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Diagnostic value of routine blood tests in differentiating between SARS-CoV-2, influenza A, and RSV infections in hospitalized children: a retrospective study

BackgroundThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), influenza A, and respiratory syncytial virus (RSV) infections have similar modes of transmission and clinical symptoms. There is a need to identify simple diagnostic indicators to distinguish these three infections, particularly for community hospitals and low- and middle-income countries that lack nucleic acid detection kits. This study used clinical data to assess the diagnostic value of routine blood tests in differentiating between SARS-CoV-2, influenza A, and RSV infections in children.MethodsA total of 1420 children treated at the Hangzhou Children’s Hospital between December 2022 and June 2023 were enrolled in this study, of whom 351 had SARS-CoV-2, 671 had influenza, and 398 had RSV. In addition, 243 healthy children were also collected. The blood test results of SARS-CoV-2 patients were compared to those of patients with influenza A and RSV and the healthy controls. The area under the receiver operating characteristic curve (AUC-ROC) was employed to evaluate each blood parameter’s diagnostic value.ResultsChildren with SARS-CoV-2 exhibited notably elevated levels of white blood cell (WBC) count, platelet (PLT) count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR) compared to influenza A patients (P < 0.05). In contrast, SARS-CoV-2 patients exhibited a decrease in the mean platelet volume to platelet count ratio (MPV/PLT) and the lymphocyte-to-monocyte ratio (LMR) when compared to other individuals (P < 0.05). These parameters had an AUC between 0.5 and 0.7. Compared to patients with RSV, SARS-CoV-2 patients had significantly higher MPV/PLT and significantly lower WBC, lymphocyte, PLT, LMR, and lymphocyte multiplied by platelet (LYM*PLT) values (P < 0.05). However, only LYM*PLT had an acceptable diagnostic value above 0.7 for all age groups. Compared to healthy children, children with COVID-19 exhibited elevated NLR and MPV/PLT levels, alongside decreased lymphocyte, PLT, LMR, and LYM*PLT values. (P < 0.05). The AUC of the LMR, LYM*PLT, and PLT were above 0.7 in all age groups, indicating promising diagnostic values.ConclusionsThe routine blood parameters among patients with COVID-19, influenza A, and RSV differ significantly early in the disease and could be used by clinicians to discriminate between the 3 types of infection.

Progression of adenomyosis: Rate and associated factors.

To evaluate the rate of disease progression and the factors associated with such progression in patients with an ultrasound diagnosis of adenomyosis. This was a single center, prospective, observational, cohort study performed at a tertiary referral center. Patients who obtained an ultrasound diagnosis of adenomyosis from May 2022 to August 2022 were recruited. Demographic, clinical and ultrasound data were recorded at the first visit (T0) and after 12 months (T1) for enrolled patients and compared between T0 and T1. The study population was divided in two groups according to progression (increase in uterine volume >20%) or stability/regression (decrease or increase in uterine volume ≤20%) of adenomyosis at T1. Primary study outcome was the rate of adenomyosis progression, while secondary study outcome was the association of adenomyosis progression with demographic and clinical factors. Post hoc subgroups analyses for primary and secondary study outcomes were performed based on hormonal therapy (untreated and treated). A total of 221 patients were enrolled in the study, with no significant difference in terms of baseline data among the two study groups and no patients were lost to follow-up. The overall rate of adenomyosis progression was 21.3% (47/221 patients). The rate was 30.77% in hormonally untreated women, and 18.34% in hormonally treated women. Progression was associated with the presence of focal adenomyosis of the outer myometrium (P = 0.037), moderate to severe dysmenorrhea (P = 0.001), chronic pelvic pain (P = 0.05), dyschezia (P = 0.05), and worsening of chronic pelvic pain (P = 0.04) at T1. Adenomyosis showed a rate of disease progression of 21.3% at the 12-month follow-up (30.77% in hormonally untreated women, and 18.34% in hormonally treated women). The presence and/or worsening of painful symptoms, such as severe dysmenorrhea, dyschezia and chronic pelvic pain, as well as the presence focal adenomyosis of the outer myometrium, might help identify patients at higher risk of disease progression and tailor their follow-up.

Three-Dimensional Photography for Evaluating the Effectiveness of Botulinum Toxin Injection for Masseter Hypertrophy.

Masseter hypertrophy is a common condition that causes a undesirable square face, and often treated with botulinum toxin type A (BoNTA). Subjective assessments of BoNTA effectiveness vary from physician to patient, necessitating an objective approach for evaluation. This study introduces three-dimensional photography (3DP) for the first time in clinical assessment to evaluate BoNTA treatment for masseter hypertrophy. Ten patients received 36U of BoNTA at three injection points on each side masseter muscle. 3DP scanner using Artec Eva® was taken at the first, third, and sixth postoperative months for objective evaluation. Patient's self-perceived prominence, patients self-rated satisfaction, and physicians provided 5-grade scores were the subjective indicators. A significant decrease in left masseter volume at the sixth month (P = 0.002, P = 0.004 at rest and clenching, respectively) was observed. Patient's self-perceived prominence decreased at the first (P = 0.021) and third (P = 0.039) months. Physicians' scores significantly decreased at all postoperative months. No significant changes were noted in the right masseter volume and patients self-rated satisfaction. Patient self-rated satisfaction did not consistently correlate with objective measures, except for left masseter with clenching at the sixth month. Three-dimensional photography accurately quantifies facial changes post-BoNTA treatment. Despite objective improvements, patient satisfaction may not align consistently. Reliable assessment tools are crucial in cosmetic surgery to manage expectations and prevent disputes. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

“Normal” breast dimensions in obese women—reference values and the effect of weight loss

BackgroundBreast hypertrophy may cause significant suffering, such as back- and breast pain, painful shoulder groves, and eczemas. Furthermore, women with breast hypertrophy may have lower quality of life than women without breast hypertrophy. Although 50% of the women undergoing breast reduction in the US have body mass index (BMI) >30 kg/m2, the current standard of normality is based on studies focusing on women <40 years of age and BMIs <25 kg/m2. This study aimed to present reference values for breast measurements for women with obesity and to investigate the relationship between BMI loss and each breast measurement. Materials and methodsOne hundred and six women underwent laparoscopic Roux-en-Y gastric bypass in Gothenburg, Sweden. The participants' breast anthropometrics were measured before and after bariatric surgery and their perception of the skin on their breasts was measured using the Sahlgrenska Excess Skin Questionnaire. ResultsBreast volume, sternal notch to nipple (SNN) distance, and ptosis increased significantly with increasing BMI. For instance, women with BMIs between 30–34.9 kg/m2 have a mean breast volume of approximately 770 ml, those with BMIs of 40–44.9 kg/m2 have approximately 1150 ml, and those with BMIs above 50 kg/m2 have approximately 1400 ml. Furthermore, the percent change in the respective breast measurements relative to percent BMI change can be predicted, for instance, with a 20% reduction in BMI, the breast volume, SNN-distance, and ptosis decrease by 25%, 4%, and 20% respectively. ConclusionsThis article presents the first standard of normality for breast anthropometrics in women with obesity and a model for predicting the change in breast anthropometrics relative to BMI. Clinical trial registrationThis is a longitudinal observation study, registered https://fou.nu/is/gsb/ansokan/49651, No: VGFOUGSB-49651.Trial registry name: “Överskottshud efter överviktskirurgi – dess utveckling samt behov och effekt av plastikkirurgi” (“Excess skin after bariatric surgery – its development and the need and effect of plastic surgery”).

The role of Ti in mitigating thermal expansion of silica from molecular dynamics simulations

AbstractMolecular dynamics simulations are performed to investigate the structural response of titania silicate glass to temperature. The coefficient of thermal expansion is computed for two titania silicate glasses with 0 and 10 mol% titania content, the structures of which are presented in terms of radial and angular distributions. Revealed by the different changing rates of intertetrahedra bond angles and bond lengths with respect to the Ti and Si atoms, the glass structures tend to exhibit a nonvectorized expansion process at elevated temperatures, leading to inconsistent expansion rates of the structures in different scales. While the average length of TiO and Si‐O bonds both increases with temperature, the decrease in the coefficient of thermal expansion by the addition of Ti atoms is associated with the different expansion rate of tetrahedra. Arising from the gradual decrease in atomic overlapping, decrease in free volume inside the glass with temperature is also identified.

Experimental study and numerical simulation on porosity dependent direct reducibility of high-grade iron oxide pellets in hydrogen

The transition to more environmentally friendly steel production methods has intensified research into hydrogen-based direct reduction (HyDR) of iron oxide pellets. The aim of this study is to systematically investigate the kinetics of the reduction process, the evolution of porosity and the resulting microstructural changes on the reduction behavior of high-quality pellets during HyDR of iron ore at different temperatures. A modified mathematical model is developed based on the shrinkage kernel model, taking into account both mass and heat transport in a hydrogen atmosphere. The effects of temperature, particle size and time on the reduction behavior of the pellets are investigated. The simulated results are validated and discussed by the results of a batch of iron oxide pellets consisting of ten almost spherical pellets subjected to the direct reduction process with pure hydrogen. The results show that the total energy input to the HyDR process is a complex balance of factors, including chemical reaction rates, diffusion dynamics and entropy generation. The increase in free volume and simultaneous decrease in pore diameter reflect the dynamic nature of the microstructure, which includes additional free volume and defects due to the volume discrepancies and associated stresses between the reactant and product phases. Furthermore, the data show that higher temperatures accelerate the reduction reactions, especially the transformation of wustite into metallic iron. This phase transition is characterized by a significant volume change that cannot be accommodated by elastic deformation alone, leading to the development of lattice defects such as cracks, creep pores and dislocations that serve as stress relief mechanisms. The trends for porosity change at 950 °C and 1000 °C observed in the experimental results are correct and in good agreement with the numerical and simulated results.

Zinc(II) coordination compound with N′-(pyridin-2-ylmethylene)nicotinohydrazide: Synthesis, crystal structure, computational and cytotoxicity studies

In this work, we report on the synthesis of a novel zinc(II) coordination compound [ZnL2] (1), which was readily obtained from the reaction of Zn(OAc)·2H2O and N′-(pyridin-2-ylmethylene)nicotinohydrazide (HL) in methanol. Recrystallization of 1 from dimethylformamide under ambient conditions allowed to produce yellow block-like crystals of 1·H2O. Complex 1·H2O was characterized by FT-IR and 1H NMR spectroscopy, while its optical properties were studied by UV–vis and spectrofluorimetry in methanol. The crystal structure of the title complex was revealed by single crystal X-ray diffraction and further explored in detail by the Hirshfeld surface analysis. Theoretical investigations based on the DFT calculations have also been applied to show the electronic properties of complex 1. The antitumor activities of the parent ligand HL and complex 1 were studied using Dalton's lymphoma malignant cancer model. Both compounds were found to induce concentration-dependent cytotoxicity and apoptotic cell death, leading to a decrease in cell viability, body weight, and tumor volume in mice with the superior activity of complex 1 over HL. Mice treated with complex 1 demonstrated an increase in life span with a survival period of 23 days. Finally, using a molecular docking approach, we have probed complex 1 to inhibit the recombinant mouse tumor-necrosis factor alpha (mTNF).

Nanoindentation creep mechanism of gradient ultrafine lamellar γ+Ni5Zr eutectic using electromagnetic levitation coupled with fall casting

A quaternary Ni50Fe20Cr20Zr10 eutectic alloy was designed based on the Ni–Fe–Cr alloy, and the gradient ultrafine lamellar γ+Ni5Zr eutectic was achieved by means of electromagnetic levitation coupled with fall casting (EML-FC). The temperature field, the process of interface migration, microstructural characteristics and the nanoindentation creep property of the alloy were systematically analyzed. During the rapid solidification, since the conical surface served as the main heat dissipation channel, the solid-liquid interface moved from the conical surface towards the top of the cone axis. The gradual decrease in cooling rate from 105 to 103 K s−1 along this direction led to the formation of the gradient ultrafine lamellar γ + Ni5Zr eutectic with the size from 59 ± 12 to 140 ± 36 nm. The nanoindentation creep behavior and mechanism were analyzed by estimating the strain rate sensitivity and activation volume. As the interlamellar spacing of the eutectic decreased, the nanohardness and creep resistance of the alloy gradually increased owing to an increase in grain boundary density and the enhancement of coupling effect between dislocation and grain boundary. In addition, the creep behavior of alloy was sensitive to the loading rate. Increasing the loading rate led to an increase in strain rate sensitivity from 7.69 × 10−3 to 18.89 × 10−3 and a decrease in activation volume from 29 to 12 b3. This special eutectic structure and its improved nanohardness and creep resistance properties offered a potential opportunity to explore a new generation of alloys for the hot-end components of 972 K ultra-supercritical fossil-fired power plants.

Anti-arthritic and immunomodulatory efficacy of Micromeria biflora Benth extract and its fractions in rats by restoring oxidative stress, metalloproteinases, pro-inflammatory and anti-inflammatory cytokines network.

Micromeria biflora (M.B) Benth has proven anti-inflammatory efficacy, thereby, the goal of the current investigation was to assess the anti-arthritic potential of M.B ethanolic extract and fractions as well as to investigate the likely mechanism of action. The effectiveness of M.B against acute arthritic manifestations was assessed using an arthritic model prompted by formaldehyde, whereas a chronic model was developed using an adjuvant called Complete Freund's in Sprague-Dawley rats. Weekly evaluations were conducted for parameters involving paw volume, body weight, and arthritic score; at the completion of the CFA model, hematological, biochemical and oxidative stress parameters as well as the level of various mediators (PGE2, IL-1β, TNFα, IL6, MMP2, 3, 9, VEGF, NF-ĸB, IL-10, and IL-4) were evaluated. The results demonstrated the plant's ability to treat arthritis by showing a significant decrease in paw volume, arthritic score, and histological characteristics. The levels of NF-ĸB, MMP2, 3, 9, IL6, IL1β, TNFα, and VEGF were all significantly reduced after treatment with plant extract and fractions. Plant extract and its fractions substantially preserved body weight loss, oxidative stress markers and levels of IL-4 and 1L-10. PGE2 levels were also shown to be reduced in the treatment groups, supporting the M.B immunomodulatory ability. Hematological and biochemical indicators were also normalized after M.B administration. Outcomes of the study validated the anti-arthritic and immunomodulatory attributes of M.B probably through modulating oxidative stress, inflammatory, pro-inflammatory and anti-inflammatory biomarkers.

Evaluation of Facial Aging in Different Age and Gender Groups With Computed Tomography-Based Calvarium and Face Measurements.

The human face is a complex area formed by the combination of many different components and varies among individuals according to gender, age, and ethnicity. The aim of this study was to evaluate age-related changes in the facial and calvarial bones in a large sample of both genders. The retrospective study included nontraumatic brain computed tomography scans of 280 Turkish adults. Participants were divided into 7-decade groups with the age ranging from 20 to 89 years. Measurements of the face and calvaria were recorded, and calvarial volume was calculated. The relationship of these parameters with age and gender was examined. Statistically significant differences were observed in all the facial and calvarial measurements, except the transverse diameter of the head, with increasing age in both genders. Regardless of age, no significant differences were found in facial and calvarial measurements between genders. In addition, there was a significant decrease in the calvarial volume in both genders after the seventh decade of life. The structure of the face and calvarium continues to change and differentiate throughout life. Taking these changes into account during surgical and facial rejuvenation procedures can help predict outcomes and avoid the use of incorrect techniques.

Analysis of Anatomy and Age-related Changes in Infraorbital Cheek Using Computed Tomography.

There is no consensus regarding age-related facial anatomical changes. In this study, aging-related changes in soft and hard cheek tissues were quantitatively analyzed using computed tomography. We performed a retrospective study of 90 Asian females who underwent facial computed tomography. Three-dimensional model of soft tissue in apple zone was reconstructed, and age-related changes in fat volume and pyriform aperture area were quantified using Mimics software. The apple zone is an aesthetic unit of the infraorbital cheek, with soft tissue located between the lateral wall of the pyriform aperture and the zygomatic major muscle. The superficial fat volume significantly decreased with age (P < 0.05). In contrast, a significant decrease in total fat volume was only observed between the young and old groups (P < 0.05). In linear regression modeling, age was a significant predictor of pyriform aperture area (R2 = 0.194, P < 0.001). These results suggest that superficial fat atrophy and bone remodeling in the cheek with age, and both of which combine to contribute to an aging facial appearance. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

285 Impact of feeding strategies on semen concentration, motility, and morphology of the mature AI boar

Abstract The objective of this experiment was to determine if varying feeding strategies of maintenance requirements of boars impacts semen concentration, motility, morphology, and cortisol of the working boar. This experiment was conducted at Purdue University over two 9-wk periods with 1-wk before each 9-wk period serving as baseline for analysis. Boars (n = 28; Acuity and Topig Norvsin) from two age groups (9 and 15 mo) and two genetics (maternal and terminal) were used. Boars were blocked by breed and age and randomly allocated to receive one of three feed intake levels of a corn-soybean meal-based diet formulated to meet NRC (2012) maintenance requirements: HIGH (150% maintenance, n = 9); MAIN (100% maintenance, n = 10); and LOW (80% maintenance, n = 9) during the first 9-wk period. During the second 9-wk period remaining HIGH and LOW boars were crossed-over to opposite treatments (HIGH-LOW, n = 9; LOW-HIGH, n = 7), and maintenance boars were unchanged (MAIN-MAIN, n = 8). Semen was collected once/wk using the gloved hand method and 3 mL of ejaculate was diluted in 27 mL of extender (Androhep Plus, Minitube). Semen concentration (Nucleocounter SP-100), motility (Computer Assisted Sperm Analysis, CASA, CEROS II), and sperm cell morphology (phase-contrast, bright-field microscopy) were analyzed. Data were analyzed using PROC MIXED in SAS 9.4 with boar as experimental unit with main effects of feed intake and age with phase (3-wk period) as repeated measure. Significance was determined at P &amp;lt; 0.05 and a trend 0.05 &amp;lt; P ≤ 0.10. Three-way interactions for the first 9-wk period of feed intake*age*phase was observed for total sperm (P &amp;lt; 0.10) and total normal sperm (P &amp;lt; 0.05) with old boars fed HIGH treatment increasing sperm production, but old boars fed MAIN and LOW decreasing sperm production while young boars had minimal changes in sperm production regardless of feeding levels in the first 9-wk period. No other interactions or main effects were observed for the first period. During the second 9-wk period two-way interactions were observed for total sperm (FI*Age; P &amp;lt; 0.05) and total normal sperm (FI*Age; P &amp;lt; 0.01) with old LOW-HIGH boars having the highest total sperm and total normal sperm concentrations and young LOW-HIGH boars having the least total sperm and total normal sperm concentrations. HIGH-LOW fed boars had the greatest decrease in semen volume compared with the other treatments (FI*Phase; P &amp;lt; 0.01). Boars fed MAIN had minimal impacts on semen parameters compared with HIGH and LOW feed intake treatments. HIGH and LOW feed intake was observed to impact semen parameters in old boars faster than young boars with neither age being able to return to their baseline semen parameters observed at the start of the trial. Future research is needed with varying ages and feed intakes to better understand how nutritional strategies impact semen quantity and quality in the boar stud.

Exploring the Epidemiology and Clinico-Demographic Characteristics of Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis

Abstract Objective This study aimed to find the prevalence and clinico-demographic profile of cystic fibrosis (CF) children with allergic bronchopulmonary aspergillosis (ABPA). Methods A cross-sectional study was conducted at a CF clinic of a tertiary care hospital. Participants included the diagnosed cases of children with CF, of both genders, from 4 to 18 years of age. Results A total of 61 patients were enrolled. Sixteen patients (26.2%) had Aspergillus fumigatus sensitization—among these, 10 (16.4%) patients fulfilled the minimum diagnostic criteria for ABPA and 6 (9.8%) had A. fumigatus sensitization only. Two patients were below the age of 5 years, while eight patients were more than 6 years old. The female-to-male ratio was 6:4. High attenuated mucus was the specific finding in our study cohort on computed tomography (CT) chest. All patients with ABPA had significantly higher median (interquartile range [IQR]) levels of total IgE, specific IgE, and IgG for A. fumigatus, and total eosinophil count compared to patients without ABPA. There was also a significant decrease in forced exhalation volume in first second (FEV1) values (6 months apart) in ABPA patients. Conclusion Our study found that ABPA affects 16.4% of our CF population, with 20% of cases occurring in children aged 4 to 5 years. We observed a higher prevalence of ABPA in patients from rural areas. Eosinophilia and serial decline in FEV1 values were observed as potential early markers for ABPA.

A study on volumetric change of mandibular condyles with osteoarthritis using cone-beam computed tomography

This study aimed to quantitatively assess three-dimensional changes in the mandibular condyle with osteoarthritis using cone-beam computed tomography (CBCT). Pre- and post-treatment CBCT images of temporomandibular joints (TMJs) from 66 patients were used to assess longitudinal changes in condylar volume within individual patients using 3D slicer software. Total volume difference (dV), net increase (dV + , bone deposition), and net decrease (dV− , bone resorption) after treatment were analyzed based on clinical and radiological factors. Condyles with surface erosion at their first visit showed significantly decreased volume after treatment compared to condyles without erosion (p < 0.05). Amounts of bone resorption and deposition were higher in condyles with surface erosion (both p < 0.01). In patients with condylar erosion, the presence of joint pain was associated with a decrease in condylar volume and an increase in net resorption (both p < 0.01). When both joint pain and condylar erosion were present, patients with parafunctional habits showed reduced condylar volume after treatment (p < 0.05). Condylar volume change after treatment was negatively correlated with the duration of pain relief (R = − 0.501, p < 0.05). These results indicate that condylar erosion and TMJ pain could be significant variables affecting TMJ volume changes after treatment. Establishing appropriate treatment strategies is crucial for managing condylar erosion and TMJ pain.

Severe hypoglycemia with reduced liver volume as an indicator of end-stage malnutrition in patients with anorexia nervosa: a retrospective observational study

BackgroundHypophosphatemia due to excessive carbohydrate administration is considered the primary pathogenesis of refeeding syndrome. However, its association with liver injury and hypoglycemia, often seen in severe malnutrition before re-nutrition, remains unclear. Autophagy reportedly occurs in the liver of patients with severe malnutrition. This study aimed to clarify the pathophysiology of liver injury and hypoglycemia by focusing on liver volume.MethodsForty-eight patients with anorexia nervosa with a body mass index (BMI) of < 13 kg/m2 were included (median BMI: 10.51 kg/m2 on admission). Liver volume was measured in 36 patients who underwent abdominal computed tomography (CT), and the “estimated liver weight/ideal body weight” was used as the liver volume index. Seventeen blood test items were analyzed during the first 60 days.ResultsLiver volume significantly decreased when abdominal CTs were conducted shortly before or after hypoglycemia compared to when the scans were performed during periods without hypoglycemia. Five patients with severe hypoglycemia on days 13–18 after admission had a very low nutritional intake; of them, four showed a marked decrease in liver volume. Severe hypoglycemia was accompanied by low serum triglycerides and liver dysfunction. Patients experiencing hypoglycemia of blood glucose levels < 55 mg/dL (< 3.05 mmol/L) (32 patients; median lowest BMI: 9.45 kg/m2) exhibited significantly poorer blood findings for most of the 17 items, except serum phosphorus and potassium, than did those not experiencing hypoglycemia (16 patients; median lowest BMI: 11.2 kg/m2). All patients with a poor prognosis belonged to the hypoglycemia group. Empirically, initiating re-nutrition at 500 kcal/day (20–25 kcal/kg/day), increasing to 700–800 kcal/day after a week, and then gradually escalating can reduce serious complications following severe hypoglycemia.ConclusionsLiver volume reduction accompanied by hypoglycemia, low serum triglyceride levels, and liver dysfunction occurs when the body's stored energy sources are depleted and external nutritional intake is inadequate, suggesting that the liver was consumed as a last resort to obtain energy essential for daily survival. This pathophysiology, distinct from refeeding syndrome, indicates the terminal stage of malnutrition and is a risk factor for complications and poor prognosis. In treatment, extremely low nutrient levels should be avoided.

Abstract PO5-03-06: Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy

Abstract Introduction: Neoadjuvant systemic therapy (NAT) has been the standard-of-care of stage II-III, locally advanced triple-negative breast cancer (TNBC). However, about 50% of TNBC patients achieve a pathological complete response (pCR) to conventional neoadjuvant chemotherapy (NAC)1. Recently approved combination of NAC with the immunotherapy pembrolizumab, has improved the pCR rate by 7.5%2, although with a 44% risk of immune-related adverse reaction3. Aside from the need to develop new therapies with higher efficacy and lower toxicity, a critical barrier to improving TNBC response is the lack of rigorous ways to personally tailor therapeutic regimens. We seek to address this challenge by employing digital twins (i.e., mathematical models that provide virtual representation of individual patients and predict the changes at future time points) to systematically evaluate individual TNBC patient’s response to different NAT regimens, thereby patient-specifically optimizing treatments. Methods: A TNBC cohort (n = 139) from the ARTEMIS trial (NCT02276433)4 was used for this study. All patients received 4 cycles of Adriamycin/Cytoxan (A/C) every 2 weeks, followed by 12 cycles of weekly Taxol or experimental therapy in Phase II trials. All patients had surgery after NAT and post-surgical pathology to assess response status. For each patient, longitudinal MRIs were collected before, during, and after A/C. We have developed digital twins to integrate the longitudinal MRIs with a mechanism-based model to accurately predict TNBC response5. The model was based on a reaction-diffusion equation that describes the change in tumor cellularity due to migration, proliferation, and drug-induced death. With parameters personalized using MRIs, the patient-specific model (i.e., digital twin) significantly improved the accuracy to predict pCR5. We investigated patient-specific treatment optimization on 37 (19 pCR, 18 non-pCR) chemo-sensitive patients (≥ 70% volume decrease after A/C) who received only NAC. We evaluated the effect of altering the A/C/Taxol schedules on patient response. Specifically, each patient’s digital twin was used to predict the patient’s response to 128 clinically reasonable schedules of A/C/Taxol; i.e., 8 candidate A/C schedules combining with 16 candidate Taxol schedules (Table 1). The predicted response (pCR or non-pCR) from each alternative schedule was compared to the patient response from the actual treatment. Results: Without changing the total dose, shortening the duration of A/C/Taxol administration increased the treatment efficacy. The effectiveness of altering the schedules varied substantially in different patients. In particular, 8 patients who had non-pCR responses to their actual treatment were predicted to achieve pCR with the dense-dose Taxol (i.e., 4 cycles Taxol, 2 weeks per cycle), indicating a 21.62% improvement of pCR rate in the cohort. Discussion and conclusion: The preliminary results with our digital twin approach provided a unique opportunity of improving TNBC response to NAT through patient-specific optimization of therapeutic schedules. The ongoing effort focuses on accounting for toxicity and investigating the effects of altering therapy types and doses in combination with the schedules on the patient response. [1] Spring et al., Clin Cancer Res, 2020. [2] Schmid et al., NEJM, 2022. [3] Shah et al., Clin Cancer Res, 2022. [4] Yam et al., Clin Cancer Res, 2021. [5] Wu et al., Cancer Res, 2022. Table 1. Candidate therapeutic schedules Citation Format: Chengyue Wu, Ernesto Lima, Casey Stowers, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane Rauch, Thomas Yankeelov. Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-06.

Abstract PO3-14-12: SIRT3 as a new potential predictive biomarker for response to CDK4/6 inhibition in ER+/HER2- metastatic breast cancer patients

Abstract Background: Several prospective, randomized clinical trials showed that the CDK4/6 inhibitor palbociclib in combination with either letrozole or fulvestrant significantly improves progression-free survival (PFS) in patients with ER+/HER2- metastatic breast cancer (MBC). However, in some cases, there is development of endocrine resistance and ultimate disease progression. Molecular analysis performed in tissue specimens collected in the PALOMA-3 study, comparing fulvestrant and Palbociclib versus fulvestrant placebo, demonstrated that one of the genes associated with an increased clinical benefit is SIRT3 (Sirtuin 3) which is thought to control mitochondrial integrity and metabolism (Cristofanilli M. et al., Lancet Oncol. 2016). This study aimed to evaluate in preclinical models the predictive role of SIRT3 in ER+/HER2- breast tumors. Methods: Using lentiviruses we generated MCF-7 and T47D cells stably expressing either control shRNA (sh ctr) or shRNA targeting SIRT3 (shSIRT3). With these models, we studied cell viability, tumor growth, apoptosis, and autophagy in MCF-7 cells treated with fulvestrant and palbociclib as a single treatment or in combination, these either alone or in combination with shSIRT3 (knockdown). Nude mice were used for our in vivo studies, and sh ctr or shSIRT3 MCF7 cells were injected. Results: We showed in vitro that the response to palbociclib was significantly associated with levels of SIRT3 expressionas high or low in ER+ cells (p&amp;lt; 0.0001). Furthermore, we found that irreversible cell growth inhibition mediates the beneficial effect of palbociclib in SIRT3 high expressing cellscompared to low expression (p&amp;lt; 0.001).Then, we evaluated the mechanistic activity of SIRT3. We showed thatSIRT3-low expression cells induced enhanced sensitivity to palbociclib by targeting the reactive oxygen species (ROS)/autophagy axis:(i) SIRT3 regulated the mitochondrial homeostasis (e.g. glucose, lactate, pyruvate, succinates), (ii) ROS levels where lower in sh crt comparing and shSIRT3 in treated and untreated cells (p&amp;lt; 0.001), (iii) in terms of senescence,a higher level of positive cells for β-gal activity was found (p≤0.05) and (iv) for autophagy, our western blot analysis showed cleaved LC3 proteins. Our in vivo studies showed that SIRT3 regulated treatment response to palbociclib with a significant decrease in tumor weight and tumor volume (p&amp;lt; 0.01) and importantly, after immunohistochemistry analysis, we validated the role of SIRT3 in regulating the proteins involved in the autophagy/senescence balance, was mainly in epithelial cells compared to stromal cells. Conclusion: Our preclinical studies demonstrated that elevated SIRT3 expression levels sensitizes ER+/HER2- breast tumors to palbociclib treatment. This study suggested that SIRT3 expression could represent a potential predictive biomarker in HR+ MBC patients treated with Palbociclib. Citation Format: Maroua Manai, Ghada Sahraoui, Raoudha Doghri, Lorenzo Gerratana, Paolo D’Amico, Youbin Zhang, Jeannine Donahue, Ami Shah, Carolina Reduzzi, Wenan Qiang, Massimo Cristofanilli. SIRT3 as a new potential predictive biomarker for response to CDK4/6 inhibition in ER+/HER2- metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-12.

Abstract PO1-26-06: The effect of localized radiotherapy in combination with chemoimmunotherapy in a humanized triple-negative breast cancer mouse model

Abstract Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that is challenging to treat. While the addition of immunotherapy (IT) with pembrolizumab (pembro) to chemotherapy prolongs overall survival in patients with programmed death-ligand 1 positive (PD-L1+) TNBC, few patients obtain long-term benefit. Radiotherapy (RT) can stimulate cellular damage, release of tumor antigens and promote the T cell anti-tumor response including at distant sites (abscopal response) when used with IT. The purpose of this study was to investigate the combination of RT with pembro and paclitaxel (pac) in a TNBC humanized mouse model. Methods: Human Immune System BRGS (BALB/c, Rag2-/-, IL2RγC-/-, NODSIRPa ) mice were engrafted with TNBC MDA-MB-231 cells in bilateral flanks. Treatments included: vehicle, pac 10 mg/kg intra-peritoneal (IP) weekly, pembro 15 mg/kg IP weekly, and RT 8 Gy x 3 fractions every other day the first week of treatment to one-sided tumors (contralateral tumors received no RT). Mice were treated and analyzed in the following groups: vehicle, pac + pembro, RT + pac, and RT + pac + pembro. Treatments began when tumors reached 100-300 mm3 and tumors were measured twice weekly. At the end of study, sera, lymph nodes (LNs), spleen, and tumor tissue were collected for immunohistochemistry, single cell suspensions, and flow cytometry analysis for immune cell populations. Results: All treatment arms resulted in a decrease in tumor volume when compared to vehicle with the greatest reduction in the RT + pac and RT + pac + pembro arms. Combination therapy with RT + paclitaxel (p=0.0002) and RT + pac + pembro (p=0.008) resulted in a statistically significant decrease in specific growth rate (SGR) when compared to vehicle. An abscopal effect was not observed in the non-RT tumors compared to RT-tumors in either group. RT + pembro was associated with an increase in hCD45 T cells in LNs and spleens but not in tumors. In mice that received RT, a decrease was noted in HLA-ABC class I and Intermediate Class II major histocompatibility complex (MHC). In addition, RT-tumors had reduced expression of PD-L1 and polio virus receptor (PVR) and increased expression of PD-1. The percentage of interferon gamma (IFNg+), tumor necrosis factor alpha (TNFa+) CD8+ T cells increased with radiation. This percentage was the highest in the triplet therapy with RT+ pembro + pac. Conclusion: Combination treatment with RT + immunochemotherapy resulted in a significant increase in anti-tumor activity when compared to immunochemotherapy alone, however, an abscopal effect was not observed in contralateral non-RT tumors. RT resulted in down-regulation of immune inhibitory receptors and tumor MHC. Citation Format: Anna Schreiber, Stacey Bagby, Stephen Smoots, Adrian Dominguez, Christine Fisher, Julie Lang, Todd Pitts, Jennifer Diamond. The effect of localized radiotherapy in combination with chemoimmunotherapy in a humanized triple-negative breast cancer mouse model [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-26-06.

Dynamic liver volume change in predicting hepatic decompensation and long-term effects of stereotactic body radiation therapy.

This study aimed to investigate the association between liver volume change and hepatic decompensation and compare the risk of hepatic decompensation in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) who underwent stereotactic body radiation therapy (SBRT). A retrospective review of SBRT-treated HCC and compensated LC without HCC patients was conducted. Liver volume was measured using auto-segmentation software on liver dynamic computed tomography scans. The decompensation event was defined as the first occurrence of refractory ascites, esophageal variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis. We evaluated the association between the rate of liver volume decrease and hepatic decompensation and compared decompensation events between the SBRT and LC cohorts using propensity score matching. A total of 138 patients from the SBRT cohort and 488 from the LC cohort were analyzed. The rate of liver volume decrease was associated with the risk of decompensation events in both cohorts. The 3-year rate of decompensation events was significantly higher in the group with a liver volume decreasing rate>7%/year compared with the group with a rate<7%/year. In the propensity score-matched cohort, the 3-year rate of decompensation events after a single session of SBRT was not significantly different from that in the LC cohort. The rate of liver volume decrease was significantly associated with the risk of hepatic decompensation in both HCC patients who received SBRT and LC patients. A single session of SBRT for HCC did not result in a higher decompensation rate compared with LC.

Understanding droplet formation in T-shaped channels with magnetic field influence: A computational investigation

This study investigates the production of ferrofluid droplets in a T-junction geometry using the level set method and magnetic force manipulation in the three-dimensional. The analysis reveals key insights into droplet formation processes in four stages: entering, blocking, necking, and detachment. The results show that increasing the Capillary number leads to a significant decrease in volume for non-ferrofluid droplets. Application of a magnetic force enhances the balance of forces during droplet formation, directly impacting droplet volume. Moreover, increasing the magnetic Bond number substantially increases droplet volume, with a more pronounced effect at lower Capillary numbers. Modifying magnetic properties influences droplet volume, with doubling the magnetization results in a significant volume increase. Overall, magnetic forces emerge as a crucial control parameter for droplet volume in ferrofluid systems, offering potential applications in droplet-based technologies and microfluidic devices.