Impact of comorbidities on immediate post-operative complications in oral cavity free flap patients.

PURPOSE: To examine the relationship between comorbidities and the development of immediate post-operative complications in patients undergoing oral cavity composite resection (OCCR) with free flap (FF) reconstruction. MATERIALS AND METHODS: Retrospective analysis was completed on all consecutive OCCRs with FF reconstruction performed at a single quaternary care facility between 1999 and 2020. Comorbidities, immediate post-operative complications, patient demographics, and tumor characteristics were collected. Odds ratios (OR) with 95 % confidence intervals were calculated for associations between comorbidities and immediate post-operative complications. RESULTS: 320 patients who underwent OCCR with FF reconstruction were included. One hundred twenty-one (37.8 %) patients developed a post-operative complication during their initial hospital admission. The most common complications were non-pneumonia cardiopulmonary events (14.1 %), pneumonia (9.4 %), and wound infection (8.4 %). Other complications included flap compromise, bleeding, and fistula. On multivariate analysis, patients without comorbid conditions were less likely to develop a post-operative complication (OR 0.64; 0.41-0.98). Atrial fibrillation (OR 2.94; 1.17-7.39) and cerebrovascular disease (OR 2.28; 1.08-4.84) were associated with increased odds of developing any complications. Furthermore, cerebrovascular disease (OR: 2.33; 1.04-5.39) and peripheral vascular disease (OR: 2.7; 1.2-6.08) were independently associated with pneumonia. CONCLUSION: In this retrospective review of patients undergoing OCCR with FF reconstruction for oral cavity SCC, lack of identifiable comorbidities appeared to be protective for post-operative complications while atrial fibrillation and cerebrovascular disease were associated with increased odds of any complication. Pre-existing vascular disease was also associated with an increased risk of pneumonia.

Acute manganese treatment restores defective autophagic cargo loading in Huntington's disease cell lines.

The molecular etiology linking the pathogenic mutations in the Huntingtin (Htt) gene with Huntington's disease (HD) is unknown. Prior work suggests a role for Htt in neuronal autophagic function and mutant HTT protein disrupts autophagic cargo loading. Reductions in the bioavailability of the essential metal manganese (Mn) are seen in models of HD. Excess cellular Mn impacts autophagic function, but the target and molecular basis of these changes are unknown. Thus, we sought to determine if changes in cellular Mn status impact autophagic processes in a wild-type or mutant Htt-dependent manner. We report that the HD genotype is associated with reduced Mn-induced autophagy and that acute Mn exposure increases autophagosome induction/formation. To determine if a deficit in bioavailable Mn is mechanistically linked to the autophagy-related HD cellular phenotypes, we examined autophagosomes by electron microscopy. We observed that a 24 h 100 uM Mn restoration treatment protocol attenuated an established HD 'cargo-recognition failure' in the STHdh HD model cells by increasing the percentage of filled autophagosomes. Mn restoration had no effect on HTT aggregate number, but a 72 h co-treatment with chloroquine (CQ) in GFP-72Q-expressing HEK293 cells increased the number of visible aggregates in a dose-dependent manner. As CQ prevents autophagic degradation this indicates that Mn restoration in HD cell models facilitates incorporation of aggregates into autophagosomes. Together, these findings suggest that defective Mn homeostasis in HD models is upstream of the impaired autophagic flux and provide proof-of-principle support for increasing bioavailable Mn in HD to restore autophagic function and promote aggregate clearance.

Cardiometabolic Improvements After Metabolic Surgery and Related Presurgery Factors.

Context: Metabolic surgery remains the most effective and durable treatment for severe obesity and related metabolic diseases. Objective: We examined cardiometabolic improvements after metabolic surgery and associated presurgery demographic and clinical factors in a large multiracial cohort. Methods: Included were 7804 patients (20-79 years) undergoing first-time metabolic surgery at Vanderbilt University Medical Center from 1999 to 2022. Pre- and 1-year postsurgery cardiometabolic profiles were extracted from medical records, including body mass index (BMI), blood pressure, blood lipids, glucose, and hemoglobin A1c. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated per American College of Cardiology/American Heart Association equations. Pre- to postsurgery cardiometabolic profiles were compared by paired t-test, and associated factors were identified by multivariable linear and logistic regression. Results: Among 7804 patients, most were women and White, while 1618 were men and 1271 were Black; median age and BMI were 45 years [interquartile range (IQR): 37-53] and 46.4 kg/m2 (IQR: 42.1-52.4). At 1-year postsurgery, patients showed significant decreases in systolic blood pressure (10.5 [95% confidence interval: 10.1, 10.9] mmHg), total cholesterol (13.5 [10.3, 16.7] mg/dL), glucose (13.6 [12.9, 14.4] mg/dL), hemoglobin A1c (1.13% [1.06, 1.20]), and 10-year ASCVD risk (absolute reduction: 1.58% [1.22, 1.94]; relative reduction: 34.4% [29.4, 39.3]); all P < .0001. Older, male, or Black patients showed less reduction in 10-year ASCVD risk and lower odds of diabetes/hypertension/dyslipidemia remission than younger, female, or White patients. Patients with a history of diabetes, hypertension, dyslipidemia, or cardiovascular disease showed less cardiometabolic improvements than those without. Results were similar with or without further adjusting for weight loss and largely sustained at 2-year postsurgery. Conclusion: Metabolic surgery results in significant cardiometabolic improvements, particularly among younger, female, or White patients and those without comorbidities.

Patient-Centered Goals After Lumbar Spine Surgery: A Secondary Analysis of Cognitive-Behavioral-Based Physical Therapy Outcomes From a Randomized Controlled Trial.

OBJECTIVE: The purpose of this study was to examine the association between goal attainment and patient-reported outcomes in patients who engaged in a 6-session, telephone-based, cognitive-behavioral-based physical therapy (CBPT) intervention after spine surgery. METHODS: In this secondary analysis of a randomized trial, data from 112 participants (mean age = 63.3 [SD = 11.2] years; 57 [51%] women) who attended at least 2 CBPT sessions (median = 6 [range = 2-6]) were examined. At each session, participants set weekly goals and used goal attainment scaling (GAS) to report goal attainment from the previous session. The number and type of goals and percentage of goals met were tracked. An individual GAS t score was computed across sessions. Participants were categorized based on goals met as expected (GAS t score ≥ 50) or goals not met as expected (GAS t score < 50). Six- and 12-month outcomes included disability (Oswestry Disability Index), physical and mental health (12-Item Short-Form Health Survey), physical function (Patient-Reported Outcomes Measurement Information System), pain interference (Patient-Reported Outcomes Measurement Information System), and back and leg pain intensity (numeric rating scale). Outcome differences over time between groups were examined with mixed-effects regression. RESULTS: Participants set a median of 3 goals (range = 1-6) at each session. The most common goal categories were recreational/physical activity (36%), adopting a CBPT strategy (28%), exercising (11%), and performing activities of daily living (11%). Forty-eight participants (43%) met their goals as expected. Participants who met their goals as expected had greater physical function improvement at 6 months (estimate = 3.7; 95% CI = 1.0 to 6.5) and 12 months (estimate = 2.8; 95% CI = 0.04 to 5.6). No other outcome differences were noted. CONCLUSIONS: Goal attainment within a CBPT program was associated with 6- and 12-month improvements in postoperative physical functioning. IMPACT: This study highlights goal attainment as an important rehabilitation component related to physical function recovery after spine surgery.

Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.

Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

Physical Performance Tests Provide Distinct Information in Both Predicting and Assessing Patient-Reported Outcomes Following Lumbar Spine Surgery.

STUDY DESIGN: Secondary analysis of randomized controlled trial data. OBJECTIVE: The aim of this study was to examine whether preoperative physical performance is an independent predictor of patient-reported disability and pain at 12 months after lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Patient-reported outcome measures (PROMs) are commonly used to assess clinical improvement after lumbar spine surgery. However, there is evidence in the orthopedic literature to suggest that PROMs should be supplemented with physical performance tests to accurately evaluate long-term outcomes. METHODS: A total of 248 patients undergoing surgery for degenerative lumbar spine conditions were recruited from two institutions. Physical performance tests (5-Chair Stand and Timed Up and Go) and PROMs of disability (Oswestry Disability Index: ODI) and back and leg pain (Brief Pain Inventory) were assessed preoperatively and at 12 months after surgery. RESULTS: Physical performance tests and PROMs significantly improved over 12 months following lumbar spine surgery (P < 0.01). Weak correlations were found between physical performance tests and disability and pain (ρ = 0.15 to 0.32, P < 0.05). Multivariable regression analyses controlling for age, education, preoperative outcome score, fusion, previous spine surgery, depressive symptoms, and randomization group found that preoperative 5-Chair Stand test was significantly associated with disability and back pain at 12-month follow-up. Each additional 10 seconds needed to complete the 5-Chair Stand test were associated with six-point increase in ODI (P = 0.047) and one-point increase in back pain (P = 0.028) scores. The physical performance tests identified an additional 14% to 19% of patients as achieving clinical improvement that were not captured by disability or pain questionnaires. CONCLUSION: Results indicate that physical performance tests may provide distinct information in both predicting and assessing clinical outcomes in patients undergoing lumbar spine surgery. Our findings suggest that the 5-Chair Stand test may be a useful test to include within a comprehensive risk assessment before surgery and as an outcome measure at long-term follow-up. LEVEL OF EVIDENCE: 3.

Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line.

In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdhQ7/Q7, a concentration of KU55933 far exceeding its IC50 for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC50s for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC50s for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5µM) or LY294002(7µM), supporting PI3K's upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line.