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Background: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment., Methods: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines., Results: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases., Conclusions: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups., (© 2024. The Author(s).)

Background: Poly-ether-ether-ketone (PEEK) was introduced in dentistry as an alternative to metal alloys., Objective: To assess the effectiveness of PEEK-fixed retainers in preserving the stability of mandibular anterior and participant satisfaction as compared to the Dead-soft coaxial fixed retainer (DSC)., Trial Design: A single-centre, two-arm parallel groups randomized clinical trial., Methods: The patients treated with pre-adjusted orthodontic appliances who have a Little's Irregularity Index (LII) ≤ 0.5 mm have been enrolled in the trial. PEEK retainers were prepared to round 0.8 mm wire by computer-aided design and manufacturing, and the DSC wire was carefully adapted to the lingual surface of the lower anterior teeth. The primary outcome was the stability of lower anterior teeth as assessed by LII, while the secondary outcomes were changes in occlusal parameters, retainer failure, and patient satisfaction. The data were collected at the debonding stage (T0), 1 month (T1), 3 months (T3), and 6 months (T6) after starting the trial, except for patient's satisfaction, which was recorded using an electronic form at T1 and T6., Blinding: Single blinding of participants., Results: A total of 46 participants with an age range of 12-28 years old were randomly allocated to the two groups (n = 23 in each). Only one participant dropped out; therefore, 45 participants were analysed. The DSC group showed a significant increase in LII at T3. Both retainer groups had comparable occlusal measurements, failure frequency, and survival time, with no significant difference. The patients in the DSC group reported a statistically significant perception of change in the position of their teeth compared to those in the PEEK group., Harms: No harmful effects have been reported., Limitations: Limited follow-up duration and the inability to blind the operator due to the nature of the intervention., Conclusions: After 6-month retention, the PEEK retainer was equally effective to DSC retainers in maintaining the teeth alignment, with no significant differences regarding the failure frequency, survival rate, and general patient satisfaction., Trial Registration: https://register.clinicaltrials.gov. (NCT05557136)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context and Aims: Eribulin is used in taxane and anthracycline refractory HER2-negative metastatic breast cancers (MBC). Patients treated in pivotal clinical trials achieved low survival rates, therefore, the identification of prognostic criteria for long progression-free survival (PFS) is still an unmet medical need. In this study, we sought to determine potential prognostic criteria for long-term eribulin response in HER2-negative MBC., Methods: Our retrospective cohort includes female patients with HER2-negative MBC treated with eribulin in Franche-Comté, France. We defined a long-term response as at least 6 months of eribulin treatment. The primary endpoint was the analysis of criteria that differ according to the progression-free survival. Secondary outcomes concerned overall survival and response rate., Results: From January 2011 to April 2020, 431 patients treated with eribulin were screened. Of them, 374 patients were included. Median PFS was 3.2 months (2.8-3.7). Eighty-eight patients (23.5%) had a long-term response to eribulin. Four discriminant criteria allowed to separate PFS in 2 arms (PFS < 3 months or > 6 months) with a 78% positive predictive value: histological grade, absence of meningeal metastasis, response to prior chemotherapy, and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival was 8.5 months (7.0-9.5)., Conclusion: Eribulin response in MBC can be driven by clinical and biological factors. Application of our nomogram could assist in the prescription of eribulin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC., Patients and Methods: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated., Results: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed., Conclusion: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment., (© 2024. The Author(s).)

We report the case of a 46-year-old Japanese woman diagnosed with Stage Ⅳ right breast cancer, cT1cN1M1(ovarian and peritoneal metastases). We administered bevacizumab+paclitaxel as the first-line treatment. In the 13th course, the peritoneal dissemination progressed, and the regimen was changed to eribulin(1.4 mg/m2)as the second-line treatment. During the second course, abdominal distension developed and was resolved during follow-up. However, abdominal distension and pain were observed from day 9 of the fourth course. Based on the results of blood chemistry and CT scans, she was diagnosed with acute pancreatitis(CT Grade 1)and was admitted to the hospital. After fasting and fluid replacement therapy, her clinical symptoms and laboratory data improved, and was discharged from the hospital 8 days later. She had no history of excessive alcohol consumption and no evidence of biliary disease, and was considered having eribulin-induced pancreatitis.

Background: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863)., Methods: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise., Findings: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months)., Interpretation: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors., (© 2024. The Author(s).)

Pseudocirrhosis, which is radiologically and clinically similar to liver cirrhosis, may develop following chemotherapy for breast cancer with liver metastasis. There are few reports of eribulin treatment. We report 5 patients with metastatic or recurrent breast cancer who developed pseudocirrhosis during eribulin treatment. All patients had diffuse liver metastasis, and the liver metastases significantly reduced in size during the early phase of eribulin treatment, when they developed pseudocirrhosis. Subsequently, the patients had poor prognoses.

The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC., Significance: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Objective: To evaluate the efficacy and safety of eribulin plus anti-angiogenic medicine in metastatic breast cancer (MBC), and explore the potential biomarkers., Study Design: Observational study. Place and Duration of the Study: Department of Medical Oncology, Xi'an International Medical Centre Hospital, Xi'an, China, from May 2022 to 2023., Methodology: A total of 40 MBC patients treated with eribulin were enrolled. Patients were divided into two groups based on whether they received eribulin monotherapy or combined therapy. Median progression-free survival (mPFS), the time from the start of erbium treatment to the time of disease progression, was calculated using the Kaplan-Meier method., Results: The eribulin plus anti-angiogenic medicine treatment group had a significantly prolonged mPFS compared to the group without anti-angiogenic medicine treatment (7.0 months vs. 2.0 months, p <0.001). The multivariate analysis identified that the combination of anti-angiogenic therapy (HR = 0.043, p = 0.004) and the occurrence of grade 3-4 neutropenia after the treatment were two predictive factors for longer PFS (HR = 0.322, p = 0.009). In contrast, prior resistance to taxane was predictive of shorter PFS (HR = 4.583, p = 0.019). Other clinic-pathological factors were not significantly associated with PFS. Fisher's exact test showed no significant increase in treatment-related adverse events (all grades) after combination with anti-angiogenic medicine., Conclusion: The eribulin plus anti-angiogenic combination may act as a potential therapy for late-line MBC patients with clinically beneficial therapeutic effects., Key Words: Metastatic breast cancer, Eribulin, Anti-angiogenic therapy, Predictive indicators of efficacy.

Background: This prospective real-world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China., Patients and Methods: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo-/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m 2 ) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed., Results: One hundred and thirty-four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3-15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first- or second-line treatment was significantly better than those who received eribulin as ≥3-line treatment (6.9 months [95% CI: 3.2-8.8] vs. 4.0 months [95% CI: 3.4-4.6], p = 0.006). The mPFS of patients with triple-negative, HER2-positive, and HER2(-)/HR(+) was 3.4 (95% CI: 2.7-4.1), 6.2 (95% CI: 2.3-10.1) and 5.0 months (95% CI: 4.1-5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6-6.3] vs. 4.0 months [95% CI: 3.3-4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non-TNBC receiving eribulin as ≤2-line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment-related adverse events., Conclusion: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real-world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: In 2010, the US Food and Drug Administration approved eribulin for the treatment of metastatic breast cancer (MBC). Since then, the treatment landscape has evolved with many new therapy classes, a more recent one being the small molecule inhibitors of phosphoinositide 3 kinase (PI3K). We sought to characterize the treatment patterns and clinical outcomes of patients with MBC who received eribulin following prior treatment with a PI3K inhibitor., Methods: A retrospective cohort study based on medical record review included MBC patients who initiated eribulin between March 2019 and September 2020 following prior treatment with a PI3K inhibitor was conducted. Patient demographics, treatment characteristics, and clinical outcomes were analyzed descriptively. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated from the initiation of eribulin therapy using Kaplan-Meier analyses., Results: 82 eligible patients were included. Patients' median age at eribulin initiation was 62 years; 86.5% had hormone receptor-positive, human epidermal growth factor receptor 2-negative tumors. Eribulin was most often administered in the second or third line (82.9%) in the metastatic setting. Best overall response on eribulin was reported as complete or partial response in 72% of the patients. The median rwPFS was 18.9 months (95% confidence interval [CI], 12.4-not estimable); median OS was not reached. The estimated rwPFS and OS rates at 12 months were 63.3% (95% CI, 50.5-73.7) and 82.6% (95% CI, 72.4-89.3), respectively., Conclusion: Our real-world study suggests that eribulin may be a potential treatment option for MBC patients who fail a prior PI3K inhibitor., (© 2024. Eisai, Incorporated.)

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1β, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1β, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options. Eribulin, a chemotherapeutic drug, induces epigenetic changes in cancer cells, suggesting a unique mechanism of action. Materials & methods: MDA-MB 231 cells were treated with eribulin and paclitaxel, and the samples from 53 patients treated with neoadjuvant eribulin were compared with those from 14 patients who received the standard-of-care treatment using immunohistochemistry. Results: Eribulin treatment caused significant DNA methylation changes in drug-tolerant persister TNBC cells, and it also elicited changes in the expression levels of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in vitro and in primary TNBC tumors. Conclusion: These findings provide new insights into eribulin's mechanism of action and potential biomarkers for predicting TNBC treatment response.

β-Hydroxybutyrate (βOHB) is the major ketone in the body, and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes, and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of optimizing either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscles.

A carbon fiber-reinforced polyetheretherketone (CFR/PEEK) hip stem with a special antibiotic elution mechanism is under development to treat periprosthetic joint infection (PJI). The antibiotic elution characteristics of intramedullary implants were experimentally investigated, and the efficacy of revision surgery using a therapeutic stem in treating ovine PJI was examined. To evaluate elution characteristics, the intramedullary vancomycin-loaded CFR/PEEK cylindrical implants were inserted in the distal femur of nine sheep, and the vancomycin elution rate was measured at 2, 7, and 21 days. To evaluate therapeutic efficacy, the PJI model with staphylococcus aureus was attempted to create for five sheep. Moreover, the therapeutic vancomycin-loaded CFR/PEEK stem was implanted during one-stage revision surgery. Three weeks after revision surgery, the treatment efficacy was evaluated based on bacterial cultures and wound findings. In addition, the vancomycin elution rate from the stem was measured. On average, the cylindrical implants eluted approximately 70% vancomycin in 21 days. Of the five sheep attempting to create a PJI model, three were successfully infected with S. aureus as intended for verification of treatment efficacy. In all three joints, negative bacterial cultures and no purulence were observed 3 weeks after revision surgery. The vancomycin elution rates from the stems were >70%. Efficient elution of vancomycin was confirmed by the experimental implant inserted into the bone marrow and the stem in actual PJI treatment. Using a novel therapeutic stem with an antibiotic elution mechanism in one-stage revision surgery, successful treatment was demonstrated in all S. aureus-induced PJIs., (© 2023 Orthopaedic Research Society.)

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex., Methods: In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4-6 mmol/L) and mild hyperglycemia (9-11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis., Results: Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5-13.6] vs. 3.5[2.2-7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3-1.6] vs. 0.4 % [0.2-0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05-0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001)., Conclusions: Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.A.P. has received honoraria for educational events from Medtronic, Novo Nordisk, Sanofi, Insulet and Abbott. His research institute has received funding from BMO Bank of Montreal and Novo Nordisk for research Support. He has served as an advisor to Boehringer Ingelheim, Sanofi, Insulet and Abbott. D.Z.I.C has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. The remaining authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: The achievement of complete response with chemotherapy after multiple treatment lines in metastatic breast cancer and the chemosensitivity in a luminal-like breast cancer are two important issues as it is often asked whether there is a potential limit to the number of therapeutic lines offered and what clinical value they may have. In this setting, eribulin mesylate is a chemotherapy option available. Several randomized and observational studies demonstrated eribulin's meaningful improvement on prolongation of survival, chronicling the disease and preventing the onset of new metastases, although the rate of complete responses is rather limited., Case Description: We report the five-year history of a luminal A breast cancer, stage IV at diagnosis, metastasized to bone and brain. After undergoing four chemotherapy lines and several radiotherapy sessions with partial response as the best response on bone and with a complete response on brain, our patient finally achieved a metabolic complete response also on bone after about a year of fifth-line treatment with eribulin. Currently the patient is in close clinical and radiological follow-up., Conclusions: This case report aims to emphasize the clinical value of a chronic chemotherapy treatment also in heavily pretreated and luminal-like metastatic breast cancer, supporting eribulin as a good choice to consider., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The three-dimensional printing titanium (3DPT) cage with excellent biomechanical properties and osseointegration capabilities has been initially used in spinal fusion, while the polyetheretherketone (PEEK) cage, a bioinert material device, has been a widely used for decades with relatively excellent clinical outcomes. This study was performed to investigate the early radiographic and clinical outcomes of 3DPT cage versus PEEK cage in patients undergoing anterior cervical discectomy and fusion (ACDF) and transforaminal lumbar interbody fusion (TLIF)., Methods: This prospective controlled trial, from December 2019 to June 2022, included patients undergoing ACDF and TLIF with 3DPT cages and compared them to patients using PEEK cages for treating spinal degenerative disorders. The outcome measures included radiographic parameters (intervertebral height [IH], subsidence, fusion status, and bone-cage interface contact) and clinical outcomes (Japanese Orthopaedic Association [JOA], Neck Disability Index [NDI], Oswestry Disability Index [ODI], Short Form 12-Item Survey [SF-12], Visual Analog Scale [VAS], and Odom's criteria). Student's independent samples t test and Pearson's chi-square test were used to compare the outcome measures between the two groups before surgery and at 1 week, 3 and 6 months after surgery., Results: For the patients undergoing ACDF, the 3DPT (18 patients/[26 segments]) and PEEK groups (18 patients/[26 segments]) had similar fusion rates at 3 months and 6 months follow-up (3 months: 96.2% vs. 83.3%, p = 0.182; 6 months: 100% vs. 91.7%, p = 0.225). The subsidence in the 3DPT group was significantly lower than that in the PEEK group (3 months: 0.4 ± 0.2 mm vs. 0.9 ± 0.7 mm p = 0.004; 6 months: 0.7 ± 0.3 mm vs. 1.5 ± 0.8 mm, p < 0.001). 3DPT and PEEK cage all achieved sufficient contact with the cervical endplates. For the patients undergoing TLIF, the 3DPT (20 patients/[26 segments]) and PEEK groups (20 patients/[24 segments]) had no statistical difference in fusion rate (3 months: 84.6% vs. 58.3%, p = 0.059; 6 months: 92.3% vs. 75%, p = 0.132). The subsidence was lower than that in the PEEK group without significantly difference (3 months: 0.9 ± 0.7 mm vs.1.2 ± 0.9 mm p = 0.136; 6 months: 1.6 ± 1.0 mm vs. 2.0 ± 1.0 mm, p = 0.200). At the 3-month follow-up, the bone-cage interface contact of the 3DPT cage was significantly better than that of the PEEK cage (poor contact: 15.4% vs. 75%, p < 0.001). The values of UAR were higher in the 3DPT group than in the PEEK group during the follow-up in cervical and lumbar fusion, there were more statistical differences in lumbar fusion. There were no significant differences in the clinical assessment between 3DPT or PEEK cage in spinal fusion., Conclusion: The 3DPT cage and PEEK cage can achieve excellent clinical outcomes in cervical and lumbar fusion. The 3DPT cage has advantage in fusion quality, subsidence severity, and bone-cage interface contact than PEEK cage., (© 2023 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Polyetheretherketone (PEEK) has emerged as a highly promising orthopedic implantation material due to its elastic modulus which is comparable to that of natural bone. This polymer exhibits impressive properties for bone implantation such as corrosion resistance, fatigue resistance, self-lubrication and chemical stability. Significantly, compared to metal-based implants, PEEK implants have mechanical properties that are closer to natural bone, which can mitigate the "stress shielding" effect in bone implantation. Nevertheless, PEEK is incapable of inducing osteogenesis due to its bio-inert molecular structure, thereby hindering the osseointegration process. To optimize the clinical application of PEEK, researchers have been working on promoting its bioactivity and endowing this polymer with beneficial properties, such as antibacterial, anti-inflammatory, anti-tumor, and angiogenesis-promoting capabilities. Considering the significant growth of research on PEEK implants over the past 5 years, this review aims to present a timely update on PEEK's modification methods. By highlighting the latest advancements in PEEK modification, we hope to provide guidance and inspiration for researchers in developing the next generation bone implants and optimizing their clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Euglycemic diabetic ketoacidosis (EDKA) is an emerging complication of diabetes associated with an increasing use of sodium-glucose transporter type 2 (SGLT-2) inhibitor drugs. This review highlights the growing incidence of EDKA and its diagnostic challenges due to the absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA). The paper presents a classification system for the severity of EDKA, categorizing it into mild, moderate, and severe based on serum pH and bicarbonate levels. Another classification system is proposed to define stages of EDKA based on anion gap and ketones at the time of diagnosis and during the treatment period. A treatment algorithm is proposed to guide clinicians in managing EDKA. This treatment algorithm includes monitoring anion gap and ketones to guide insulin and fluid management, and slower transition to subcutaneous insulin to prevent a relapse. Increased awareness of EDKA is essential for a timely diagnosis because an early diagnosis and treatment can improve clinical outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown., Objectives: The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS., Methods: In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period., Results: KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: -5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered., Conclusions: Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768)., Competing Interests: Funding Support and Author Disclosures This study was supported by the Independent Research Fund Denmark (0134-00043B), The Danish Heart Foundation (19-R135-A9280-22126), the Novo Nordisk Foundation (NNF17OC0028230), the Arvid Nilsson Foundation, and Ellen og Ivan Osiiers Legat. Dr Wiggers has been the principal or a subinvestigator in studies involving MSD, Bayer, Daiichi-Sankyo, Novartis, Novo Nordisk, Sanofi-Aventis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Study Design: Prospective cohort study., Objectives: To perform a cost-utility analysis and to investigate the clinical outcomes and patient's quality of life after anterior cervical discectomy and fusion (ACDF) to treat cervical spondylosis compared between fusion with polyetheretherketone (PEEK) and fusion with tricortical iliac bone graft (IBG) in Thailand., Summary of Background Data: ACDF is one of the standard treatments for cervical spondylosis. The fusion material options include PEEK and tricortical IBG. No previous studies have compared the cost-utility between these 2 fusion material options., Patients and Methods: Patients with cervical spondylosis who were scheduled for ACDF at Siriraj Hospital (Bangkok, Thailand) during 2019-2020 were prospectively enrolled. Patients were allocated to the PEEK or IBG fusion material group according to the patient's choice of fusion material. EuroQol-5 dimensions 5 levels and relevant costs were collected during the operative and postoperative periods. A cost-utility analysis was performed using a societal perspective. All costs were converted to 2020 United States dollars (USD), and a 3% discount rate was used. The outcome was expressed as the incremental cost-effectiveness ratio., Results: Thirty-six patients (18 ACDF-PEEK and 18 ACDF-IBG) were enrolled. Except for Nurick grading, there was no significant difference in patient baseline characteristics between groups. The average utility at 1 year after ACDF-PEEK and ACDF-IBG were 0.939 ± 0.061 and 0.798 ± 0.081, respectively ( P < 0.001). The total lifetime cost of ACDF-PEEK and ACDF-IBG was 83,572 USD and 73,329 USD, respectively. The incremental cost-effectiveness ratio of ACDF-PEEK when compared with that of ACDF-IBG showed a gain of 4468.52 USD/quality-adjusted life-years, which is considered cost-effective at the Thailand willingness-to-pay threshold of 5115 USD/quality-adjusted life-year gained., Conclusions: ACDF-PEEK was found to be more cost-effective than ACDF-IBG for treating cervical spondylosis in Thailand., Level of Evidence: Level II., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Effects of ketone supplements as well as relevant dose-response relationships and time effects on blood β-hydroxybutyrate (BHB), glucose and insulin are controversial., Objective: This study aimed to summarize the existing evidence and synthesize the results, and demonstrate underlying dose-response relationships as well as sustained time effects., Methods: Medline, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant randomized crossover/parallel studies published until 25th November 2022. Three-level meta-analysis compared the acute effects of exogenous ketone supplementation and placebo in regulating blood parameters, with Hedge's g used as measure of effect size. Effects of potential moderators were explored through multilevel regression models. Dose-response and time-effect models were established via fractional polynomial regression., Results: The meta-analysis with 327 data points from 30 studies (408 participants) indicated that exogenous ketones led to a significant increase in blood BHB (Hedge's g = 1.4994, 95% CI [1.2648, 1.7340]), reduction in glucose (Hedge's g = -0.3796, 95% CI [-0.4550, -0.3041]), and elevation in insulin of non-athlete healthy population (Hedge's g = 0.1214, 95%CI [0.0582, 0.3011]), as well as insignificant change in insulin of obesity and prediabetes. Nonlinear dose-response relationship between ketone dosage and blood parameter change was observed in some time intervals for BHB (30-60 min; >120 min) and insulin (30-60 min; 90-120 min), with linear relationship observed for glucose (>120 min). Nonlinear associations between time and blood parameter change were found in BHB (>550 mg/kg) and glucose (450-550 mg/kg), with linear relationship observed in BHB (≤250 mg/kg) and insulin (350-550 mg/kg)., Conclusion: Dose-response relationships and sustained time effects were observed in BHB, glucose and insulin following ketone supplementation. Glucose-lowering effect without increasing insulin load among population of obesity and prediabetes was of remarkable clinical implication., Registry and Registry Number: PROSPERO (CRD42022360620)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The focus of this study was to examine whether the conversion of cytotoxic conjugated unsaturated ketones (or enones) into the corresponding thiol adducts leads to a reduction or abolition of cytotoxic potencies. A number of enones and related thiol adducts were evaluated against human HCT116 and HT29 colon cancer cells. Some 63% of the IC 50 values are less than 10 μM and several compounds are more toxic than 5-FU. The thiol adducts are either more potent or are equipotent with the corresponding enones. A number of compounds are far more toxic to HCT116 and HT29 neoplasms than non-malignant CRL1790 cells leading to impressive Selectivity Index figures. An additional positive feature of these compounds is that they have favorable ADME properties.

Background: Polyetheretherketone (PEEK) is a synthetic material with many favorable characteristics; PEEK implants are increasingly used for a variety of applications ranging from cranioplasty to orthopedic surgery and facial implants., Methods: This study is a retrospective review of patients who underwent PEEK implant placement in our department over the last 5 years. Polyetheretherketone computer-aided design and manufacture facial implants were designed from high-resolution computed tomography (CT) scans of each patient. The implants placed were onlay implants used for facial rehabilitation purposes to correct malformative and posttraumatic malformations., Results: Twenty-eight consecutive patients (11 males and 17 females) underwent PEEK implant positioning between January 2015 and December 2020. Common indications were anterior plagiocephaly, hemifacial microsomia, and residual facial imbalance after orthognathic surgery. No complications of implant breakdown, exposure, infection, or displacement were noticed during the follow-up period. During routine controls on 3 patients, we requested a craniomaxillofacial CT scan for reasons unrelated to the implanted prostheses. The CT scans were all high resolution (<1-mm slices). The CT images indicated that bone was starting to form around the implant in all 3 patients as well as in the penetrating holes that were planned in the implants., Conclusions: In our experience, computer-designed, patient-specific PEEK onlay implants are a valid option for the treatment of malformative and posttraumatic malformations. This is, to the best of our knowledge, the first clinical report on bone reaction to PEEK implantation in the maxillofacial field. Moreover, based on the signs of bone regrowth that we observed in CT controls we can presume that the design of this type of prosthesis can probably take advantage of some technical stratagems not yet codified and fully exploited. Despite our preliminary favorable results, further multicentric and comparative studies are necessary to evaluate outcomes and better understand the behavior of this promising material and thus optimize its use in craniomaxillofacial surgery., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: There have been many studies in the operative management of pyogenic spondylodiscitis with foreign materials. However, it still remains an issue of debate on whether the allografts may be used in pyogenic spondylodiscitis. This study sought to evaluate the safety and effectiveness of PEEK cages and the cadaveric allograft in transforaminal lumbar interbody fusion (TLIF) for treating lumbar pyogenic spondylodiscitis., Methods: From January 2012 to December 2019, 56 patients underwent surgery for lumbar pyogenic spondylodiscitis. The posterior debridement of all patients and their fusion with allografts, local bone grafts, and bone chip cages were performed before posterior pedicle screw fusion. An assessment of the residual pain, the grade of neurological injury, and the resolution of infection was conducted on 39 patients. The clinical outcome was evaluated using a visual analog scale (VAS) and the Oswestry Disability Index (ODI), and neurological outcomes were appraised based on Frankel grades. The radiological outcomes were evaluated via focal lordosis, lumbar lordosis, and the state of the fusion., Results: Staphylococcus aureus and Staphylococcus epidermidis were the most common causative organisms. The mean preoperative focal lordosis was -1.2° (-11.4° to 5.7°), and the mean postoperative focal lordosis increased to 10.3° (4.3°-17.2°). At the final follow-up, there were five cases with subsidence of the cage, no case of recurrence, and no case with cage and screw loosening or migration. The mean preoperative VAS and ODI scores were 8.9 and 74.6%, respectively, and improvements in VAS and ODI were 6.6 ± 2.2 and 50.4 ± 21.3%, respectively. The Frankel grade D was found in 10 patients and grade C in 7. Following the final follow-up, only one patient improved from Frankel grade C to grade D while the others recovered completely., Conclusion: The PEEK cage and cadaveric allograft combined with local bone grafts is a safe and effective choice for intervertebral fusion and restoring sagittal alignment without increased incidence of relapse for treating lumbar pyogenic spondylodiscitis., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Huo-Liang Zheng et al.)

Objective: To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions., Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dL) and insulin (-52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study., Conclusions: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover., (© 2023 by the American Diabetes Association.)

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

New Findings: What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field., Abstract: Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis., (© 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications used by individuals with type 2 diabetes that reduce hyperglycaemia by targeting glucose transport in the kidney, preventing its reabsorption, thereby inducing glucosuria. Besides improving HbA 1c and reducing body weight and blood pressure, the SGLT2 inhibitors have also been demonstrated to improve cardiovascular and kidney outcomes, an effect largely independent of their effect on blood glucose levels. Indeed, the mechanisms underlying these benefits remain elusive. Treatment with SGLT2 inhibitors has been found to modestly increase systemic ketone levels. Ketone bodies are an ancillary fuel source substituting for glucose in some tissues and may also possess intrinsic anti-oxidative and anti-inflammatory effects. Some have proposed that ketones may in fact mediate the cardio-renal benefits of this drug category. However, a rare complication of SGLT2 inhibition is ketoacidosis, sometimes with normal or near-normal blood glucose concentrations, albeit occurring more frequently in patients with type 1 diabetes who are treated (predominately off-label) with one of these agents. We herein explore the notion that an underpinning of one of the more serious adverse effects of SGLT2 inhibitors may, in fact, explain, at least in part, some of their benefits-a potential 'double-edged sword' of this novel drug category., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The nanohydroxyapatite/polyamide-66 (n-HA/PA66) cage is a novel bioactive nonmetal cage that is now used in some medical centers, while the polyetheretherketone (PEEK) cage is a typical device that has been widely used for decades with excellent clinical outcomes. This study was performed to compare the long-term radiographic and clinical outcomes of these two different cages used in transforaminal lumbar interbody fusion (TLIF)., Methods: In this retrospective and matched-pair case control study, we included 200 patients who underwent TLIF from January 2010 to December 2014 with a minimum 7-year follow-up. One hundred patients who used n-HA/PA66 cages were matched with 100 patients who used PEEK cages for age, sex, diagnosis, and fusion level. The independent student's t-test and Pearson's chi-square test were used to compare the two groups regarding radiographic (fusion status, cage subsidence rate, segmental angle [SA], and interbody space height [IH]) and clinical (Oswestry Disability Index [ODI], and Visual Analog Scale [VAS] for back and leg) parameters preoperatively, postoperatively, and at the final follow-up., Results: The n-HA/PA66 and PEEK groups had similar fusion rates of bone inside and outside the cage at the final follow-up (95.3% vs 91.8%, p = 0.181, 92.4% vs 90.1%, p = 0.435). The cage union ratios exposed to the upper and lower endplates of the n-HA/PA66 group were significantly larger than those of the PEEK group (p < 0.05). The respective cage subsidence rates in the n-HA/PA66 and PEEK groups were 10.5% and 17.5% (p = 0.059). There were no significant differences between the two groups in the SA, IH, ODI scores, or VAS scores at any time point. The n-HA/PA66 group showed high fusion and low subsidence rates during long-term follow-up., Conclusion: Both n-HA/PA66 and PEEK cages can achieve satisfactory long-term clinical and radiographic outcomes in TLIF. However, the n-HA/PA66 group showed significantly larger cage union ratios than the PEEK group. Therefore, the results indicated that the n-HA/PA66 cage is an ideal alternative material comparable to the PEEK cage in TLIF., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.

We herein report a rare case of unresectable liposarcoma that showed a complete response to eribulin. Furthermore, a low expression of phosphorylated AKT (p-AKT) on an immunohistological evaluation was observed. This result is consistent with our previous preclinical study that demonstrated the significance of p-AKT signaling for eribulin resistance in multiple subtypes of soft tissue sarcoma (STS) cells. This case highlights the potential benefits of eribulin as well as the mechanism underlying resistance to eribulin in patients with unresectable or metastatic STS, especially liposarcoma.

Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). β-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that β-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.

Objective: A multicenter, randomized, single-blind, parallel-controlled noninferiority study was used to evaluate the short-term safety and effectiveness of domestic polyether-ether-ketone (PEEK) suture anchor for rotator cuff repair by comparing with the imported PEEK suture anchor commonly used in clinical practice., Methods: A total of 59 patients with rotator cuff tears who were admitted between May 2019 and October 2019 were selected as the research objects. Among them, 3 patients were excluded because they did not meet the selection criteria, and 1 patient withdrew from the study because of serious adverse events. A total of 55 patients were included in the study. They were randomly divided into trial group ( n =27) and control group ( n =28). The trial group used PEEK suture anchors produced from REJOIN Company, and the control group used PEEK suture anchors from American Arthrex Company. Two patients in control group were lost to follow-up. Twenty-seven patients in trial group and 26 patients in control group were included in the final quantitative analysis. There was no significant difference ( P >0.05) in gender, age, disease duration, side and sizes of rotator cuff tears, composition ratio of patients with type 2 diabetes, and preoperative American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley score, University of California at Los Angeles (UCLA) score, and visual analogue scale (VAS) score. The patients were followed up regularly after operation. The postoperative follow-up included safety evaluation (complications, anchor position, and anchor bone reaction) and effectiveness evaluation (shoulder joint function and pain scores, rotator cuff integrity based on Sugaya classification criteria)., Results: The operations in both groups were successfully completed, and there was no complication related to the operation and suture anchor. All incisions healed by first intention. There was no significant difference in follow-up time between trial group [(5.85±0.77) months] and control group [(5.96±0.72) months] ( t =0.535, P =0.595). MRI examination indicated that the repaired tendons were fixed and the anchors did not get loose or torn. At 1 day, 3 months, and 6 months after operation, there was no patient with grade 3-4 anchor bone reaction in the two groups, and there was no significant difference in the bone reaction grading between groups ( P >0.05). After operation, the VAS scores of the two groups gradually decreased, and the ASES scores, Constant-Murley scores, and UCLA scores gradually increased, and there were significant differences between groups at each time point ( P <0.05). There was no significant difference between groups at different time points ( P >0.05). There was no significant difference in Sugaya classification of rotator cuff integrity at 1 day, 3 months, and 6 months after operation between groups ( P >0.05)., Conclusion: The short-term safety and effectiveness of domestic PEEK suture anchors in rotator cuff tear repair are not significant different from those of imported PEEK suture anchors commonly used in clinical practice.

Background: Eribulin therapy has been reported to prolong overall survival (OS) but not progression-free survival, probably because it prevents the development of metastatic lesions; however, this effect has not yet been confirmed., Methods: We reviewed the medical charts of 50 patients with metastatic breast cancer who underwent eribulin monotherapy at our hospital between 2014 and 2019. Patients were divided into two groups, namely, those who discontinued eribulin because of disease progression due to development of new lesions (NL group) and those who discontinued eribulin for other reasons, such as lesion growth and unacceptable side effects (non-NL group). Survival times were estimated for both groups and we investigated if eribulin-mediated suppression of new metastasis increased OS., Results: Median OS for all patients, from eribulin initiation, was 14.4 months (range 1.2-60.1), whereas it was 4.6 months (range 1.7-24.7) in the NL group and 16.8 months (range 1.2-60.1) in the non-NL group. OS was significantly poorer in the NL group than in the non-NL group (p < 0.05)., Conclusion: Eribulin monotherapy-mediated suppression of new metastatic lesions results in a better prognosis in patients with metastatic breast cancer.

Background: Despite some evidence of the helpful role of ketones in some neuropsychiatric disorders, there are no clinical trials that examine these agents for posttraumatic stress disorder (PTSD). Our aim was to investigate whether ketone salt supplementation can improve PTSD symptoms in a randomized, placebo-controlled trial., Methods: A total of 21 participants were recruited and randomized to placebo or ketone supplement. Each dose of ketone supplement included 7 g of ketones in the form of beta-hydroxybutyrate for a total of 14 g/d. Data were collected through questionnaires to assess PTSD symptoms. We used Fisher's exact tests for categorical variables and 2-sample t tests for continuous variables to examine differences in baseline values between treatment groups. Mixed models were employed to examine changes over time between groups on the PTSD Checklist for DSM-5 (PCL-5)., Results: There were no statistically significant differences in PCL-5 medians between the ketone and control groups at pretest (P = 1.0000) or post-test (P = .6020). The ketone group had a statistically significant decrease in median PCL-5 scores from 58.5 (pretest) to 54.0 (posttest; P = .0003) but the control group did not change (34 at pretest and at posttest; P = .4418)., Conclusions: The ketone group showed a significant decrease in PCL-5 score at posttest compared with pretest that was not seen in the control group, although these changes were not statistically significant between groups. The small sample size limited the study and likely contributed to the lack of significance. Larger trials are needed to more definitively examine these findings.

Background: Insulin-treated patients with long duration of type 2 diabetes mellitus (T2DM) are at increased risk of ketoacidosis related to sodium-glucose co-transporter 2 inhibitor (SGLT2i). The extent of circulating ketone elevation in these patients remains unknown. We conducted this study to compare the serum ketone response between dapagliflozin, an SGLT2i, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, among insulin-treated T2DM patients., Methods: This was a randomized, open-label, active comparator-controlled study involving 60 insulin-treated T2DM patients. Participants were randomized 1:1 for 24-week of dapagliflozin 10 mg daily or sitagliptin 100 mg daily. Serum β-hydroxybutyrate (BHB) levels were measured at baseline, 12 and 24 weeks after intervention. Comprehensive cardiometabolic assessments were performed with measurements of high-density lipoprotein cholesterol (HDL-C) cholesterol efflux capacity (CEC), vibration-controlled transient elastography and echocardiography., Results: Among these 60 insulin-treated participants (mean age 58.8 years, diabetes duration 18.2 years, glycosylated hemoglobin 8.87%), as compared with sitagliptin, serum BHB levels increased significantly after 24 weeks of dapagliflozin (P=0.045), with a median of 27% increase from baseline. Change in serum BHB levels correlated significantly with change in free fatty acid levels. Despite similar glucose lowering, dapagliflozin led to significant improvements in body weight (P=0.006), waist circumference (P=0.028), HDL-C (P=0.041), CEC (P=0.045), controlled attenuation parameter (P=0.007), and liver stiffness (P=0.022). Average E/e', an echocardiographic index of left ventricular diastolic dysfunction, was also significantly lower at 24 weeks in participants treated with dapagliflozin (P=0.037)., Conclusion: Among insulin-treated T2DM patients with long diabetes duration, compared to sitagliptin, dapagliflozin modestly increased ketone levels and was associated with cardiometabolic benefits.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

Plants have profound therapeutic benefits, more economical treatments, fewer side effects, and a relatively cheap cost, making them a source of drugs for protective, preventative, curative, or conducive purposes and creating novel phytomedicines. Plant derived medicines are relatively safe compared to synthetic medicines. Many plants have proved to successfully aid in the treatment of diabetes including Filago hurdwarica (Wall. ex DC.) Wagenitz. The current investigations were therefore designed to assess the phytochemical, antioxidant, antidiabetic, and antihyperlipidemic activities of F. hurdwarica. The phytochemical investigations and antioxidant activities of different extracts were carried out using standard chemical tests, DPPH, and H2O2 scavenging assays. F. hurdwarica plant extract in Hydromethanolic solution were prepared by Soxhletation method and stored in refrigerator at 4°C for two days before use. Swiss Albino mice were made diabetic by a single dose of alloxan (150 mg/kg). Hydromethanolic plant extract and fractions of F. hurdwarica were screened for antidiabetic activity and given to the alloxan-induced diabetic mice at a concentration of 150-250 mg/kg of body weight in different groups of 6 diabetic mice each orally once a day for 15 days. Glibenclamide is also given to another group to as a standard drug to support the result at a dose of 10 mg/kg of body weight orally once a day for 15 days. Blood glucose levels and body weights of mice were measured on 0, 4, 7, 11 and 15th days. The study found that the extract was safe up to the dose level of 2000 mg/kg and the dose response effect of chloroform extract (150-250 mg/kg) of F. hurdwarica showed expressive antihyperglycemic effects and also improved other altered biochemical parameters associated with diabetes. The FTIR and XRD spectra demonstrated the occurrence of phenols, alcohols, alkenes, alkyl halides, ketones, and aromatic compounds and confirmed the amorphous nature of the extract. GC-MS spectral analysis showed the tentative presence of 31 phytochemical constituents in the chloroform extract of F. hurdwarica with different retention time. To conclude, the chloroform extract (250 mg/kg) of F. hurdwarica revealed considerable antioxidant, antihyperglycemic, and antihyperlipidemic potential and is safe for treating diabetes and related complications.

Background: Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity., Methods: Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the compounds were evaluated using a SYBR Green-based assay. In parallel, in vitro cytotoxic data were obtained using the MTT assay., Results: Among the eight compounds, compound 1 was the most active and selective against P. falciparum (IC50 = 0.98 µM; SI > 60). Six targets were identified in BraMMT that interact with compounds exhibiting a stronger binding energy than the crystallographic ligand: P. falciparum triophosphate phosphoglycolate complex (1LYX), P. falciparum reductase (2OK8), PfPK7 (2PML), P. falciparum glutaredoxin (4N0Z), PfATP6, and PfHT., Conclusions: The physicochemical properties of compound 1 were compatible with the set of criteria established by the Lipinski rule and demonstrated its potential as a drug prototype for antiplasmodial activity.

The medicinal plant Artabotrys hexapetalus (synonyms: A. uncinatus and A. odoratissimus ) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei . Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

Background: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics., Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis-defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P <0.05 with false discovery rate-adjusted P <0.10 was used to determine statistical significance., Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis-defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate-adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group., Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02653482.

Purpose: Choroidal neovascularization (CNV) is the major cause of irreversible vision loss associated with age-related macular disease (AMD). The currently clinical chemical therapeutic strategies are of high cost and facing supply chain shortage. In our study, we aim to investigate EV11, a novel derivative from Sorafenib, as a new approach to inhibit the formation of CNV., Methods: Cell viability assay, wound healing assay, transwell assay and tube formation assay were applied to explore the effects of EV11 on human vascular endothelial cells (HUVECs). Western blotting analysis was performed to investigate the pathways when EV11 acts on HUVECs. Laser-induced CNV in mice and intravitreal injection of EV11 were applied to find out the efficacy of the drug in vivo. Histological examination and electroretinogram (ERG) evaluated the retinal morphology and visual function after drug application., Results: EV11 influenced the HUVECs cell viability as the concentration increasing after 24 hour incubation. It influenced HUVECs through suppressing AKT and ERK1/2 pathway. EV11 reduced CNV area with the optimal concentration of 200uM in mice eyes and compared with Bevacizumab, it had the same effect. The retinal thickness around the optic in each group was not influenced. The amplitudes of the a- and b-waves on scotopic and photopic ERG were not reduced after intravitreal injection., Conclusion: The present study indicated that EV11 affected the proliferation, migration and tube formation of HUVECs, inhibited the area of neovascular of laser induced choroidal neovascularization in mice eyes with no toxicity. EV11 could block the AKT/ERK1/2 signaling pathway in effects of HUVECs. This study unveiled a novel perspective drug EV11 to be a potential candidate for neovascularization., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice. We found that two months of 1,3-BD administration raised circulatory ketone levels to ≥1.2 mM, attenuated autophagic buildup in type 2 muscle fibers, and preserved muscle strength and function in ERT-treated GAA-KO mice. Collectively, ERT-BD was more effective vs. standard ERT and ERT-KETO in terms of autophagic clearance, dampening of oxidative stress, and muscle maintenance. However, the addition of multi-ingredient antioxidants (ERT-BD-MITO) provided the most consistent benefits across all outcome measures and normalized mitochondrial protein expression in GAA-KO mice. We therefore conclude that nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants may provide an alternative to ketogenic diets for inducing ketosis and enhancing autophagic flux in PD patients., Competing Interests: Declaration of Competing Interest Exerkine Corporation is a biotechnology company that develops and commercializes therapies based on nutritional supplements, exercise-derived factors (‘exerkines’), and extracellular vesicles to treat and diagnose genetic disorders, chronic diseases, and aging. M.A.T. is the founder, C.E.O., and C.S.O. of Exerkine Corporation, which provided support in the form of salaries for M.I.N., A.L.B., and B.P.H. M.A.T., M.I.N., A.L.B., and B.P.H. are shareholders in the company. A patent has been filed by Exerkine related to the product herein (WO202004187)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Exercise is part of type 1 diabetes (T1D) management due to its cardiovascular and metabolic benefits. However, despite using continuous glucose monitoring, many patients are reluctant to exercise because of fear for hypoglycaemia., Aims: We assessed trends in glucose, lactate and ketones during anaerobic and aerobic exercise in people with T1D and compared incremental area under the curve (AUC) between both exercises., Methods: Twenty-one men with T1D (median [IQR]: age 29 years [28-38], body mass index (BMI) 24.4 kg/m 2 [22.3-24.9], HbA1c 7.2% [6.7-7.8]), completed a cardiopulmonary exercise test (CPET) and a 60-min aerobic exercise (AEX) at 60% VO 2 peak on an ergometer bicycle within a 6-week period. Subjects consumed a standardised breakfast (6 kcal/kg, 20.2 g CHO/100 ml) before exercise without pre-meal insulin and basal insulin for pump users., Results: During CPET, glucose levels increased, peaking at 331 mg/dl [257-392] 1-3 h after exercise and reaching a nadir 6 h after exercise at 176 mg/dl [118-217]. Lactate levels peaked at 6.0 mmol/L [5.0-6.6] (max 13.5 mmol/L). During AEX, glucose levels also increased, peaking at 305 mg/dl [245-336] 80 min after exercise and reaching a nadir 6 h after exercise at 211 mg/dl [116-222]. Lactate levels rose quickly to a median of 4.3 mmol/L [2.7-6.7] after 10 min. Ketone levels were low during both tests (median ≤ 0.2 mmol/L). Lactate, but not glucose or ketone AUC, was significantly higher in CPET compared to AEX (p = 0.04)., Conclusions: Omitting pre-meal insulin and also basal insulin in pump users, did prevent hypoglycaemia but induced hyperglycaemia due to a too high carbohydrate ingestion. No ketosis was recorded during or after the exercises., Clinical Trial Registration: ClinicalTrials.gov: NCT05097339., (© 2022 John Wiley & Sons Ltd.)

Study Design: Prospective, randomized, blinded clinical trial., Objective: To examine clinical and radiological outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF) surgeries randomized to receive either polyether-ether-ketone (PEEK) or structural bone allografts., Summary of Background Data: The biomechanical qualities as well as osteoconductive, osteogenic, and osteoinductive properties of various graft materials have been previously evaluated. There remain questions, however, as to whether there are any clinical and/or radiographic outcome differences in the selection of interbody graft types for ACDF., Methods: Patients undergoing one- to three-level ACDF with single anterior plate fixation were randomized (1:1 ratio) to receive either cortical allograft or PEEK interbody spacers. Radiographic and clinical outcomes were assessed at 3, 6, 12, and 24 months with an additional postoperative radiographic assessment., Results: A total of 120 patients were enrolled and randomized. Comparing clinical outcomes, no differences in arm or neck pain scores were noted; however, there was a statistically significant (≤0.041) improvement in SF-36 PCS scores for the allograft group at all follow-up time points and a tendency toward lower disability scores. Overall, evidence of radiographic fusion was achieved in 87 (91.6%) patients: five (10.2%) and three (6.5%) patients had pseudoarthrosis (P = 0.72) in the PEEK and allograft groups, respectively. At 24 months' follow-up time, any cervical or segmental alignment restoration achieved with surgery was lost and no statistically significant changes were detected when all levels of surgery were included. Likewise, there were no statistically significant differences between the groups for anterior or posterior body height measurements at the 24 months' follow-up. Approximately 20% of patients had anterior and posterior subsidence, all grade 0 regardless of the group assignment., Conclusion: Comparable radiographic outcomes were observed for patients undergoing one- to three-level PEEK versus allograft-assisted ACDF surgeries. Although MCID comparisons suggest that allograft and PEEK-treated patients have similar clinical outcomes, testing that incorporates the magnitude of the change suggests that there may be a statistically significant greater magnitude of improvement for the allograft group patients, but further studies with a larger sample size would be helpful to determine if a true effect exists., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Preservation of retinal barrier function is critical to maintenance of retinal health. Therefore, it is not surprising that loss of barrier integrity is a pathologic feature common to degenerative retinal diseases such as diabetic retinopathy. Our prior studies demonstrate the importance of hydroxycarboxylic acid receptor 2/GPR109A (HCAR2/GPR109A) expression in the retinal pigment epithelium (RPE) to outer retinal barrier integrity. However, whether HCAR2/GPR109A is expressed in retinal endothelial cells and has a similar relationship to inner blood retinal barrier regulation is not known. In the current study, we examined relevance of receptor expression to endothelial cell dependent-blood retinal barrier integrity. siRNA technology was used to modulate HCAR2/GPR109A expression in human retinal endothelial cells (HRECs). Cells were cultured in the presence or absence of VEGF, a pro-inflammatory stimulus, and/or various concentrations of the HCAR2/GPR109A-specific agonist beta-hydyroxybutyrate (BHB). HCAR2/GPR109A expression was monitored by qPCR and electrical cell impedance sensing (ECIS) was used to evaluate barrier function. Complementary in vivo studies were conducted in wildtype and HCAR2/GPR109A knockout mice treated intraperitoneally with lipopolysaccharide and/or BHB. Vascular leakage was monitored using fluorescein angiography and Western blot analyses of albumin extravasation. Additionally, retinal function was evaluated by OptoMotry. Decreased (siRNA knockdown) or absent (gene knockout) HCAR2/GPR109A expression was associated with impaired barrier function both in vitro and in vivo. BHB treatment provided some protection, limiting disruptions in retinal barrier integrity and function; an effect that was found to be receptor (HCAR2/GPR109A)-dependent. Collectively, the present studies support a key role for HCAR2/GPR109A in regulating blood-retinal barrier integrity and highlight the therapeutic potential of the receptor toward preventing and treating retinal diseases such as diabetic retinopathy in which compromised barrier function is paramount., (Copyright © 2022. Published by Elsevier Ltd.)