Integrated Genome-Wide Analysis of DNA Methylation and Gene Expression in the Hippocampi of 5xFAD Alzheimer's Disease Mouse Model.

BACKGROUND: DNA methylation forms 5-methylcytosine and its regulation in the hippocampus is critical for learning and memory. Indeed, dysregulation of DNA methylation is associated with neurological diseases. Alzheimer's disease (AD) is the predominant of dementia and a neurodegenerative disorder. METHODS: We examined the learning and memory function in 3- and 9-month-old wild-type and 5xfamiliar Alzheimer's disease (5xFAD) transgenic mice by performing the object recognition memory and Y-maze tests, and identified the hippocampal amyloid beta burden. To investigate the epigenetically regulated genes involved in the development or neuropathology of AD, we performed genome-wide DNA methylation sequencing and RNA sequencing analyses in the hippocampus of 9-month-old wild-type and 5xFAD tg mice. To validate the genes inversely regulated by epigenetics, we confirmed their methylation status and mRNA levels. RESULTS: At 9 months of age, 5xFAD tg mice showed significant cognitive impairment and amyloid-beta plaques in the hippocampus. DNA methylation sequencing identified a total of 13,777 differentially methylated regions, including 4484 of hyper- and 9293 of hypomethylated regions, that are associated with several gene ontology (GO) terms including 'nervous system development' and 'axon guidance'. In RNA sequencing analysis, we confirmed a total of 101 differentially expressed genes, including 52 up- and 49 downregulated genes, associated with GO functions such as 'positive regulation of synaptic transmission, glutamatergic' and 'actin filament organization'. Through further integrated analysis of DNA methylation and RNA sequencing, three epigenetically regulated genes were selected: thymus cell antigen 1, theta (Thy1), myosin VI (Myo6), and filamin A-interacting protein 1-like (Filip1l). The methylation level of Thy1 decreased and its mRNA levels increased, whereas that of Myo6 and Filip1l increased and their mRNA levels decreased. The common functions of these three genes may be associated with the neural cytoskeleton and synaptic plasticity. CONCLUSIONS: We suggest that the candidate genes epigenetically play a role in AD-associated neuropathology (i.e., amyloid-beta plaques) and memory deficit by influencing neural structure and synaptic plasticity. Furthermore, counteracting dysregulated epigenetic changes may delay or ameliorate AD onset or symptoms.

An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

Which interbody device minimized nonunion, subsidence, and reoperation after anterior cervical discectomy and fusion? A systematic review and meta-analysis comparing allograft versus polyetheretherketone cage.

OBJECTIVE: Nonunion and significant subsidence after anterior cervical discectomy and fusion (ACDF) are associated with poor clinical outcomes, which occasionally lead to revision surgery. Allograft and polyetheretherketone (PEEK) cages are the two most commonly used interbody spacer devices for ACDF. Although studies have been conducted to compare the efficacies of these two interbody materials, the question remains regarding the superiority of one over the other. Therefore, the authors conducted a systematic review and meta-analysis to compare nonunion, subsidence, and reoperation rates after ACDF using allograft and PEEK cages as interbody devices. METHODS: In this systematic review and meta-analysis, the authors systematically searched the MEDLINE, EMBASE, and Cochrane Library databases for studies published prior to November 2023 that compared the efficacy and safety of allograft and PEEK cages for ACDF. A pooled analysis was designed to identify differences in nonunion, subsidence, and reoperation rates between the two interbody devices. RESULTS: Ten studies involving 1462 patients (allograft, 852 patients; PEEK cage, 610 patients) were included. The pooled analysis demonstrated that allograft had a significantly lower rate of nonunion compared to that of PEEK cages (OR 0.33, 95% CI 0.14-0.79; p = 0.01). Furthermore, the reoperation rate due to nonunion was significantly higher with PEEK cages compared to that with allograft (OR 0.28, 95% CI 0.11-0.71; p < 0.01), whereas the reoperation rate due to overall causes did not display significant results (OR 0.38, 95% CI 0.11-1.29; p = 0.12). The incidence of significant subsidence (OR 0.66, 95% CI 0.28-1.55; p = 0.34) and the mean amount of subsidence (standard mean difference 0.03, 95% CI -0.42 to 0.47; p = 0.90) did not demonstrate significant differences between allograft and PEEK cages. CONCLUSIONS: Overall, the current meta-analysis suggests the advantages of allograft over PEEK cages used for ACDF, due to an enhanced fusion rate and minimized revision risk, with no increase in the risk of subsidence.

The Application of High-Intensity Ultrasound on Wet-Dry Combined Aged Pork Loin Induces Physicochemical and Oxidative Alterations.

This research investigated the synergic outcome of high intensity ultrasound (HIU) treatment and wet-dry combined aging (WDCA) on physiochemical characteristics and lipid oxidation during refrigerated storage to ameliorate pork meat's quality and shelf life. The CIE b* values, cooking loss (CL %), and pH of the HIU treated samples were higher than those of the control over the aging period. They were significantly (p<0.05) modified by the aging period and ultrasound (US) treatment. However, the released water (RW %) and moisture were not significantly influenced by US treatment (p>0.05). The Warner-Bratzler shear force of HIU-treated samples was lower over control values except in 7-14 d, and it showed a significant difference between control and US treatment according to the significance of HIU (p<0.05). The thiobarbituric acid reactive substance of HIU-treated samples was significantly higher (p<0.05) than control values over the aging period. These results suggested that HIU treatment and WDCA showed a synergistic effect of maximizing the tenderness, but lipid oxidation was higher than before ultrasonic treatment. In agreement with this, the most favorable approach would involve implementing wet aging for a period of two weeks followed by dry aging for a period not exceeding one week after the application of HIU.

Hearing impairment increases the risk of hip fracture-related mortality and recurrent hip fractures: A propensity score matching analysis.

PURPOSE: Despite the ongoing rise in hip fractures and the adverse effects of hearing impairment (HI) on increased mortality and morbidity, research addressing the influence of HI on mortality risk or complications in patients with hip fractures remains absent. This study aimed to analyze the effects of HI on mortality and treatment outcomes among patients with hip fracture. METHODS: We retrospectively collected data from consecutive patients diagnosed with hip fractures between January 2007 and March 2022 who had auditory examination records. From the initially enrolled 265 patients, data for 58 with HI and 58 without HI (control group) were extracted using a 1:1 propensity score matching. The primary outcome included comparison of mortality rates, and the secondary outcome encompassed the comparison of postoperative medical and surgical complications. RESULTS: The 1-year cumulative mortality rate was not significantly different between the HI and control groups, but the overall cumulative mortality rate was significantly higher in the HI than in the control group (63.0 % and 48.6, respectively; P = 0.046) in a follow-up period of up to 16 years. The HI group had a significantly higher incidence of "second hip fractures due to falls" than the control group (P = 0.016), although no differences in other medical and surgical complications were revealed. CONCLUSIONS: Awareness of the long-term risk of higher mortality when managing patients with hip fracture and HI is important. To reduce the risk of second hip fractures, paying more attention to fall prevention education and taking a more proactive approach, especially for those with HI.

Low-Power Fully Integrated 256-Channel Nanowire Electrode-on-Chip Neural Interface for Intracellular Electrophysiology.

Intracellular electrophysiology, a vital and versatile technique in cellular neuroscience, is typically conducted using the patch-clamp method. Despite its effectiveness, this method poses challenges due to its complexity and low throughput. The pursuit of multi-channel parallel neural intracellular recording has been a long-standing goal, yet achieving reliable and consistent scaling has been elusive because of several technological barriers. In this work, we introduce a micropower integrated circuit, optimized for scalable, high-throughput in vitro intrinsically intracellular electrophysiology. This system is capable of simultaneous recording and stimulation, implementing all essential functions such as signal amplification, acquisition, and control, with a direct interface to electrodes integrated on the chip. The electrophysiology system-on-chip (eSoC), fabricated in 180nm CMOS, measures 2.236 mm × 2.236 mm. It contains four 8 × 8 arrays of nanowire electrodes, each with a 50 µm pitch, placed over the top-metal layer on the chip surface, totaling 256 channels. Each channel has a power consumption of 0.47 µW, suitable for current stimulation and voltage recording, and covers 80 dB adjustable range at a sampling rate of 25 kHz. Experimental recordings with the eSoC from cultured neurons in vitro validate its functionality in accurately resolving chemically induced multi-unit intracellular electrical activity.

[Pedunculated Giant Condyloma Acuminatum of the Scrotum].

The patient was a 71-year-old male whose chief complaint was a scrotum mass. The mass had gradually increased in size without any associated symptoms. The physical examination revealed a pedunculated, radish brown, and elastic soft tumor (4. 5×3. 5×3. 0 cm) in the right scrotum. Blood chemical analysis of HbA1c and squamous carcinoma antigen were 8. 3% and 38. 4 ng/ml (≦1. 5), respectively. This tumor was successfully treated with surgical resection. Histopathological examination showed condyloma acuminatum without malignant findings. Giant condyloma acuminatum commonly affects the genital and perianal areas. An immunocompromised state generally exists in the background of the patients.

The Accessibility and Effect of Cardiac Rehabilitation in COVID-19 Pandemic Era.

Objective: To prospectively compare the efficacy of conventional center-based cardiac rehabilitation (CBCR) and home-based cardiac rehabilitation (HBCR) during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Ninety Patients were divided into HBCR and CBCR groups based on cardiovascular risk stratification and individual preference. The CBCR group performed supervised in-hospital exercise training 2-3 times/week and subsequent self-exercise at home. The HBCR group performed self-exercise at home after one or two sessions of exercise education. The cardiopulmonary exercise test results at baseline and those at the 3-, 6-, and 12-month follow-ups were analyzed as primary outcome. Results: The peak oxygen consumption (peak VO2, mL/kg/min) in the CBCR group was 20.1 and 24.0 at baseline and 12 months, respectively, showing significant improvement (p=0.006). In the HBCR group, it only increased from 24.4 to 25.5, showing suboptimal improvement. A significant increase in the Korean activity scale/index was confirmed only in the CBCR group (p=0.04). The cardiovascular outcome did not differ between the two groups, nor did the dropout rate or demographic factors. Conclusion: During the COVID-19 pandemic, only CBCR was associated with a significant improvement in peak VO2 and physical activity levels, a finding that differs from those of other studies and seems to be affected by COVID-19. Therefore, in situations where the importance of HBCR is emphasized, it is essential to introduce measures to monitor and enhance exercise adherence among participants.

What is the Optimal Nail Length to Treat Osteoporotic Subtrochanteric Fractures? A Finite Element Analysis.

Background: Operative management with intramedullary nail fixation remains the definitive treatment of choice for osteoporotic subtrochanteric (ST) fractures; however, there remains no consensus regarding the proper nail length. We aimed to use 3-dimensional finite element (FE) analysis to determine the optimal nail length for the safe fixation of osteoporotic ST fractures. Methods: Nine modes of FE models were constructed using 9 different lengths of cephalomedullary nails (short nails: 170, 180, and 200 mm; long nails: 280, 300, 320, 340, 360, and 380 mm) from the same company. The interfragmentary motion was analyzed. Additionally, the peak von Mises stress (PVMS) in the cortical bone, cancellous bone of the femoral head, and the nail were measured, and the yielding risk for each subject was investigated. Results: Long nails were associated with less interfragmentary motion. In the cortical bone, the PVMS of short nails was observed at the distal locking screw holes of the femoral medial cortex; however, in long nails, the PVMS was observed at the lag screw holes on the lateral cortex. The mean yielding risk of long nails was 40.1% lower than that of short nails. For the cancellous bone of the femoral head, the PVMS in all 9 FE models was in the same area: at the apex of the femoral head. There was no difference in the yielding risk between short and long nails. For implants, the PVMS was at the distal locking screw hole of the nail body in the short nails and the nail body at the fracture level in the long nails. The mean yielding risk was 74.9% lower for long nails than that for short nails. Conclusions: Compared to short nails, long nails with a length of 320 mm or more showed less interfragmentary motion and lower yielding risk in low-level osteoporotic ST fractures. The FE analysis supports long nails as a safer option than short nails, especially for treating transverse-type low-level osteoporotic ST fractures.

Clinical and Radiological Outcomes of Computer-Assisted Navigation in Primary Total Knee Arthroplasty for Patients with Extra-articular Deformity: Systematic Review and Meta-Analysis.

Background: Computer-assisted navigation surgery (CAS) during primary total knee arthroplasty (TKA) may help improve outcomes for patients with extra-articular deformity (EAD); however, this has not been extensively studied. Therefore, we aimed to investigate the clinical and radiological outcomes following primary TKA using CAS in patients with EAD. Methods: We searched Medline, Embase, and the Cochrane Library up to March 3, 2023 for studies investigating surgical outcomes of using the navigation system for TKA to treat patients with EAD. From 14 studies, 539 knees with EAD that underwent navigation TKA were enrolled. We investigated the knee range of motion (ROM), outcome scores at final follow-up (Knee Society Score [KSS] and Knee Functional Score [KFS]), and pre- and postoperative mechanical hip-knee-ankle (mHKA) angle using lower extremity scanogram. The meta-analysis was based on the single-arm method, and all data were pooled using a random-effects model. Results: Following our meta-analyses, the mean knee ROM changed from 87.0° (95% confidence interval [CI], 75.9°-98.1°) preoperatively to 109.4° (95% CI, 97.9°-120.8°) postoperatively. The adjusted KSS was 93.45 points (95% CI, 88.36-98.54 points), and the adjusted KFS was 91.57 points (95% CI, 86.80-96.33 points) in knees with EAD that underwent CAS-TKA. As a radiological outcome, the mHKA angle changed from 169.53° (95% CI, 166.90°-172.16°) preoperatively to 178.81° (95% CI, 178.31°-179.30°) postoperatively. Conclusions: CAS-TKA yielded positive clinical results and demonstrated a satisfactory alignment of the lower limb's mechanical axis. CAS-TKA showed promise for primary TKA procedures, demonstrating favorable clinical and radiological outcomes even in complex cases involving EAD.

Photocatalytic Conversion of CO2 to Formate/CO by an (η6-para-Cymene)Ru(II) Half-Metallocene Catalyst: Influence of Additives and TiO2 Immobilization on the Catalytic Mechanism and Product Selectivity.

The catalytic efficacy of the monobipyridyl (η6-para-Cymene)Ru(II) half-metallocene, [(p-Cym)Ru(bpy)Cl]+ was evaluated in both mixed homogeneous (dye + catalyst) and heterogeneous hybrid systems (dye/TiO2/Catalyst) for photochemical CO2 reduction. A series of homogeneous photolysis experiments revealed that the (p-Cym)Ru(II) catalyst engages in two competitive routes for CO2 reduction (CO2 to formate conversion via RuII-hydride vs CO2 to CO conversion through a RuII-COOH intermediate). The conversion activity and product selectivity were notably impacted by the pKa value and the concentration of the proton source added. When a more acidic TEOA additive was introduced, the half-metallocene Ru(II) catalyst leaned toward producing formate through the RuII-H mechanism, with a formate selectivity of 86%. On the other hand, in homogeneous catalysis with TFE additive, the CO2-to-formate conversion through RuII-H was less effective, yielding a more efficient CO2-to-CO conversion with a selectivity of >80% (TONformate of 140 and TONCO of 626 over 48 h). The preference between the two pathways was elucidated through an electrochemical mechanistic study, monitoring the fate of the metal-hydride intermediate. Compared to the homogeneous system, the TiO2-heterogenized (p-Cym)Ru(II) catalyst demonstrated enhanced and enduring performance, attaining TONs of 1000 for CO2-to-CO and 665 for CO2-to-formate.

Solar Carboxylation Using CO2: Interfacially Synthesized Flexible Covalent Organic Frameworks Film as a Photocatalyst for Highly Selective Solar Carboxylation of Arylamines with CO2.

Carbon dioxide (CO2) conversion into value-added chemicals/fuels by utilizing solar energy is a sustainable way to mitigate our dependence on fossil fuels and stimulate a carbon-neutral economy. However, the efficient and affordable conversion of CO2 is still an ongoing challenge. Here, we report an interfacially synthesized visible-light-active Ni(II)-integrated covalent organic frameworks (TaTpBpy-Ni COFs) film as a photocatalyst for efficient CO2 conversion into carboxylic acid under ambient conditions. Notably, the TaTpBpy-Ni COFs film showed excellent photocatalytic activity for the carboxylation of various arylamines with CO2 to the corresponding arylcarboxylic acid via C-N bond activation under solar-light irradiation. Moreover, this carboxylation protocol exhibits mild reaction conditions and good functional group tolerance without the necessity of using stoichiometric metallic reductants. This work shows a benchmark example of not only the interfacially synthesized COFs film used as a photocatalyst for solar-light energy utilization but also the selective solar chemical production system of arylcarboxylic acid directly from CO2.

The effect of support surface on the prevention of pressure injury in acute care settings: A multi-center prospective observational study.

PURPOSE: This study aimed to analyze if a multi-foam core mattress with a laminated cover can reduce the incidence of pressure injuries, compared to an alternating air mattress overlay among critically ill patients in acute settings. DESIGN: Prospective observational study. PARTICIPANTS: and setting: Patients with a Braden scale score ≤16 on intensive care unit admission at five general hospitals in Korea were included in this study between February 2022 and March 2022. METHODS: One hundred and twenty patients in acute settings were enrolled and categorized into two groups: a multi-form core mattress with a laminated cover group (n = 60) and an alternating air mattress overlay group (n = 60). Data were collected for 7 days by wound care nurses. RESULTS: Pressure injury developed at a significantly lower rate in the multi-form core mattress with a laminated cover group (n = 4/60, 6.7 %) than in the alternating air mattress overlay group (n = 25/60, 25.0 %) (P = 0.011). Using a multi-foam core mattress with a laminated cover demonstrated a protective effect against pressure injuries (odds ratio 0.123, 95 % confidence interval 0.024-0.620, P = 0.011). CONCLUSIONS: A multi-foam core mattress with a laminated cover was significantly more effective than an alternating air mattress overlay in preventing pressure injury in critically ill patients.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: A nationwide population-based study.

This study aimed to investigate the impact of the cumulative burden of metabolic syndrome (MetS) on the incidence of retinal vein occlusion (RVO) in young adults. We included 1,408,093 subjects aged ≥20 and <40 years without a history of RVO who underwent four consecutive annual health examinations during 2009-2012 from the database of the Korean National Health Insurance Service. The metabolic burden was evaluated based on the cumulative number of MetS diagnoses at each health examination (0-4 times) and the cumulative number of each MetS component diagnosed at each health examination (0-4 times per MetS component). Cox proportional hazards models were used to estimate the risk of RVO according to metabolic burden. The risk of RVO was positively correlated with the cumulative number of MetS diagnoses over the four health examinations. All five MetS components were independently associated with an increased risk of RVO. Subgroup analysis for the impact of MetS on RVO occurrence revealed that MetS had a greater impact on female subjects (P <0.001). Prompt detection of metabolic derangements and their treatment might be important to decrease the risk of RVO in young adults, especially women.

Development and validation of a reliable method for automated measurements of psoas muscle volume in CT scans using deep learning-based segmentation: a cross-sectional study.

OBJECTIVES: We aimed to develop an automated method for measuring the volume of the psoas muscle using CT to aid sarcopenia research efficiently. METHODS: We used a data set comprising the CT scans of 520 participants who underwent health check-ups at a health promotion centre. We developed a psoas muscle segmentation model using deep learning in a three-step process based on the nnU-Net method. The automated segmentation method was evaluated for accuracy, reliability, and time required for the measurement. RESULTS: The Dice similarity coefficient was used to compare the manual segmentation with automated segmentation; an average Dice score of 0.927 ± 0.019 was obtained, with no critical outliers. Our automated segmentation system had an average measurement time of 2 min 20 s ± 20 s, which was 48 times shorter than that of the manual measurement method (111 min 6 s ± 25 min 25 s). CONCLUSION: We have successfully developed an automated segmentation method to measure the psoas muscle volume that ensures consistent and unbiased estimates across a wide range of CT images.

Mosaicism-independent mechanisms contribute to Pcdh19-related epilepsy and repetitive behaviors in Xenopus.

Protocadherin19 (PCDH19)-related epilepsy syndrome is a rare disorder characterized by early-onset epilepsy, intellectual disability, and autistic behaviors. PCDH19 is located on the X chromosome and encodes a calcium-dependent single-pass transmembrane protein, which regulates cell-to-cell adhesion through homophilic binding. In human, 90% of heterozygous females, containing PCDH19 wild-type and mutant cells due to random X inactivation, are affected, whereas mutant males, containing only mutant cells, are typically not. The current view, the cellular interference, is that the altered interactions between wild-type and mutant cells during development, rather than loss of function itself, are responsible. However, studies using Pcdh19 knockout mice showed that the complete loss of function also causes autism-like behaviors both in males and females, suggesting that other functions of PCDH19 may also contribute to pathogenesis. To address whether mosaicism is required for PCDH19-related epilepsy, we generated Xenopus tropicalis tadpoles with complete or mosaic loss of function by injecting antisense morpholino oligonucleotides into the blastomeres of neural lineage at different stages of development. We found that either mosaic or complete knockdown results in seizure-like behaviors, which could be rescued by antiseizure medication, and repetitive behaviors. Our results suggest that the loss of PCDH19 function itself, in addition to cellular interference, may also contribute to PCDH19-related epilepsy.

Blunted cardiovascular responses to exercise by inhibiting afferent feedback via spinal cord stimulation in heart failure.

This case study investigated the impact of SCS on alterations in blood pressure during constant-load exercise in a female patient with heart failure. Three different SCS frequencies [No SCS (~0 Hz), Low SCS (~100 Hz), and High SCS (~1000 Hz)] with and without ischaemic stimulation of the legs (cuffs) were randomly applied during constant-load exercise. To determine cardiovascular and ventilatory responses to exercise following SCS frequencies, BP, heart rate (HR), and respiratory gas exchange were measured. This experiment was duplicated in visit 1 and visit 2 with a random application of SCS frequency order and the data were averaged. There were no significant differences among three frequencies with no leg ischaemia. However, High SCS demonstrated lower BP, HR, and respiratory gas exchange relative to No SCS and Low SCS. SCS may be effective in improving cardiovascular and ventilatory responses in HF and high-frequency stimulation provides more clinical benefit; however, further studies are needed.