Publications by Year: 2026

OBJECTIVE: The Wound, Ischaemia, and foot Infection (WIfI) staging system for chronic limb threatening ischaemia (CLTI) predicts outcomes after revascularisation, but individual components of WIfI have not been evaluated. This study was designed to evaluate changes in WIfI ischaemia grade as a predictor of major amputation after open and endovascular revascularisation in the Best Endovascular versus Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial.

METHODS: A secondary analysis was conducted of patients with CLTI randomised to surgical bypass or endovascular therapy as part of the BEST-CLI trial with available WIfI ischaemia scores at baseline and one month post-procedure. Risk adjusted Cox regression models were used to assess the effect of change in WIfI ischaemia grade on the rate of major amputation, while controlling for potential confounders.

RESULTS: Among 785 patients with CLTI who underwent revascularisation and were alive at one year, 629 (80.1%) achieved improvement in their WIfI ischaemia grade within 30 days after undergoing surgical and or endovascular interventions. Patients with improved ischaemia grade were younger and were more likely to smoke, have lower baseline ankle brachial indices, and have a worse overall WIfI stage at the time of revascularisation compared with patients with worsening or no improvement in limb perfusion (p < .050 for all comparisons). The major amputation incidence at one year was 14% and was increased among those with higher baseline WIfI stage (3/4 vs. 1/2) and with unchanged or worse WIfI ischaemia grade after revascularisation. Patients with improved WIfI ischaemia grade early after revascularisation had a statistically significantly lower likelihood of major amputation at one year (hazard ratio 0.27, 95% confidence interval 0.18 - 0.41; p < .001) after risk adjustment.

CONCLUSION: Achieving early improvement in limb perfusion based on WIfI ischaemia grade predicts major amputation following revascularisation independent of other risk factors. Changes in ischaemia grade after interventions should be closely monitored to determine the adequacy of revascularisation, risk of CLTI progression, and need for major amputation.

OBJECTIVES: Chronic ankle instability (CAI) is not only associated with those peripheral neuromuscular impairments but also with the functional changes in the supraspinal regions. Nevertheless, the characteristics of the cortical elements in CAI remain poorly understood. This study aimed to examine the dynamics of resting-state BOLD and ankle-related functional performance in recreational athletes with CAI, as well as explore the associations between neural fluctuations and ankle functional performance.

METHODS: This cross-sectional design study recruited 82 participants, comprising 41 active recreational athletes with CAI (CAI group) and 41 active recreational athletes without CAI (Control group). Data on joint position sense, one-leg standing balance, and resting-state fMRI were collected from both groups. A two-sample t-test was used to determine the difference in amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) between the two groups. Linear regression analysis evaluated the associations between functional performance and dynamics of resting-state BOLD in the two groups.

RESULTS: Compared with control group, athletes with CAI had lower ALFF values in the bilateral supplementary motor area and reduced ReHo values in the right precentral gyrus and postcentral gyrus, while higher ALFF and ReHo values in the right cerebellum. Moreover, athletes with CAI had lower fALFF values in the left superior frontal gyrus and the right superior frontal gyrus than controls. The sway velocities of center of pressure in the one-leg standing with eyes closed condition were negatively associated with ALFF and ReHo values in the right cerebellum cluster.

CONCLUSIONS: Athletes with severely right-sided CAI had different neural fluctuations compared with controls. Elevated ALFF and ReHo values in the right cerebellum cluster were associated with balance control, suggesting that high ipsilateral cerebellar activity and homogeneity may compensate for balance control in athletes with CAI.

Expanding the number of clinically approved choices for osteoanabolic therapy represents the next hurdle on the osteoporosis treatment horizon. The WNT pathway is involved in stimulating new bone formation, and the most recent FDA-approved anabolic therapy-sclerostin neutralizing antibody-works by stimulating the WNT pathway in bone. The challenge with all current osteoanabolic therapies is the short treatment window in which they are efficacious. One strategy to dealing with this limited anabolic window is to further maximize bone formation during the window, using combination therapy. For example, simultaneous pharmacological or genetic inhibition of the WNT antagonists sclerostin and DKK1 potentiate the already strong effects of sclerostin inhibition alone, particularly in cancellous bone. Considerable interest has emerged regarding other candidates that might be co-inhibited along with sclerostin to potentiate its effects in bone, with specific action on cortical bone. In this communication, partnering sclerostin inhibition with the inhibition of another secreted WNT antagonist, NOTUM, is explored. NOTUM is a secreted WNT deacylase that inactivates WNT ligands and has preferential effects on cortical bone. To evaluate combination therapy involving sclerostin/NOTUM inhibition, double knockout mice for Sost and Notum (Sost-/-;Notum-/-) were generated and compared to single knockouts and WT controls. Further experiments were conducted using pharmacologic inhibitors, rather than genomic mutations, for sclerostin (sclerostin neutralizing antibody) and a small molecule inhibitor of NOTUM (LP-922056). Each experiment included evaluation by DXA-derived radiography, μCT, biomechanical testing and bone dynamic histomorphometry. Deletion of Notum alone had mild cortical effects but co-deletion of Sost and Notum improved cortical and some cancellous parameters significantly beyond Sost-/- mice. Co-inhibition of the protein products with antibody/small molecule were less synergistic, with only a small cortical effect, particularly in younger mice. Taken together, the results suggest the potential to improve efficacy of sclerostin inhibition using NOTUM inhibition is promising, but development of additional NOTUM inhibiting tools and optimization of current tools might be necessary to strengthen the partnership.

BACKGROUND CONTEXT: Failure to accurately predict length of stay (LOS) and discharge disposition in the setting of spine fusion episodes of care can have substantial impact on patient care and resource allocation. Mandatory upcoming bundled payment models for spinal fusion will focus solely on traditional Medicare (TM) beneficiaries; however, less is known about episode of care metrics in this subgroup compared with patients in other insurance classes.

PURPOSE: We sought to compare time-based trends among TM and Medicare Advantage (MA) in (1) LOS and home discharge, (2) readmission and emergency department visits, and (3) prevalence of medical comorbidities and social vulnerability.

STUDY DESIGN/SETTING: The Epic Cosmos dataset (comprising longitudinal records for over 300 million patients from over 1,700 hospitals) was used for this retrospective cohort study.

PATIENT SAMPLE: Episodes of care containing single-level lumbar fusions performed in adults between January 1st, 2016, to December 31st, 2024.

OUTCOME MEASURES: The primary outcome was LOS in days. Secondary outcomes included rates of discharge home, 30-day readmission rates, and 30-day emergency department visits.

METHODS: Time-based trends and differences among primary insurance classes in LOS were assessed via a negative binomial regression model that included a 2-way interaction between primary insurance class and time, with adjustment for sociodemographic, clinical, and institutional covariates. Primary insurance classes included TM, MA, Commercial, and Medicaid. Post-hoc tests were adjusted for multiple comparisons via the Holm-Bonferroni method.

RESULTS: Among 126,304 spinal fusion episodes, LOS for TM patients decreased at an adjusted rate of 1.1% ([95% CI 0.4, 1.7], p<.001) faster per year compared with MA (TM: 2016-2024 unadjusted LOS 3.37-2.54; MA 3.53-3.12 days). Between 2016 and 2024, TM and MA both saw increases in home discharge, however by 2024 MA had higher adjusted rates of home discharge (unadjusted 2016-2024 raw rates TM 77.2%-86.8%; MA 76.0%-87.9%; adjusted 2024 rate 33% higher than TM [95% CI 18%, 51%, p<.001]). Over the study period, the MA cohort changed to become the group with the greatest number of Hierarchical Conditional Categories (2016 to 2024, 0.45-0.77; 15% increase compared to TM [10%, 22%, p<.001]). At the end of the study period, TM and Commercial had similar social vulnerability index (SVI) (unadjusted 50th vs. 50th percentile, adjusted p>.05) and MA and Medicaid had similar SVI (unadjusted 56th and 63rd percentile, adjusted p>.05). There were no differences in time-based trends between groups for readmission rates and emergency department visits.

CONCLUSIONS: We observed longer LOS and increased home discharge rates with MA compared to TM over time without apparent improvements in readmission rates or emergency department visits. TM now has LOS and SVI approximating the commercially insured. The changes demonstrated in this study underscore widening gaps between TM and MA beneficiaries, despite the fact that upcoming mandatory bundled payment models will focus solely on TM beneficiaries. As MA becomes the dominant insurance class in the geriatric population, spine surgeons should be aware of patterns specific to MA patients, such as prolonged LOS and increasing denials for postacute care. Clinicians play a key role in setting patient expectations at the point-of-care and presurgical discharge planning may be important for certain subgroups.

LEVEL OF EVIDENCE: III.

BACKGROUND: Age remains an important factor in decision-making and operative outcomes in patients with chronic limb-threatening ischemia (CLTI). Prior studies have used arbitrary age categories. Our aim is to identify an evidence-based age cutoff to differentiate patient outcomes between open and endovascular therapy (ET) in Best Endovascular vs Best Surgical Therapy in Patients with CLTI.

METHODS: The Best Endovascular vs Best Surgical Therapy in Patients with CLTI trial dataset was queried to include all patients who underwent open surgical bypass or ET. Patient age on the day of the index revascularization was identified as a continuous variable. Restricted cubic splines were generated to examine the moderating effect of age on the outcomes of procedure type in cohort 1 (bypass with single-segment saphenous vein [SSGSV] vs ET) and cohort 2 (bypass with an alternative conduit vs ET). Four separate spline models for each cohort were generated corresponding to our outcomes of interest: major amputation (above ankle), all-cause mortality, major adverse limb events (MALE defined as above-ankle amputation or major reintervention), and MALE/death.

RESULTS: Our study included 1780 patients with a mean age of 67.2 ± 9.7 years (range, 27.9-94.1 years). In cohort 1, the MALE/death spline model showed a lower hazard for SSGSV compared with ET across all ages; however, the upper limit of the hazard ratio confidence interval approaches 1.0 at age 72. There was no age inflection point identified with regard to mortality. Amputation risk was lower with SSGSV compared with ET up to around the age of 57, beyond which there was no difference between the two treatment modalities. Furthermore, the risk of MALE was consistently lower with SSGSV for patients up to age 83. In contrast, in cohort 2, age was not found to be an effect modifier in revascularization outcomes or survival among patients undergoing bypass with an alternative conduit compared with ET.

CONCLUSIONS: In this study, we confirmed that bypass with SSGSV was associated with superior MALE-free survival compared with ET up to the age of 72, beyond which there was no significant difference in outcomes between the two strategies. MALE was significantly higher for ET for patients up to age 83. Patient age was not found to favor one revascularization method over the other if the bypass was performed using an alternative conduit. Further studies are needed to compare the effectiveness of revascularization strategies among older patients with CLTI.

INTRODUCTION: Nature experienced with peers may mitigate the harmful outcomes of loneliness on health and wellbeing. The H2020 RECETAS 'Friends in Nature (FiN)-Helsinki' group intervention for lonely older adults in Helsinki assisted living facilities (ALFs) aimed to investigate the effects on participants' loneliness and health-related quality of life (HRQoL). We also examined factors influencing effects between the intervention and the outcomes.

METHODS: Lonely participants were recruited from 22 ALFs in Helsinki area, Finland and randomised into two groups: (i) nature-based group intervention once a week for 9 weeks (n = 162) and (ii) usual care (n = 157). Loneliness (modified De Jong Gierveld Loneliness Scale = mDJGLS) and HRQoL (15D) were assessed as the primary outcomes at baseline, 3, 6 and 12 months.

RESULTS: Most participants (mean age 83 years, 73% women) were living with frailty (66%) and had dementia (55%). Whilst loneliness was reduced in the intervention group at three months (mean change -2.2 points [95% confidence interval (CI) -3.5 to -0.9] in mDJGLS, it remained at baseline level amongst controls (mean change -0.1 (95% CI -1.4 to 0.9); P = .025 between groups). During the 6- and 12-month follow-ups the difference was reduced. No difference emerged between groups in changes of HRQoL according to the 15D. However, the 'sleep' dimension in 15D improved in the intervention relative to controls during the 12-month follow-up. Frequent attendance in group sessions and extended time spent outdoors affected effects on both HRQoL and loneliness. High self-efficacy at baseline influenced effect on both HRQoL and mDJGLS. Being male, <85 years old, non-frail, having Mini-Mental-State Examination >20 and exhibiting a high Nature Connection Index at baseline influenced the magnitude of effect in reducing loneliness.

CONCLUSIONS: Group intervention with nature contacts had favourable effects on loneliness and sleep amongst physically and cognitively frail, lonely older adults in ALFs.

TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT05507684. Registration 19/08/2022.

BACKGROUND: Type I interferons (IFN-I) and type II interferon (IFN-γ) contribute to the pathogenesis of inflammatory diseases, but measurement of these cytokines remains challenging in the clinical setting.

OBJECTIVE: We aimed to develop a clinical test that rapidly captures the activity of IFN-I and IFN-γ.

METHODS: We compared RNA sequencing data from healthy controls and patients with macrophage activation syndrome, multisystem inflammatory syndrome in children, and systemic lupus erythematosus to evaluate biomarkers of IFN-I and IFN-γ signaling. We utilized a flow cytometry assay to measure interferon-inducible markers. The findings were verified by a clinical laboratory that independently developed and validated this assay.

RESULTS: We identified CD274 (programmed death ligand 1, or PD-L1) as a biomarker of IFN-γ signaling and confirmed CD169 (SIGLEC-1) as a readout of IFN-I activity. We utilized a flow cytometry assay to quantify CD169 and CD274 expression on monocytes and demonstrated the validity of this method for rapid screening of interferon dysregulation in patients with various inflammatory diseases including, among others, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, multisystem inflammatory syndrome in children, systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis. We further demonstrated the utility of this test for assessment of interferon dysregulation in monogenic inflammatory diseases and for efficacy monitoring of medications that target the interferon pathways including Janus kinase inhibitors, emapalumab, and anifrolumab. Finally, we outlined the steps of assay validation and clinical implementation, and we showed reproducible findings in a clinical laboratory.

CONCLUSION: Flow cytometry analysis of CD169 and CD274 is an effective method to rapidly quantify IFN-I and IFN-γ activity in the clinical setting.

Mitoxantrone (MIT) is a chemotherapeutic drug widely used for its DNA intercalation and inhibition of topoisomerase. In this work, we show that MIT also affects cytoplasmic RNA-ribosome organization. In human cancer cells, MIT induced stress granules (SGs) that contained large ribosomal subunit proteins, including eL8, together with polyadenylated mRNA. These MIT-induced SGs were different from arsenite-induced SGs: they formed without eIF2α phosphorylation, mTOR inhibition, or 4E-BP1 activity, and they remained stable in the presence of cycloheximide and after drug withdrawal. In vitro assays further demonstrated that MIT promotes ribosome aggregation in a concentration- and salt-dependent manner. Taken together, our results identify a distinct type of ribosome-enriched SGs that form through RNA-ribosome condensation rather than classical translational stress pathways. This mechanism provides a direct example of how a clinically used drug can reorganize cytoplasmic RNA-protein complexes, with possible consequences for mRNA regulation, cancer therapy, and neurodegenerative disease.

There is no consensus for identifying ideal candidates for extracorporeal membrane oxygenation (ECMO), a life-sustaining technology that can supply oxygenated blood to a patient whose heart and/or lungs are not properly functioning. Without clear and standardized guidelines, the decision about who to cannulate often falls upon one or several clinicians who weigh the procedure's risks and benefits. Limited data, and therefore substantial clinical judgment, guides ECMO candidacy determination, rendering the process particularly susceptible to heuristic-based decision-making and cognitive biases resulting from mental shortcuts. This can lead to candidates being inappropriately accepted or declined for ECMO and suboptimal allocation of a limited resource. This article presents a hypothetical case based on real clinical scenarios highlighting the impact that cognitive biases may play in ECMO candidacy and discussing their potential harms. We argue that ECMO candidacy determination is especially vulnerable to cognitive biases and offer several ways to mitigate their influence on candidacy selection. Our aim was to stimulate the recognition and mitigation of cognitive bias in ECMO deliberations as one step toward the standardization of ECMO candidacy determinations, with the goal of achieving more equitable and effective care for patients who would most benefit from this technology.