Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade.

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.

Evaluation of blood and urine based biomarkers for detection of clinically-significant prostate cancer.

BACKGROUND: Recognizing the limitations of prostate-specific antigen (PSA) screening and the morbidity of prostate biopsies, several blood- and urine-based biomarkers have been proposed for pre-biopsy risk stratification. These assays aim to reduce the frequency of unnecessary biopsies (i.e., negative or Grade Group 1 [GG1]) while maintaining highly sensitive detection of clinically significant cancer (GG ≥ 2) prostate cancer. METHODS: We reviewed the literature describing the use of currently available blood- and urine-based biomarkers for detection of GG ≥ 2 cancer, including the Prostate Health Index (PHI), 4Kscore, MyProstateScore (MPS), SelectMDx, ExoDx Prostate Intelliscore (EPI), and IsoPSA. To facilitate clinical application, we focused on the use of biomarkers as a post-PSA secondary test prior to biopsy, as proposed in clinical guidelines. Our outcomes included test performance measures-sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV)-as well as clinical outcomes resulting from biomarker use (i.e., unnecessary biopsies avoided, GG ≥ 2 cancers missed). RESULTS: Contemporary validation data (2015-2023) reveal that currently available biomarkers provide ~15-50% specificity at a sensitivity of 90-95% for GG ≥ 2 PCa. Clinically, this indicates that secondary use of biomarker testing in men with elevated PSA could allow for avoidance of up to 15-50% of unnecessary prostate biopsies, while preserving detection of 90-95% of GG ≥ 2 cancers that would be detected under the traditional "biopsy all" approach. CONCLUSIONS: The contemporary literature further supports the proposed role of post-PSA biomarker testing to reduce the use of invasive biopsy while maintaining highly sensitive detection of GG ≥ 2 cancer. Questions remain regarding the optimal application of biomarkers in combination or in sequence with mpMRI.

Third-Generation Anticancer Photodynamic Therapy Systems Based on Star-like Anionic Polyacrylamide Polymer, Gold Nanoparticles, and Temoporfin Photosensitizer.

Photodynamic therapy (PDT) is a non-invasive anticancer treatment that uses special photosensitizer molecules (PS) to generate singlet oxygen and other reactive oxygen species (ROS) in a tissue under excitation with red or infrared light. Though the method has been known for decades, it has become more popular recently with the development of new efficient organic dyes and LED light sources. Here we introduce a ternary nanocomposite: water-soluble star-like polymer/gold nanoparticles (AuNP)/temoporfin PS, which can be considered as a third-generation PDT system. AuNPs were synthesized in situ inside the polymer molecules, and the latter were then loaded with PS molecules in an aqueous solution. The applied method of synthesis allows precise control of the size and architecture of polymer nanoparticles as well as the concentration of the components. Dynamic light scattering confirmed the formation of isolated particles (120 nm diameter) with AuNPs and PS molecules incorporated inside the polymer shell. Absorption and photoluminescence spectroscopies revealed optimal concentrations of the components that can simultaneously reduce the side effects of dark toxicity and enhance singlet oxygen generation to increase cancer cell mortality. Here, we report on the optical properties of the system and detailed mechanisms of the observed enhancement of the phototherapeutic effect. Combinations of organic dyes with gold nanoparticles allow significant enhancement of the effect of ROS generation due to surface plasmonic resonance in the latter, while the application of a biocompatible star-like polymer vehicle with a dextran core and anionic polyacrylamide arms allows better local integration of the components and targeted delivery of the PS molecules to cancer cells. In this study, we demonstrate, as proof of concept, a successful application of the developed PDT system for in vitro treatment of triple-negative breast cancer cells under irradiation with a low-power LED lamp (660 nm). We consider the developed nanocomposite to be a promising PDT system for application to other types of cancer.

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Applicant Perceptions of Postinterview Communication During the 2022 to 2023 Neurosurgery Recruitment Cycle: A Cross-Sectional Survey Study.

OBJECTIVES: To evaluate and describe neurosurgery applicant perceptions of the postinterview communication (PIC) process during the US residency match. METHODS: A voluntary and anonymous postmatch web-based survey was developed and sent to 209 candidates who applied to 1 academic neurosurgery practice during the 2022-2023 recruitment cycle, approximately 1 week following match day. Survey questions focused on their perceptions of and participation behaviors with PIC and how this impacted their final rank list. RESULTS: Seventy-eight (37.3%) of the 209 candidates responded to the survey. Sixty-four (84.2%) respondents reported submitting a letter of intent (LOI) to their number 1 ranked program. Sixty-one (82%) felt pressured to send a LOI to improve their rank status, fearing that it may harm them if they did not. Fifty-four (73.0%) respondents felt pressured to send an early LOI despite not seeing the program in person to communicate interest before programs certified their rank lists. Fourteen (18.9%) respondents agreed that a second look experience impacted their rank list enough to where they regretted an early LOI. Fifty-five (76.4%) respondents disagreed that second-look attendance had no impact on their rank status with a program. Fifty (71.4%) respondents agreed that PIC causes undue stress during the match process. Sixty-one (84.7%) respondents agreed that aspects of PIC require universal guidelines. CONCLUSIONS: This is the first study to describe the perceptions of PIC and behaviors of neurosurgery applicants during the US residency match process. Standardized PIC practices may help to ensure transparency and relieve stress for applicants during the match process.

Childhood cancer incidence & survival in Aotearoa, New Zealand 2010-2019.

OBJECTIVE: To provide updated estimates of childhood cancer incidence and survival in Aotearoa, New Zealand. METHOD: Registrations for children under the age of 15 years diagnosed with cancer between 2010 and 2019 were extracted from the New Zealand Children's Cancer Registry. Cases were stratified by age, sex, prioritised ethnicity (Maori, Pacific peoples, and non-Maori) and cancer type. Age-standardised incidence rates (ASRs) per million person years and observed survival rates were calculated. RESULTS: During the study period, 1522 children were diagnosed with cancer providing an ASR of 169.1 per million per year (95 % Confidence Interval, CI: 157.0-181.2). For all childhood cancers combined, survival at 5-years was 85.6 % (95 % CI 83.7-87.3). There was a gap in 5-year survival between Maori (80.9 %, 95 % CI 76.5-84.6), Pacific peoples (82.6 %, 95 % CI 75.6-87,7) and Non-Maori (87.8 %, 95 % CI 85.6-89.7) In both adjusted and unadjusted models, this difference in survival was most marked (p < 0.05) among children who were 10-14 years of age at diagnosis. CONCLUSION: Childhood cancer incidence and survival rates in Aotearoa, New Zealand remain comparable to other high-income countries. Further research is required to understand the survival difference between ethnic groups.

A self-selected 16:8 time-restricted eating quasi-experimental intervention improves various markers of cardiovascular health in middle-age male cyclists.

OBJECTIVES: Time-restricted eating (TRE) is a dietary intervention that may offer some protection against cardiovascular disease (CVD), while also preserving performance in athletes. To date however, research on TRE in an active population has only been conducted in college-age cohorts and the effects of TRE in an older, trained population are less understood. Therefore, the aim of this study was to compare the effects of a 4-wk, 16:8 TRE intervention on markers of CVD risk in middle-age, male cyclists. METHODS: Participants (N = 12; age, 51.9 ± 8.6 y; training duration/wk, 375 ± 140 min; peak aerobic capacity, 41.8 ± 5.6 mL/kg/min) reported to the laboratory for two sessions (i.e., at baseline and post-TRE) where blood was drawn from an antecubital vein after an 8-h overnight fast. Dependent variables measured at baseline and post-TRE included insulin, cortisol, brain-derived neurotropic factor, free testosterone, thyroxine, triiodothyronine, C-reactive protein, advanced oxidative protein products, glutathione, tumor necrosis factor (TNF)-α, glucose, and a full lipid profile. RESULTS: Compared with baseline, TRE significantly lowered TNF-α (12.3 ± 3.4 versus 9.2 ± 2.4 pg/mL; P = 0.02) and glucose concentrations (93.4 ± 9.7 versus 87.5 ± 7.9 mg/dL; P = 0.01), as well as significantly elevated high-density lipoprotein cholesterol levels (45.7 ± 13.7 versus 49.2 ± 12.3 mg/dL; P = 0.04), respectively. No further significant changes were observed between the remaining variables (all P > 0.05). CONCLUSION: Overall, these data suggest that incorporating a 4-wk TRE intervention with habitual endurance training can significantly improve some markers of CVD risk and may compliment the robust health benefits derived from a regular exercise regimen.

Chronic calcific tendonitis of the rotator cuff: a systematic review and meta-analysis of randomized controlled trials comparing operative and nonoperative interventions.

BACKGROUND: Calcific tendinitis is a relatively common shoulder disorder, with 7%-17% of individuals with shoulder pain having rotator cuff calcium deposits. Several nonoperative interventions, extracorporeal shockwave therapy (ESWT) and ultrasonography-guided needling (UGN), and surgical techniques have been described to treat calcific tendonitis with satisfactory outcomes. Clinical guidelines are lacking for surgical excision in cases refractory to nonoperative treatment. Several arthroscopic and open operative techniques have been described to treat calcific tendonitis with satisfactory clinical outcomes. The purpose of this systematic review of randomized controlled trials is to compare outcomes and complications of nonoperative vs. operative management of chronic calcific tendinitis of the rotator cuff, to provide evidence-based treatment guidelines for practitioners. METHODS: EMBASE, PubMed, and OVID [MEDLINE] were searched from database inception until February 20, 2022, for randomized controlled trials reporting outcomes related to operative or nonoperative management for calcific tendonitis of the shoulder. Clinical outcomes including pain on visual analog scale (VAS), Constant-Murley Shoulder Outcome Score (CMS), and resolution of calcific deposits were evaluated. Continuous data at last follow-up was pooled into mean differences using a random effects model for meta-analysis. RESULTS: A total of 27 studies (2212 nonoperative patients and 140 operative patients) met the final inclusion criteria. Pooled mean difference in VAS for ESWT was -3.83 (95% confidence interval [CI] -5.38, -2.27); P < .001), compared to -4.83 (95% CI -5.44, -4.22; P < .001) for UGN, and -4.65 (95% CI -5.47, -3.82; P < .001) for the operative interventions. Pooled mean difference in CMS score after ESWT was 18.30 (95% CI 10.95, 25.66; P < .001) compared to 22.01 (95% CI 8.17, 35.84; P = .002) for UGN, and 38.35 (95% CI 31.68, 45.02; P < .001) for the operative interventions. Eighty-five percent of patients receiving operative and 67% of patients receiving UGN management had complete radiographic resolution of calcific deposit. CONCLUSIONS: Surgical treatment of chronic calcific tendonitis of the rotator cuff results in larger improvement in functional outcome scores and comparable pain reduction to nonoperative interventions, particularly UGN. Both operative and nonoperative treatment modalities are likely to have clinically significant improvements in function and pain, and thus it is reasonable to trial UGN and ESWT as first-line treatment. Cost-effectiveness analyses will be needed to support one treatment over the other. High-quality randomized controlled trials directly comparing nonoperative interventions to operative interventions in patients prior to failing conservative treatment are needed to establish high-quality evidence-based guidelines.

Comparison of Static and Articulating Spacers After Periprosthetic Joint Infection.

INTRODUCTION: There is no consensus on whether articulating or static spacers are superior during two-stage exchange arthroplasty for periprosthetic joint infection. We aimed to compare surgical time, need for extensile exposure, surgical costs, and treatment success for articulating and static spacers. METHODS: This was a retrospective review of 229 periprosthetic joint infections treated with two-stage exchange with a minimum of one-year follow-up. For articulating and static spacers, we compared the need for extensile exposure during reimplantation and treatment failure based on an updated definition. Surgical time and costs at both stages were also compared. Subgroup analysis was performed for total knee and hip arthroplasties. RESULTS: There was no difference in the surgical time for spacer insertion; however, articulating spacers demonstrated reduced surgical time during reimplantation (181 vs. 234 minutes, P < 0.001). In multivariate analysis, there was no difference in extensile exposures (odds ratio 2.20, P = 0.081), but treatment failure was more likely for static spacers (odds ratio 2.17, P = 0.009). Overall surgical costs for two-stage exchange were similar between groups (23,782 vs. 23,766, P = 0.495). CONCLUSION: Articulating spacers demonstrated shorter surgical times and a trend toward decreased extensile exposures during reimplantation. They also had higher treatment success rates and similar surgical costs for overall two-stage exchange.

Effects of Betaine Supplementation on Markers of Metabolic Flexibility, Body Composition, and Anaerobic Performance in Active College-Age Females.

Betaine (BET) has shown to be effective in improving body composition and performance, although research in women is lacking. This study investigated the effects of BET supplementation on markers of metabolic flexibility, body composition, and anaerobic performance in college females. Twenty-three active subjects with 21.8 ± 3.0 years of age, 66.6 ± 8.8 kg body mass, 1.6 ± 0.1 m height, and 23.2 ± 5.3% body fat performed a graded exercise test on a cycle ergometer consisting of 4 incremental, 3 min stages for collection of fat and carbohydrate oxidation rates. Three 10 s sprint tests were then completed against a resistance of 7.5% of body mass, separated by 2.5 min of recovery. The study comprised 3 phases: (a) pre-supplementation, (b) randomization to supplement for 2-weeks with either 2.4 g/day BET or placebo (parallel design), and (c) post-supplementation. Repeated-measures analysis of variance were conducted to determine interactions or main effects. There were no group differences for substrate oxidation rates (p > 0.05). Although body composition improved pre-post for both groups (p < 0.05), only the BET group experienced a significant increase in fat free mass (p < 0.01; ∼3%). Further, only the BET group experienced improvements to performance such as a higher mean power output during the final sprint (p = 0.02; ∼3%) and a lower RPE during the final stage of the graded exercise test (p = 0.02). Results from this study suggest BET supplementation may improve body composition and some markers of performance during exercise in collegiate women.

Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors.

Protein arginine methyltransferase 5 (PRMT5) is a master epigenetic regulator and an extensively validated therapeutic target in multiple cancers. Notably, PRMT5 is the only PRMT that requires an obligate cofactor, methylosome protein 50 (MEP50), to function. We developed compound 17, a novel small-molecule PRMT5:MEP50 protein-protein interaction (PPI) inhibitor, after initial virtual screen hit identification and analogue refinement. Molecular docking indicated that compound 17 targets PRMT5:MEP50 PPI by displacing the MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel. In vitro analysis indicates IC50 < 500 nM for prostate and lung cancer cells with selective, specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression, and RNA-seq analysis suggests that compound 17 may dysregulate TGF-ß signaling. Compound 17 provides a proof of concept in targeting PRMT5:MEP50 PPI, as opposed to catalytic targeting, as a novel mechanism of action and supports further preclinical development of inhibitors in this class.

Plasma protein alterations during human large vessel stroke: A controlled comparison study.

BACKGROUND: Stroke is a major cause of death and disability in the United States. Mechanical thrombectomy (MT) and tissue plasminogen activator are the current treatments for ischemic stroke, which have improved clinical outcomes. Despite these treatments, functional and cognitive deficits still occur demonstrating a need for predictive biomarkers for beneficial clinical outcomes which can be used as therapeutic targets for pharmacotherapy. The aim of this study compares the proteomic expression of systemic arterial blood collected at the time of MT to those from a matched cerebrovascular disease (CVD) control cohort. METHODS: The Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683) collects and banks arterial blood, both distal and proximal to the thrombus, from ischemic stroke subjects undergoing MT. Arterial blood from patients undergoing a diagnostic angiogram was also collected and banked as CVD controls. Changes in cardiometabolic and inflammatory proteins between stroke and CVD controls were analyzed via Olink Proteomics. RESULTS: Proteins including ARTN, TWEAK, HGF, CCL28, FGF-5, CXCL9, TRANCE and GDNF were found to be decreased in stroke subjects when compared to CVD controls. CXCL1, CCL5, OSM, GP1BA, IL6, MMP-1, and CXCL5 were increased in stroke subjects when compared to CVD controls. These proteins were also significantly correlated to stroke outcome metrics such as NIHSS, infarct volume and MoCA scoring. CONCLUSION: Overall, acute stroke patients had an increase in inflammatory proteins with a decrease in trophic proteins systemically compared to matched CVD controls. Using our CVD controls, proteins of interest were directly compared to stroke patients with the same cerebrovascular risk factors instead of statistically controlling for comorbidities. The novel methodology of matching an arterial blood CVD control group to a stroke group, as well as controlling for age and comorbid status add to the literature on prognostic stroke biomarkers, which are specific targets for future therapeutics.

Nickel-Catalyzed Tandem Ueno-Stork Cyclization: Stereoselective 1,2-Dicarbofunctionalization of Cyclic Alkenes.

A nickel-catalyzed tandem Ueno-Stork cyclization is developed to enable stereoselective 1,2-dicarbofunctionalization of cyclic alkenes and efficiently build various bicyclic products. This new protocol does not involve any toxic or difficult-to-remove tin reagent and is scalable and amenable to build all-carbon quaternary centers.

Effect of Player Position on Serum Biomarkers during Participation in a Season of Collegiate Football.

This prospective cohort study examined the relationship between a panel of four serum proteomic biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], total Tau, and neurofilament light chain polypeptide [NF-L]) in 52 players from two different cohorts of male collegiate student football athletes from two different competitive seasons of Division I National Collegiate Athletic Association Football Bowl Subdivision. This study evaluated changes in biomarker concentrations (as indicators of brain injury) over the course of the playing season (pre- and post-season) and also assessed biomarker concentrations by player position using two different published classification systems. Player positions were divided into: 1) speed (quarterbacks, running backs, halfbacks, fullbacks, wide receivers, tight ends, defensive backs, safety, and linebackers) versus non-speed (offensive and defensive linemen), and 2) "Profile 1" (low frequency/high strain magnitudes positions including quarterbacks, wide receivers, and defensive backs), "Profile 2" (mid-range impact frequency and strain positions including linebackers, running backs, and tight ends), and "Profile 3" (high frequency/low strains positions including defensive and offensive linemen). There were significant increases in GFAP 39.3 to 45.6 pg/mL and NF-L 3.5 to 5.4 pg/mL over the course of the season (p < 0.001) despite only five players being diagnosed with concussion. UCH-L1 decreased significantly, and Tau was not significantly different. In both the pre- and post-season blood samples Tau and NF-L concentrations were significantly higher in speed versus non-speed positions. Concentrations of GFAP, Tau, and NF-L increased incrementally from "Profile 3," to "Profile 2" to "Profile 1" in the post-season. UCH-L1 did not. GFAP increased (by Profiles 3, 2, 1) from 42.4 to 49.6 to 78.2, respectively (p = 0.051). Tau increased from 0.37 to 0.61 to 0.67, respectively (p = 0.024). NF-L increased from 3.5 to 4.9 to 8.2, respectively (p < 0.001). Although GFAP and Tau showed similar patterns of elevations by profile in the pre-season samples they were not statistically significant. Only NF-L showed significant differences between profiles 2.7 to 3.1 to 4.2 in the pre-season (p = 0.042). GFAP, Tau, and NF-L concentrations were significantly associated with different playing positions with the highest concentrations in speed and "Profile 1" positions and the lowest concentrations were in non-speed and "Profile 3" positions. Blood-based biomarkers (GFAP, Tau, NF-L) provide an additional layer of injury quantification that could contribute to a better understanding of the risks of playing different positions.

Impact of Time Restricted Feeding on Markers of Cardiometabolic Health and Oxidative Stress in Resistance-Trained Firefighters.

ABSTRACT: McAllister, MJ, Gonzalez, AE, and Waldman, HS. Impact of time restricted feeding on markers of cardiometabolic health and oxidative stress in resistance-trained firefighters. J Strength Cond Res 36(9): 2515-2522, 2022-Firefighters are often exposed to numerous occupational stressors that cause inflammation, oxidative stress (OS), and elevated risk for developing cardiometabolic disease. Time-restricted feeding (TRF) has been shown to result in favorable changes in markers of inflammation and cardiometabolic health. This study investigated the impact of a 6-week TRF intervention (14:10; fasting:feeding) in resistance-trained firefighters. Blood was analyzed for several markers of inflammation, OS, and cardiometabolic health: insulin, ghrelin, leptin, glucagon, adiponectin, resistin, advanced glycated end products (AGE), advanced oxidation protein products, total nitrite-nitrate levels, tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-10, as well as glucose and lipid levels. A graded exercise test was also conducted before and after the TRF intervention, and substrate oxidation rates were calculated and compared before and after the intervention. Comparisons pre and post TRF were determined with dependent t -tests. Time-restricted feeding resulted in significant reductions in advanced oxidation protein products (∼31%) and AGEs (∼25%); however, no other changes were found. These findings suggest that TRF may be a nutrition intervention aimed at improving some select markers of cardiometabolic health in firefighters, namely, by the reductions in advanced oxidation protein products and AGEs.

Physical activity and aging research: opportunities abound.

Aging is associated with large between-subjects variability in motor function among older adults, which can compromise identifying the mechanisms for age-related reductions in motor performance. This variability is in part explained by differences among older adults in habitual physical activity. Quantifying and accounting for physical activity levels of the participants in aging studies will help differentiate those changes in motor function associated with biological aging rather than those induced by inactivity. Novelty: Quantification of physical activity levels in studies with older participants will help differentiate the effects of aging rather than physical inactivity.

Surgical repair of a meningoencephalocoele in a kakapo (Strigops habroptilus).

CASE HISTORY: A kakapo (Strigops habroptilus) chick hatched on an off-shore island of New Zealand with a small white mass protruding through the cranial skin of the head. The chick's growth followed a normal pattern for kakapo but at 3 weeks of age the cranium mass was non-reducible and fixed in place and the chick was removed from the island for diagnostic imaging and hand-rearing. CLINICAL FINDINGS AND TREATMENT: A computed tomography (CT) examination revealed a full-thickness circular defect in the central cranium with suspected herniation of brain and dura. Surgery was performed at 37 days of age, and the herniated dura was dissected from the open fontanelle. Attempts to reduce the herniated tissue were unsuccessful, so the herniated dura and cortex were clamped and resected. The dura was closed and the periosteum of the skull was scarified and monofilament polypropylene mesh was secured tautly over the fontanelle. The mesh graft was infused with autologous bone marrow harvested from the ulna in an attempt to stimulate osteogenesis in the mesh repair. The skin flap was then closed. Post-operative recovery and healing were without complication. A CT examination 4 weeks after surgery showed no recurrence of the hernia, and a composite of mesh and scar over the open fontanelle which had reduced in diameter. The chick was released back onto an off-shore island with a radio transmitter and it continues to be monitored regularly. PATHOLOGICAL FINDINGS: The tissue resected at surgery consisted of a cylindrical core of cerebral parenchyma overlain by a mildly hyperplastic epidermis, and large amounts of oedematous fibrovascular tissue arising from the leptomeninges. DIAGNOSIS: Rostral parietal meningoencephalocoele. CLINICAL RELEVANCE: This is the first report of successful surgical resolution of a meningoencephalocoele in any bird. Techniques from human neurosurgery were adapted for the unique anatomical features of the avian skull. The risks of the procedure included increased intra-cranial pressure resulting in anaesthetic complications or death, cerebrospinal fluid leakage, meningitis or recurrence of the meningoencephalocoele. In the longer term, there was a risk of developmental deficits in cognition or behaviour. None of these complications eventuated in the short to medium term, probably due to the small size of the meningoencephalocoele.

Defining recovery trajectories after shoulder arthroplasty: a latent class analysis of patient-reported outcomes.

BACKGROUND: Patients undergoing total shoulder arthroplasty (TSA) can have varying levels of improvement after surgery. As patients typically demonstrate a nonlinear recovery trajectory, advanced analysis investigating the degrees of variation in outcomes is needed. Latent class analysis (LCA) is a mixed and multilevel model that estimates random slope variance to evaluate heterogeneity in outcome patterns among patient subgroups and can be used to outline differing recovery trajectories. The purpose of this study was to determine recovery trajectory patterns after TSA and to identify factors that predict a given trajectory. METHODS: Data from a prospectively collected single institutional database of patients undergoing anatomic and reverse TSA were utilized. Patients were included if they had American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores preoperatively, as well as postoperative scores at 6 weeks, 6 months, 1 year, and 2 years. Patients were excluded if they underwent a revision procedure or hemiarthroplasty or had prior infection. LCA was used to subdivide the patient cohort into subclasses based on postoperative recovery trajectory. This was performed for all patients as well as anatomic TSA and reverse TSA as separate groups. Unpaired Student t tests, analysis of variance, and Fisher exact test were used to compare classes based on factors including age, body mass index, sex, preoperative diagnosis, and type of arthroplasty. RESULTS: A total of 244 TSAs were included in the final analysis, comprising 89 anatomic TSA and 155 reverse TSA. In the combined group, LCA modeling revealed 3 patterns for recovery: Resistant Responders had low baseline scores (ASES < 30) and poor final results (ASES < 50), Steady Progressors had moderate baseline scores (ASES 30-50) with moderate final results (ASES 50-75), and High Performers had moderate baseline scores (ASES > 50) with excellent final results (ASES > 75). For anatomic TSA, we identified Delayed Responders with moderate baseline scores and a delayed response before ultimately achieving moderate final results, Steady Progressors with moderate baseline scores and a steady progression to achieve moderate final results, and High Performers who had moderate baseline scores and excellent final results. For reverse TSA, we identified Late Regressors with low baseline scores and poor final results, Steady Progressors with moderate baseline scores and moderate final results, and High Performers with moderate baseline scores and excellent final results. CONCLUSIONS: Patients recover in a heterogenous manner following TSA. Through LCA, we identified different recovery trajectories for patients undergoing anatomic TSA and reverse TSA.

Prebiotics and Community Composition Influence Gas Production of the Human Gut Microbiota.

Prebiotics confer benefits to human health, often by promoting the growth of gut bacteria that produce metabolites valuable to the human body, such as short-chain fatty acids (SCFAs). While prebiotic selection has strongly focused on maximizing the production of SCFAs, less attention has been paid to gases, a by-product of SCFA production that also has physiological effects on the human body. Here, we investigate how the content and volume of gas production by human gut microbiota are affected by the chemical composition of the prebiotic and the community composition of the microbiota. We first constructed a linear system model based on mass and electron balance and compared the theoretical product ranges of two prebiotics, inulin and pectin. Modeling shows that pectin is more restricted in product space, with less potential for H2 but more potential for CO2 production. An ex vivo experimental system showed pectin degradation produced significantly less H2 than inulin, but CO2 production fell outside the theoretical product range, suggesting fermentation of fecal debris. Microbial community composition also impacted results: methane production was dependent on the presence of Methanobacteria, while interindividual differences in H2 production during inulin degradation were driven by a Lachnospiraceae taxon. Overall, these results suggest that both the chemistry of the prebiotic and the composition of the microbiota are relevant to gas production. Metabolic processes that are relatively prevalent in the microbiome, such as H2 production, will depend more on substrate, while rare metabolisms such as methanogenesis depend more strongly on microbiome composition.IMPORTANCE Prebiotic fermentation in the gut often leads to the coproduction of short-chain fatty acids (SCFAs) and gases. While excess gas production can be a potential problem for those with functional gut disorders, gas production is rarely considered during prebiotic design. In this study, we combined the use of theoretical models and an ex vivo experimental platform to illustrate that both the chemical composition of the prebiotic and the community composition of the human gut microbiota can affect the volume and content of gas production during prebiotic fermentation. Specifically, more prevalent metabolic processes such as hydrogen production were strongly affected by the oxidation state of the probiotic, while rare metabolisms such as methane production were less affected by the chemical nature of the substrate and entirely dependent on the presence of Methanobacteria in the microbiota.

Conventional and nano-copper pesticides are equally toxic to the estuarine amphipod Leptocheirus plumulosus.

Modern nano-engineered pesticides have great promise for agriculture due to their extended, low dose release profiles that are intended to increase effectiveness but reduce environmental harm. Whether nanopesticides, including copper (Cu) formulations, cause reduced levels of toxicity to non-target aquatic organisms is unclear but important to assess. Predicting how aquatic species respond to incidental exposure to Cu-based nanopesticides is challenging because of the expected very low concentrations in the environment, and the two forms of exposure that may occur, namely to Cu ions and Cu nanoparticles. We conducted Cu speciation, tissue uptake, and 7-day toxicity laboratory experiments to test how a model estuarine organism, the amphipod Leptocheirus plumulosus, responded to two popular Cu-based nanopesticides, CuPRO and Kocide, and conventional CuCl2. Exposure concentrations ranged from 0 to 2.5 ppm, which were similar to those found in estuarine water located downstream of agricultural fields. Cu dissolution rates were much slower for the nanopesticides than the ionic formula, and Cu body burden in amphipods increased approximately linearly with the nominal exposure concentration. Amphipod survival declined in a normal dose-response manner with no difference among Cu formulations. Growth and movement rates after 7 days revealed no difference among exposure levels when analyzed with conventional statistical methods. By contrast, analysis of respiration rates, inferred from biomass measurements, with a bioenergetic toxicodynamic model indicated potential for population-level effects of exposure to very low-levels of the two nanopesticides, as well as the control contaminant CuCl2. Our results indicate that toxicity assessment of environmental trace pollutant concentrations may go undetected with traditional ecotoxicological tests. We present a process integrating toxicity test results and toxicodynamic modeling that can improve our capacity to detect and predict environmental impacts of very low levels of nanomaterials released into the environment.