification) method was used to localize the lesions prior to surgery. Either with a mammogram or ultrasound scan position of the Tag was recorded, including the distance of the lesion from the center of the lesion and the lesion depth from the skin in millimeters. The rate of re-excision was documented and examined in relation to the parameters mentioned above. RESULTS: Two hundred and twenty RFID Tags were inserted in two hundred and seventeen (three patient had bilateral tags insertion), patients aged between 30 and 85 had a localizer Tag inserted between Oct 2020 and Oct 2022. Three patients had non-palpable breast lesions in both breasts. Fourteen were inserted under stereotactic guidance and two hundred and six under ultrasound guidance. Ten patients subsequently had wire insertion also due to Tag position. Of 210 procedures, RFIF Tags within the lesion was seen in hundred and sixty patients (76.19 %). An additional 50 procedures were performed using the RFID Tag system, which were not directly related to the lesion but were deemed appropriate to proceed with. Out of a total of 220 procedures, positive margins were observed in 38 cases (17.27 %). Among these cases, eleven (28.94 %) involved the use of the RFID Tag system, not within the lesion but adjacent to it (within 15 mm surrounding the lesion). CONCLUSION: RFID is a good alternative to wire localization of non-palpable breast lesions. Re-excision rates are higher in patients with Tag outside the lesion compared to those with Tag within the lesion.

Determination of N-Acetyl-L-cysteine Ethyl Ester (NACET) by Sequential Injection Analysis.

New sequential injection analysis (SIA) methods with optical sensing for the determination of N-acetyl-L-cysteine ethyl ester (NACET) have been developed and optimized. NACET is a potential drug and antioxidant with advantageous pharmacokinetics. The methods involve the reduction of Cu(II) in its complexes with neocuproine (NCN), bicinchoninic acid (BCA), and bathocuproine disulfonic acid (BCS) to the corresponding chromophoric Cu(I) complexes by the analyte. The absorbance of the Cu(I) complexes with NCN, BCA, and BCS was measured at their maximum absorbance wavelengths of 458, 562, and 483 nm, respectively. The sensing manifold parameters and experimental conditions were optimized for each of the Cu(II) complexes used. Under optimal conditions, the corresponding linear calibration ranges, limits of detection, and sampling rates were 8.0 × 10-6-2.0 × 10-4 mol L-1, 5.5 × 10-6 mol L-1, and 60 h-1 for NCN; 6.0 × 10-6-1.0 × 10-4 mol L-1, 5.2 × 10-6 mol L-1, and 60 h-1 for BCA; and 4.0 × 10-6-1.0 × 10-4 mol L-1, 2.6 × 10-6 mol L-1, and 78 h-1 for BCS. The Cu(II)-BCS complex was found to be best performing in terms of sensitivity and sampling rate. Usual excipients in pharmaceutical preparations did not interfere with NACET analysis.

A Compact Broadside Coupled Stripline 2-D Beamforming Network and Its Application to a 2-D Beam Scanning Array Antenna Using Panasonic Megtron 6 Substrate.

This article presents a 4-way 2-D butler matrix (BM)-based beamforming network (BFN) using a multilayer substrate broadside coupled stripline (BCS). To achieve the characteristics of a compact, wide-bandwidth, high-gain phased array, a BCS coupler is implemented using the Megtron 6 substrate. The compact 2-D BFN is formed by combining planarly two horizontal BCS couplers and two vertical BCS couplers. The BFN is proposed without a crossover and without a phase shifter, generating phase responses of ±90° in the x- and y-directions, respectively. The proposed BFN exhibits a wide operating band of 66.7% (3-7 GHz) and a compact physical area of just 0.25 λ0 × 0.25 λ0 × 0.04 λ0. The planar 2-D BFN is easily integrated with the patch antenna radiation elements to construct a 2-D multibeam array antenna that generates four fixed beams, one in each quadrant, at an elevation angle of 30° from the broadside to the array axis when the element separation is 0.6 λ0. The physical area of the 2-D multibeam array antenna is just 0.8 λ0 × 0.8 λ0 × 0.04 λ0. The prototypes of the BCS coupler, the 2-D BFN, and the 2-D multibeam array antenna were fabricated and measured. The measured and simulated results were in good agreement. A gain of 9.1 to 9.9 dBi was measured.

Enhancing oral bioavailability of Ca-DTPA by self double emulsifying drug delivery system (SDEDDS).

OBJECTIVE: BCS class III drug (highly soluble, poorly permeable) possesses low oral bioavailability. The research work highlights the utility of self-double emulsifying drug delivery system (SDEDDS) which are stable isotropic mixture of w/o primary emulsion and hydrophilic surfactants for improving oral bioavailability of Ca-DTPA (Calcium diethylenetriamine pentaacetate). Upon oral administration, SDEDDS rapidly emulsifies into w/o/w double emulsions in the aqueous gastrointestinal environment, with hydrophilic drugs entrapped inside oil reservoirs. METHODS: SDEDDS formulation was successfully developed using excipients, that is, medium chain triglycerides, oleic acid, phospholipids, Span 80, Tween 80 using double emulsification technique. RESULTS: The optimized formulation F4 (Aq. phase: 11.6%w,w; MCT & oleic acid: 70.9%w/w; Span 80:17.5%w/w; Lecithin:16%w/w and Tween 80 (10%w/w)) appeared bright yellow liquid which upon dilution appeared milky white within 2 min, droplet size (501.7 nm), pdi value (0.044), zeta potential (-52 mV), entrapment efficiency (79.6 ± 1.63), viscosity (72.2 ± 1.8 mpA.s), significant high cumulative in vitro drug permeation (CDP) and 2.17-fold increase in apparent permeability coefficient. Pharmacokinetic studies in rats showed 1.17-fold increases in AUC of F4 and comparatively higher plasma levels (Cmax) compared with pure drug administered orally. The Absolute (OF4, OD) and Relative bioavailability was found to be 14.52%, 12.35%, and 117.47%, respectively. CONCLUSION: The present studies have clearly demonstrated that SDEDDS could readily form w/o/w double emulsions in vivo with enhanced in vitro and in vivo oral bioavailability. Therefore, considerable augmentation in the rate and extent of oral drug absorption ratified the better performance of the SDEDDS in enhancing the bioavailability of Ca-DTPA.

An empirical predictive model for determining the aqueous solubility of BCS class IV drugs in amorphous solid dispersions.

CONTEXT: Determining solubility of drugs is laborious and time-consuming process that may not yield meaningful results. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. OBJECTIVE: This study aimed to develop a predictive model to estimate the solubility of a compound from the ASDs in polymer matrices. METHODS: ASDs of model drugs (acetazolamide, chlorothiazide, furosemide, hydrochlorothiazide, sulfamethoxazole) with model polymers (PVP, PVPVA, HPMC E5, Soluplus) and a surfactant (TPGS) were prepared using hotmelt process. The prepared ASDs were characterized using DSC, FTIR, and XRD. The aqueous solubility of the model drugs was determined using shake-flask method. Multiple linear regression was used to develop a predictive model to determine aqueous solubility using the molecular descriptors of the drug and polymer as predictor variables. The model was validated using Leave-One-Out Cross-Validation. RESULTS: The ASDs' drug components were identified as amorphous via DSC and XRD Studies. There were no significant chemical interactions between the model drugs and the polymers based on FTIR studies. The ASDs showed a significant (p < 0.05) improvement in solubility, ranging from a 3-fold to 118-fold, compared with the pure drug. The developed empirical model predicted the solubility of the model drugs from the ASDs containing model polymer matrices with an accuracy greater than 80%. CONCLUSION: The developed empirical model demonstrated robustness and predicted the aqueous solubility of model drugs from the ASDs of model polymer matrices with an accuracy greater than 80%.

Exploring Co-Amorphous Formulations Of Nevirapine: Insights From Computational, Thermal, And Solubility Analyses.

This study aimed to assess the formation of nevirapine (NVP) co-amorphs systems (CAM) with different co-formers (lamivudine-3TC, citric acid-CAc, and urea) through combined screening techniques as computational and thermal studies, solubility studies; in addition to develop and characterize suitable NVP-CAM. NVP-CAM were obtained using the quench-cooling method, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and polarized light microscopy (PLM), in addition to in vitro dissolution in pH 6.8. The screening results indicated intermolecular interactions occurring between NVP and 3TC; NVP and CAc, where shifts in the melting temperature of NVP were verified. The presence of CAc impacted the NVP equilibrium solubility, due to hydrogen bonds. DSC thermograms evidenced the reduction and shifting of the endothermic peaks of NVP in the presence of its co-formers, suggesting partial miscibility of the compounds. Amorphization was proven by XRD and PLM assays. In vitro dissolution study exhibited a significant increase in solubility and dissolution efficiency of NVP-CAM compared to free NVP. Combined use of screening studies was useful for the development of stable and amorphous NVP-CAM, with increased NVP solubility, making CAM promising systems for combined antiretroviral therapy.

Evaluation of cilnidipine-loaded self-micro-emulsifying drug delivery system (SMEDDS) by quantification of comparative pharmacokinetic parameters using validated LC-ESI-MS/MS bioanalytical method and pharmacodynamic assessment.

OBJECTIVE: Regardless of having desired therapeutic properties many of the recently approved drugs are removed from the developmental pipeline for their clinical use due to low solubility and permeability. Conventional dosage forms are found relatively unsuitable for achieving desired pharmacokinetic and pharmacodynamics profiles. Cilnidipine is 1,4 dihydropyridine derivative calcium channel blocker used for the treatment of hypertension. METHOD: The aim and objective of this study was to develop a precise and significant method in LC-MS/MS for quantification of pharmacokinetic parameters of a cilnidipine-loaded self-micro-emulsifying drug delivery system in rat plasma and simultaneously assessed pharmacodynamic characters in comparison with the marketed cilnidipine tablet. Another potential aim of this study is to reduce the dose of the drug in order to counter the dose-dependent toxicities related to chronic use. In the present study, the parent and product ion of cilnidipine was m/z 491.3\237.1. RESULT: The plasma was extracted by protein precipitation technique. The calibration standard concentrations were 1.875, 3.75, 7.50, 15.00, 30.00, 60.00ng/mL and LLOQ, low-quality control, middle-quality control and high-quality control were 1.87, 5.62, 22.50, 45.00ng/mL, respectively. The mobile phase composition was 0.1% formic acid in Milli Q water with 10mM Ammonium acetate as an aqueous solvent and 0.1% formic acid in methanol as an organic solvent. Following oral administration of optimized formulation Cmax (peak plasma concentration) was achieved 21.02±3.17ng/mL at 0.866±0.11h (Tmax), whereas in the case of marketed tablet Cmax (peak plasma concentration) was achieved 10.16±0.89ng/mL at 0.93±0.11h (Tmax). DISCUSSION: The in-vivo characterizations of the optimized SMEDDS showed significantly better pharmacokinetic parameters in Wistar rats and showed almost 2.4 times enhanced relative bioavailability as compared to the marketed tablet of cilnidipine which was observed to be correlating to our findings with noninvasive blood pressure parameter of Wistar rats.

Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study.

BACKGROUND: Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge. METHODS: From 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). RESULTS: After post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02). CONCLUSION: In patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor's hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings.

Nuclear-encoded mitochondrial ribosomal proteins are required to initiate gastrulation.

Mitochondria are essential for energy production and although they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear-encoded mitochondrial proteins and in-depth characterization of mouse embryos mutant for the Mrp genes Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22 Loss of each MRP results in successful implantation and egg-cylinder formation, followed by severe developmental delay and failure to initiate gastrulation by embryonic day 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pre-gastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are crucial at specific time points during mammalian development.

Predicting the Pharmacokinetics of Orally Administered Drugs across BCS Classes 1-4 by Virtual Bioequivalence Model.

To evaluate the influence of solubility and permeability on the pharmacokinetic prediction performance of orally administered drugs using avirtual bioequivalence (VBE) model, a total of 23 orally administered drugs covering Biopharmaceutics Classification System (BCS) classes 1-4 were selected. A VBE model (i.e., a physiologically based pharmacokinetic model integrated with dissolution data) based on a B2O simulator was applied for pharmacokinetic (PK) prediction in a virtual population. Parameter sensitivity analysis was used for input parameter selection. The predictive performances of PK parameters (i.e., AUC0-t, Cmax, and Tmax), PK profiles, and bioequivalence (BE) results were evaluated using the twofold error, average fold error (AFE), absolute average fold error (AAFE), and BE reassessment metrics. All models successfully simulated the mean PK profiles, with AAFE < 2 and AFE ranging from 0.58 to 1.66. As for the PK parameters, except for the time of peak concentration, Tmax, of isosorbide mononitrate, other simulated PK parameters were all within a twofold error. The simulated PK behaviors were comparable to the observed ones, both for test (T) and reference (R) products, and the simulated T/R arithmetic mean ratios were all within 0.88-1.16 of the observed values. These four evaluation metrics were distributed equally among BCS class 1-4 drugs. The VBE model showed powerful performance to predict the PK behavior of orally administered drugs with various combinations of solubility and permeability, irrespective of the BCS category.

Identification of risk factors for ewe mortality during the pregnancy and lambing period in extensively managed flocks.

BACKGROUND: Ewe mortality during pregnancy and lambing is an issue for sheep producers globally, resulting in reduced productivity and profitability, compromised ewe welfare, and poor consumer perception. Despite these negative consequences, there was little investigation into factors associated with ewe death during this time. Therefore, this study aimed to assess associations between ewe body condition score (BCS), weight, reproductive parameters, and risk of mortality during pregnancy and lambing. METHODS: Four cohorts from three commercial New Zealand farms participated, with 13,142 ewe lambs enrolled and followed over time. Data were collected for five consecutive lambings. Visits aligned with key on-farm management times, specifically: prior to breeding, at pregnancy diagnosis (PD), prior to lambing (set-stocking), and, at weaning of their lambs. At each visit, ewes were weighed, BCS assessed and reproductive status was recorded when relevant (litter size at PD and lactation status after lambing). Ewes that died or were culled were recorded, and any ewes that were absent from consecutive visits were presumed dead. Logistic regressions were developed to assess the relationship between weight and BCS at each visit, PD result (single or multiple-bearing) and lactation status (wet or dry) in each year, and, risk of mortality during the pregnancy and lambing period in each year. RESULTS: In the PD to weaning period, mortality incidence ranged from 6.3 to 6.9% for two-tooth (18-months-old at breeding) to mixed-age (54-months-old at breeding) ewes. For ewe lambs (7 to 8-months-old at breeding), mortality was 7.3% from set-stocking to weaning. Heavier ewe lambs at PD were less likely to die during lambing (OR: 0.978, p = 0.013), as were those with greater set-stocking BCS. In subsequent years, BCS was a predictor of ewe death, with odds of mortality greatest for ewes < BCS 2.5. Additionally, for poorer BCS ewes, increasing weight reduced risk of mortality, but there was no impact of increasing weight in greater BCS ewes. CONCLUSIONS: This study identified risk factors associated with ewe mortality during the pregnancy and lambing period. Flock owners can use these to either cull at-risk ewes or proactively intervene to reduce likelihood of mortality, thereby improving flock productivity, profitability and welfare.

Welfare assessment of slow loris (Nycticebus spp.) at an Indonesian primate rehabilitation center: Development and validation of body condition score.

Body condition scoring (BCS) assessment can reflect animal welfare status and help the veterinarian to make a quick health management decision, including for confiscated slow loris (Nycticebus spp.). The confiscated slow loris should be rehabilitated in a rehabilitation center before being released. It is essential to monitor the welfare of slow loris to ensure that candidates are released. Assessment of animal welfare status requires representative measurable criteria and indicators. However, there is no standardized BCS for slow loris yet. This study focuses on developing and validating BCS based on body weight and circumference. In this study, 180 individuals were evaluated and scored. We measured body weight and circumferences to validate the assessment of BCS. There are no significant differences in body weight and circumferences within species and sexes. Muscle mass and fat deposits were palpated, visually viewed, and grouped in five BCS. There was a significant difference in body weight and circumference between BCS levels. According to this study, the development of BCS is valid and can be used to slow loris in prevailing circumstances and any ex-situ facilities.