Efficacy of Interval Training in Improving Body Composition and Adiposity in Apparently Healthy Adults: An Umbrella Review with Meta-Analysis.

BACKGROUND: Although the efficacy of interval training for improving body composition has been summarized in an increasing number of systematic reviews in recent years, discrepancies in review findings and conclusions have been observed. OBJECTIVE: This study aims to synthesize the available evidence on the efficacy of interval training compared with moderate-intensity continuous training (MICT) and nonexercise control (CON) in reducing body adiposity in apparently healthy adults. METHODS: An umbrella review with meta-analysis was performed. A systematic search was conducted in seven databases (MEDLINE, EMBASE, Cochrane Database, CINAHL, Scopus, SPORTDiscus, and Web of Science) up to October 2023. Systematic reviews with meta-analyses of randomized controlled trials (RCTs) comparing interval training and MICT/CON were included. Literature selection, data extraction, and methodological quality assessment (AMSTAR-2) were conducted independently by two reviewers. Meta-analyses were performed using a random-effects model. Subgroup analyses were conducted based on the type of interval training [high-intensity interval training (HIIT) and sprint interval training (SIT)], intervention duration, body mass index, exercise modality, and volume of HIIT protocols. RESULTS: Sixteen systematic reviews, including 79 RCTs and 2474 unique participants, met the inclusion criteria. Most systematic reviews had a critically low (n = 6) or low (n = 6) AMSTAR-2 score. Interval training demonstrated significantly greater reductions in total body fat percent (BF%) compared with MICT [weighted mean difference (WMD) of - 0.77%; 95% confidence interval (CI) - 1.12 to - 0.32%] and CON (WMD of - 1.50%; 95% CI - 2.40 to - 0.58%). Significant reductions in fat mass, visceral adipose tissue, subcutaneous abdominal fat, and android abdominal fat were also observed following interval training compared to CON. Subgroup analyses indicated that both HIIT and SIT resulted in superior BF% loss than MICT. These benefits appeared to be more prominent in individuals with overweight/obesity and longer duration interventions (≥ 12 weeks), as well as in protocols using cycling as a modality and low-volume HIIT (i.e., < 15 min of high-intensity exercise per session). CONCLUSIONS: This novel umbrella review with large-scale meta-analysis provides an updated synthesis of evidence with implications for physical activity guideline recommendations. The findings support interval training as a viable exercise strategy for reducing adiposity in the general population.

Systematic Reporting of Eosinophils in Transbronchial Biopsies After Lung Transplantation Defines a Distinct Inflammatory Response.

BACKGROUND: Descriptions of eosinophils in transbronchial biopsy (TBBx) pathology reports after lung transplantation (LTx) are associated with poor long-term outcomes. The absence of routine reporting and standardization precludes accurate assessment of this histologic predictor. A systematic reporting scheme for the presence of TBBx eosinophils after LTx was implemented. This report aims to assess this scheme by describing the presence, pattern, and gradation of TBBx eosinophils and clinical associations. METHODS: A prospective cross-sectional study of all TBBx reports was performed including all patients presenting for a surveillance or diagnostic TBBx between January 2020 and June 2023. Each TBBx was systematically reported in a blinded manner. Mixed-effects logistic regression was performed to measure the association between concurrent clinical and histologic features, and the presence of TBBx eosinophils. RESULTS: A total of 410 TBBx reports from 201 patients were systematically reported. In 43.8% recipients, any TBBx eosinophils were detected and in 17.1% recipients, higher-grade eosinophils (≥3 per high power field) were present. Adjusted analysis showed that retransplantation, A- and B-grade cellular rejection, positive bronchoalveolar lavage (BAL) bacterial microbiology, and elevated blood eosinophil count were independently associated with the presence of any TBBx eosinophils. Diagnostic "for-cause" procedures were independently associated with higher quantities of TBBx eosinophils. CONCLUSIONS: Systematic reporting demonstrates that TBBx eosinophils are a distinct inflammatory response associated with rejection, infection, and peripheral eosinophilia. Although these findings require multicenter external validation, standardized reporting for TBBx eosinophils may assist in identifying recipients at risk of poor outcomes and provides a platform for mechanistic research into their role after lung transplantation.

Effects of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity: Study protocol for a randomized controlled trial.

Objective: This study aims to examine the comparative effects of 75 min of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity. Methods: This assessor-blinded, three-arm, randomized controlled trial will recruit 315 physically inactive adults with central obesity (aged ≥18 years, body mass index ≥23, waist circumference ≥90 cm for men and ≥80 cm for women). Participants will be randomly allocated to the once-weekly HIIT, thrice-weekly HIIT or usual care control group. Participants in the HIIT groups will receive weekly exercise training sessions for 16 weeks, prescribed either once or three times weekly. Each HIIT session will consist of a supervised program of four 4-min high-intensity intervals at 85%-95% peak heart rate (HRpeak) interspersed with 3-min active recovery intervals at 50%-70% HRpeak. Participants in the once-weekly HIIT group will perform the 25-min HIIT bout three times with a break between each 25-min HIIT bout. The usual care control group will receive bi-weekly health education classes. The outcome assessments will be conducted at baseline, 16 weeks (post-intervention) and 32 weeks (follow-up). The primary outcome will be total body adiposity assessed by dual-energy X-ray absorptiometry (DXA). The secondary outcome measures will include markers of cardiovascular and metabolic health (body composition, cardiorespiratory fitness, blood pressure, and blood lipids), mental health, cognitive performance, health-related quality of life, sleep quality, habitual physical activity, diet, medication, adverse events and adherence to the intervention. Impact of the project: The findings from this study are expected to consolidate the therapeutic efficacy of HIIT for the management of central obesity and inform the comparative compliance, feasibility and suitability of once-weekly and thrice-weekly HIIT as exercise strategies to manage obesity. In particular, the present study is expected to provide a novel perspective on the utility of low-frequency HIIT (i.e., once-weekly) as an effective and sustainable exercise strategy to tackle the obesity pandemic. The anticipated findings will hold substantial translational value by informing public health policies and enhancing exercise compliance in the physically inactive obese population. Trial registration: ClinicalTrials.gov (NCT04887454).

The effect of different high-intensity interval training protocols on cardiometabolic and inflammatory markers in sedentary young women: A randomized controlled trial.

Few studies have reported the cardiovascular health effects of different high-intensity interval training (HIIT) protocols among sedentary young women. We investigated the impact of a traditional HIIT programme and a high-intensity circuit training (HICT) programme on lipid profiles and inflammatory cytokine levels in sedentary young women. Forty-two women were randomly assigned to HICT (body weight-based training), HIIT (cycling-based training), or control groups (n = 14 each). HICT and HIIT participants completed an 8-week training programme of three sessions per week. Total cholesterol (TC), triglyceride, high- and low-density lipoprotein, leptin, resistin, tumour necrosis factor-alpha (TNF-α), interleukin-8, and interferon-gamma levels were measured before and after the intervention. Post-intervention, TC and leptin were decreased in the HICT group. The HICT group also demonstrated increased lean mass, upper and lower limb strength, and balance, while the HIIT group displayed improved lower limb strength. Additionally, the control group showed significant increases in triglyceride levels, weight, body mass index, and fat mass. In conclusion, although both HICT and HIIT interventions showed improvements in cardiovascular health and physical fitness, participants in the HICT group experienced more health benefits.

The Effect of Time-Restricted Eating Combined with Exercise on Body Composition and Metabolic Health: A Systematic Review and Meta-Analysis.

BACKGROUND: Time-restricted eating (TRE) is increasingly popular, but its benefits in combination with exercise still need to be determined. OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the efficacy of TRE combined with exercise compared with control diet with exercise in improving the body composition and metabolic health of adults. METHODS: Five electronic databases were searched for relevant studies. Randomized controlled trials (RCTs) examining the effect of TRE combined with exercise on body composition and metabolic health in adults were included. All results in the meta-analysis are reported as mean difference (MD) with 95% confidence interval (CI). Study quality was assessed using the revised Cochrane Risk of Bias Tool and Grading of Recommendations Assessment, Development, and Evaluation assessment. RESULTS: In total, 19 RCTs comprising 568 participants were included in this systematic review and meta-analysis. TRE combined with exercise likely reduced the participants' body mass (MD: -1.86 kg; 95% CI: -2.75, -0.97 kg) and fat mass (MD: -1.52 kg; 95% CI: -2.07, -0.97 kg) when compared with the control diet with exercise. In terms of metabolic health, the TRE combined with exercise group likely reduced triglycerides (MD: -13.38 mg/dL, 95% CI: -21.22, -5.54 mg/dL) and may result in a reduction in low-density lipoprotein (MD: -8.52 mg/dL; 95% CI: -11.72, -5.33 mg/dL) and a large reduction in leptin (MD: -0.67 ng/mL; 95% CI: -1.02, -0.33 ng/mL). However, TRE plus exercise exhibited no additional benefit on the glucose profile, including fasting glucose and insulin, and other lipid profiles, including total cholesterol and high-density lipoprotein concentrations, compared with the control group. CONCLUSIONS: Combining TRE with exercise may be more effective in reducing body weight and fat mass and improving lipid profile than control diet with exercise. Implementing this approach may benefit individuals aiming to achieve weight loss and enhance their metabolic well-being. This study was registered in PROSPERO as CRD42022353834.

Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors.

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.

Cure can be Achieved by Conversion to Microwave Ablation following Atezolizumab-Bevacizumab Therapy in Unresectable Hepatocellular Carcinoma.

Introduction: Atezolizumab/bevacizumab is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) and may facilitate curative conversion through resection and locoregional therapies. However, there have been very few reports on curative conversion using microwave ablation (MWA). This study aimed to determine the curative conversion rate with MWA using atezolizumab-bevacizumab as the first-line treatment in patients with uHCC, and to compare the characteristics and survival of patients with and without curative conversion. Methods: Consecutive patients with uHCC who were started on atezolizumab-bevacizumab from May 2021 and December 2023 in a single tertiary center were included. Objective response (ORR) and disease control rate (DCR) were based on the RECIST 1.1 and mRECIST criteria. Results: Twenty consecutive patients with uHCC (60% advanced-stage) were included, 90% exceeding the up-to-7 criteria. The ORR and DCR were 35% and 60%, and 35% and 55% using RECIST and mRECIST, respectively. Five (25%) patients underwent successful curative conversion with MWA (4 advanced and 1 intermediate stage) despite a median HCC size of 6.1 (range: 2.4-7.3) cm. Two of these patients were tumor and drug-free 132-133 weeks from the 1st atezolizumab-bevacizumab dose. Patients who underwent curative conversion had significantly longer survival than those who did not. (p=0.024) Other factors associated with survival were male sex, Child-Pugh class A, and an objective response. Conclusions: Despite the relatively large tumor size, successful curative conversion with MWA was achieved with first-line atezolizumab-bevacizumab in uHCC. However, data from prospective multicenter trials are required to determine whether this strategy is universally applicable.

MUSTANG: Multi-sample spatial transcriptomics data analysis with cross-sample transcriptional similarity guidance.

Spatially resolved transcriptomics has revolutionized genome-scale transcriptomic profiling by providing high-resolution characterization of transcriptional patterns. Here, we present our spatial transcriptomics analysis framework, MUSTANG (MUlti-sample Spatial Transcriptomics data ANalysis with cross-sample transcriptional similarity Guidance), which is capable of performing multi-sample spatial transcriptomics spot cellular deconvolution by allowing both cross-sample expression-based similarity information sharing as well as spatial correlation in gene expression patterns within samples. Experiments on a semi-synthetic spatial transcriptomics dataset and three real-world spatial transcriptomics datasets demonstrate the effectiveness of MUSTANG in revealing biological insights inherent in the cellular characterization of tissue samples under study.

Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.

Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

Measurement of very low-molecular weight metabolites by traveling wave ion mobility and its use in human urine samples.

The collision cross-sections (CCS) measurement using ion mobility spectrometry (IMS) in combination with mass spectrometry (MS) offers a great opportunity to increase confidence in metabolite identification. However, owing to the lack of sensitivity and resolution, IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites (VLMs ≤ 250 Da). Here, we describe an analytical method using ultrahigh-performance liquid chromatography (UPLC) coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples. The experimental CCS values, along with mass spectral properties, were reported for the 174 metabolites. The experimental data included the mass-to-charge ratio (m/z), retention time (RT), tandem MS (MS/MS) spectra, and CCS values. Among the studied metabolites, 263 traveling wave ion mobility spectrometry (TWIMS)-derived CCS values (TWCCSN2) were reported for the first time, and more than 70% of these were CCS values of VLMs. The TWCCSN2 values were highly repeatable, with inter-day variations of <1% relative standard deviation (RSD). The developed method revealed excellent TWCCSN2 accuracy with a CCS difference (ΔCCS) within ±2% of the reported drift tube IMS (DTIMS) and TWIMS CCS values. The complexity of the urine matrix did not affect the precision of the method, as evidenced by ΔCCS within ±1.92%. According to the Metabolomics Standards Initiative, 55 urinary metabolites were identified with a confidence level of 1. Among these 55 metabolites, 53 (96%) were VLMs. The larger number of confirmed compounds found in this study was a result of the addition of TWCCSN2 values, which clearly increased metabolite identification confidence.

High-intensity interval training and cardiorespiratory fitness in adults: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: High-intensity interval training (HIIT) is characterized by repeated bouts of relatively intense exercise interspersed with recovery periods. Previous studies have evaluated this exercise strategy with various population subgroups, regimens, and comparator groups, limiting the generalizability of findings. We performed a novel umbrella review to generate an up-to-date synthesis of the available evidence regarding the effect of HIIT on cardiorespiratory fitness (CRF) in adults as compared to non-exercise control and traditional continuous forms of exercise such as moderate-intensity continuous training (MICT). METHODS: An umbrella review was conducted in accordance with the Preferred Reporting Items for Overviews of Reviews guideline. Seven databases (MEDLINE, EMBASE, Cochrane Database, CINAHL, Scopus, SPORTDiscus, and Web of Science) were searched until February 2024. Systematic reviews with meta-analyses comparing HIIT and active/non-active control conditions were included. Literature search, data extraction, and methodological quality assessment (AMSTAR-2) were conducted independently by two reviewers. RESULTS: Twenty-four systematic reviews with meta-analyses, representing 429 primary studies and 12 967 unique participants, met the inclusion criteria. Most of the systematic reviews received moderate-to-critically low AMSTAR-2 scores. The data showed that HIIT, including the particularly intense variant "sprint interval training" (SIT), significantly increases CRF in adults compared to non-exercise control (standardized mean difference [SMD]: 0.28 to 4.31; weighted mean difference [WMD]: 3.25 to 5.5 mL/kg/min) and MICT (SMD: 0.18 to 0.99; WMD: 0.52 to 3.76 mL/kg/min). This effect was consistently observed across specific groups of individuals (e.g., apparently healthy adults, individuals with overweight/obesity, older adults, and high-level athletes) and HIIT modalities (e.g., low-volume HIIT, whole-body HIIT, home-based HIIT, aquatic HIIT, and short SIT). CONCLUSION: Existing evidence from systematic reviews consistently supports the effect of HIIT on enhancing CRF in adults when compared to non-exercise control and MICT. Our findings offer a comprehensive basis that may potentially contribute to informing physical activity guidelines aimed at improving CRF in the general population.

Label-free optical imaging for brain cancer assessment.

Advances in label-free optical imaging offer a promising avenue for brain cancer assessment, providing high-resolution, real-time insights without the need for radiation or exogeneous agents. These cost-effective and intricately detailed techniques overcome the limitations inherent in magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) scans by offering superior resolution and more readily accessible imaging options. This comprehensive review explores a variety of such methods, including photoacoustic imaging (PAI), optical coherence tomography (OCT), Raman imaging, and IR microscopy. It focuses on their roles in the detection, diagnosis, and management of brain tumors. By highlighting recent advances in these imaging techniques, the review aims to underscore the importance of label-free optical imaging in enhancing early detection and refining therapeutic strategies for brain cancer.

Therapeutic drug monitoring in inflammatory bowel disease patients on vedolizumab.

OBJECTIVE: We aimed to investigate whether vedolizumab (VDZ) levels were associated with inflammatory markers or clinical or endoscopic scoring in inflammatory bowel disease (IBD). METHODS: Besides demographic data, clinical scoring, endoscopic data, and laboratory markers of IBD patients treated with VDZ from 2015 to 2020 who had trough levels drawn on maintenance therapy were collected at baseline and at follow-up (after at least 8 weeks on VDZ therapy or after change in dose frequency). Low drug levels were defined as VDZ trough <20 µg/mL. RESULTS: We identified 89 patients with a mean age of 42.9 years. Of the 90 total trough levels drawn, 61.1% were low. Among patients on every 8 week (Q8 week) VDZ dosing, 81.5% had low troughs. After increasing dosing frequency to Q4 weeks, all patients showed improvement in VDZ levels, but 30.6% remained <20 µg/mL. Higher VDZ levels on Q8 week dosing were associated with higher albumin levels (P = 0.01). While higher VDZ levels on Q4 week dosing were associated with higher albumin (P = 0.02), lower erythrocyte sedimentation rate (P = 0.04) and higher likelihood of having mild disease or endoscopic remission (P = 0.01). No significant association was found between VDZ levels and clinical scoring, body mass index, hemoglobin, vitamin D or platelet levels on either Q8 or Q4 week dosing. CONCLUSIONS: Higher VDZ troughs were associated with higher albumin, mild endoscopic disease or endoscopic remission. Patients who continue to have low VDZ troughs despite Q4 week dosing may require a change in therapy.

Plasma ctDNA enables early detection of temozolomide resistance mutations in glioma.

Background: Liquid biopsy based on circulating tumor DNA (ctDNA) is a novel tool in clinical oncology, however, its use has been limited in glioma to date, due to low levels of ctDNA. In this study, we aimed to demonstrate that sequencing techniques optimized for liquid biopsy in glioma patients can detect ctDNA in plasma with high sensitivity and with potential clinical utility. Methods: We investigated 10 glioma patients with tumor tissue available from at least 2 surgical operations, who had 49 longitudinally collected plasma samples available for analysis. Plasma samples were sequenced with CAPP-seq (AVENIO) and tissue samples with TSO500. Results: Glioma-derived ctDNA mutations were detected in 93.8% of plasma samples. 25% of all mutations detected were observed in plasma only. Mutations of the mismatch repair (MMR) genes MSH2 and MSH6 were the most frequent circulating gene alterations seen after temozolomide treatment and were frequently observed to appear in plasma prior to their appearance in tumor tissue at the time of surgery for recurrence. Conclusions: This pilot study suggests that plasma ctDNA in glioma is feasible and may provide sensitive and complementary information to tissue biopsy. Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.

Plasma ctDNA liquid biopsy of IDH1, TERTp, and EGFRvIII mutations in glioma.

Background: Circulating tumor DNA has emerging clinical applications in several cancers; however, previous studies have shown low sensitivity in glioma. We investigated if 3 key glioma gene mutations IDH1, TERTp, and EGFRvIII could be reliably detected in plasma by droplet digital polymerase chain reaction (ddPCR) thereby demonstrating the potential of this technique for glioma liquid biopsy. Methods: We analyzed 110 glioma patients from our biobank with a total of 359 plasma samples (median 4 samples per patient). DNA was isolated from plasma and analyzed for IDH1, TERTp, and EGFRvIII mutations using ddPCR. Results: Total cfDNA was significantly associated with tumor grade, tumor volume, and both overall and progression-free survival for all gliomas as well as the grade 4 glioblastoma subgroup, but was not reliably associated with changes in tumor volume/progression during the patients' postoperative time course. IDH1 mutation was detected with 84% overall sensitivity across all plasma samples and 77% in the preoperative samples alone; however, IDH1 mutation plasma levels were not associated with tumor progression or survival. IDH1m plasma levels were not associated with pre- or postsurgery progression or survival. The TERTp C228T mutation was detected in the plasma ctDNA in 88% but the C250T variant in only 49% of samples. The EGFRvIII mutation was detected in plasma in 5 out of 7 patients (71%) with tissue EGFRvIII mutations in tumor tissue. Conclusions: Plasma ctDNA mutations detected with ddPCR provide excellent diagnostic sensitivity for IDH1, TERTp-C228T, and EGFRvIII mutations in glioma patients. Total cfDNA may also assist with prognostic information. Further studies are needed to validate these findings and the clinical role of ctDNA in glioma.

Glenohumeral Osteoarthritis: A Biological Advantage or a Missed Diagnosis?

(1) Background: Osteoarthritis is a degenerative joint disease that is commonly diagnosed in the aging population. Interestingly, the lower extremity joints have a higher published incidence of osteoarthritis than the upper extremity joints. Although much is known about the disease process, it remains unclear why some joints are more affected than others. (2) Methods: A comprehensive literature review was conducted utilizing the search engines PubMed, Google Scholar, and Elsevier from 2014 to 2024, directing our search to osteoarthritis of various joints, with the focus being on glenohumeral osteoarthritis. (3) Results and Discussion: The literature review revealed a publication difference, which may be explained by the inconsistency in classification systems utilized in the diagnosis of shoulder osteoarthritis. For instance, there are six classification systems employed in the diagnosis of glenohumeral osteoarthritis, making the true incidence and, therefore, the prevalence unobtainable. Furthermore, susceptibility to osteoarthritis in various joints is complicated by factors such as joint anatomy, weight-bearing status, and prior injuries to the joint. (4) Conclusions: This review reveals the lack of understanding of shoulder osteoarthritis's true incidence and prevalence while considering the anatomy and biomechanics of the glenohumeral joint. In addition, this is the first paper to suggest a single criterion for the diagnosis of glenohumeral osteoarthritis.

Acute effects of various doses of nitrate-rich beetroot juice on high-intensity interval exercise responses in women: a randomized, double-blinded, placebo-controlled, crossover trial.

BACKGROUND: This study investigated the acute effects of various doses of nitrate-rich beetroot juice on the responses to high-intensity interval exercise in women. METHODS: A double-blinded, randomized, placebo-controlled, crossover trial was conducted with 13 recreationally active young women (age = 23 ± 2 years). All participants performed interval exercise (8 × 1-min bouts of cycling at 85% of peak power output [PPO] interspersed with 1-min active recovery at 20% of PPO) 2.5 h after consumption of the randomly assigned beetroot juice containing 0 mmol (placebo), 6.45 mmol (single-dose), or 12.9 mmol (double-dose) NO3-. The heart rate (HR), blood pressure, blood lactate, blood glucose, oxygen saturation, rating of perceived exertion (RPE), and emotional arousal were assessed. RESULTS: Nitrate supplementation significantly altered the HR and RPE responses across the three trials. The mean HR was lower in the single- and double-dose groups than in the placebo control group during both work intervals and recovery periods, as well as across the overall protocol (all p < .05). The mean RPE was lower in the single- and double-dose groups than in the control group during recovery periods and across the overall protocol (all p < .001). However, there was no significant difference in either HR or RPE between the single- and double-dose groups at any time point. CONCLUSIONS: Acute nitrate ingestion led to significant decreases in the mean HR and RPE during high-intensity interval exercise, but no additional benefit was observed with higher nitrate content. These findings may assist practitioners in implementing more effective nitrate supplementation strategies during high-intensity interval exercise.

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.