Feasibility of self-measurement telemonitoring using a handheld heart sound recorder in patients with heart failure - SELPH multicenter pilot study.

BACKGROUND: Multi-parametric assessment, including heart sounds in addition to conventional parameters, may enhance the efficacy of noninvasive telemonitoring for heart failure (HF). We sought to assess the feasibility of self-telemonitoring with multiple devices including a handheld heart sound recorder and its association with clinical events in patients with HF. METHODS: Ambulatory HF patients recorded their own heart sounds, mono­lead electrocardiograms, oxygen saturation, body weight, and vital signs using multiple devices every morning for six months. RESULTS: In the 77 patients enrolled (63 ±â€¯13 years old, 84 % male), daily measurements were feasible with a self-measurement rate of >70 % of days in 75 % of patients. Younger age and higher Minnesota Living with Heart Failure Questionnaire scores were independently associated with lower adherence (p = 0.002 and 0.027, respectively). A usability questionnaire showed that 87 % of patients felt self-telemonitoring was helpful, and 96 % could use the devices without routine cohabitant support. Six patients experienced ten HF events of re-hospitalization and/or unplanned hospital visits due to HF. In patients who experienced HF events, a significant increase in heart rate and diastolic blood pressure and a decrease in the time interval from Q wave onset to the second heart sound were observed 7 days before the events compared with those without HF events. CONCLUSIONS: Self-telemonitoring with multiple devices including a handheld heart sound recorder was feasible even in elderly patients with HF. This intervention may confer a sense of relief to patients and enable monitoring of physiological parameters that could be valuable in detecting the deterioration of HF.

Three-year efficacy and safety of omidenepag isopropyl in patients with normal tension glaucoma.

PURPOSE: To retrospectively evaluate the 3-year efficacy and safety of single-agent omidenepag isopropyl in patients with normal tension glaucoma (NTG). STUDY DESIGN: Retrospective. METHODS: One hundred patients (100 eyes) who had newly been administered omidenepag isopropyl were enrolled in this study. Intraocular pressure (IOP) was compared at baseline and 6, 9, 12, 18, 24, 30, and 36 months after administration. The mean deviation values at baseline and 12, 24, and 36 months measured using the Humphrey visual field test (30-2 Swedish Interactive Threshold Algorithm standard) were compared. Adverse reactions and dropouts were assessed. RESULTS: IOP significantly decreased from 15.5±2.7 mmHg at baseline to 13.8 ±2.3 mmHg after 6 months, 13.9± 2.3 mmHg after 12 months, 13.9±2.3 mmHg after 18 months, 13.8±2.1 mmHg after 24 months, 13.9±2.0 mmHg after 30 months, and 13.6±1.7 mmHg after 36 months (P < 0.0001). There was no significant difference in the mean deviation values at baseline (-3.66±3.49 dB), 12 months (-3.41±3.80 dB), 24 months (-3.13±3.81 dB), and 36 months (-3.06±3.30 dB). Adverse reactions occurred in 11 patients (11.0%), including conjunctival hyperemia in 6 patients. Fifty-two patients (52.0%) were excluded from the analysis because they discontinued treatment either due to IOP measurement by NCT or the use of additional drugs. CONCLUSION: After the administration of omidenepag isopropyl, IOP in patients with NTG decreased within 3 years, visual fields were maintained, and safety was satisfactory. Thus, omidenepag isopropyl can be used as the first-line treatment for patients with NTG.

Evaluation of Steroid Pulse Therapy Responsiveness in Myelin-Oligodendrocyte Glycoprotein Antibody-Positive Optic Neuritis.

PURPOSE: Myelin-oligodendrocyte glycoprotein antibody-positive optic neuritis (MOGON) is usually responsive to the steroid, but, for some patients, steroid pulse therapy alone may be inadequate. This study aimed to investigate the factors predicting the response to steroid pulse therapy in MOGON. METHODS: This study included 17 patients (24 eyes) with MOGON, who received single steroid pulse therapy as initial treatment. Best corrected visual acuity (BCVA) and mean deviation (MD) values after treatment were examined concerning findings at onset. RESULTS: No correlation was found between BCVA at onset and after treatment, but a correlation was observed between MD values at onset and after treatment (correlation coefficient 0.48, p=0.01, Spearman's rank correlation coefficient). Age, gender, duration from onset to treatment, magnetic resonance imaging findings, and optical coherence tomography findings did not affect visual function after treatment. CONCLUSIONS: Severe visual field impairment at onset may indicate that additional treatment may be necessary.

Respiratory paralysis in a patient with myasthenia gravis after ingestion of marine carnivorous gastropods: A case report.

The salivary glands of marine carnivorous gastropods contain tetramines, which usually cause mild symptoms of poisoning. However, these symptoms may be fatal in rare cases. A 58-year-old woman with a history of myasthenia gravis complained of dyspnea after consuming marine carnivorous gastropods with intact salivary glands. Upon arrival at the hospital, her blood gas analysis revealed type II respiratory failure with a pCO2 of 154 mmHg. Tracheal intubation was immediately performed. Her respiratory condition improved the following day, and she therefore could be weaned off the ventilator. Tetramine poisoning can be fatal for patients with certain underlying medical conditions.

Glaucoma progression due to refraining examination amid the pandemic of COVID-19.

PURPOSE: Some patients refrained from seeking an ophthalmologist due to the anxiety and morbidity associated with the coronavirus disease (COVID-19) pandemic. We investigated progressive visual field defects in patients with glaucoma who refrained from ophthalmological examinations. METHODS: This was a retrospective study. We analyzed data from 886 patients with glaucoma who visited Inouye Eye Hospital in June 2022 and were followed-up prior to January 2020. We examined the number of times patients canceled visits between January 2020 and May 2022 due to coronavirus concerns. We assessed the mean deviation (MD) values of the Humphrey Visual Field Assessment (HFA) program 30-2 SITA Standard values after visit interruptions for worsening beyond the MD values predicted by the MD slope. Factors influencing this difference were analyzed using logistic regression analysis. RESULTS: The study included 374 men and 512 women. The mean age was 68.7 ± 12.0 years. Visit interruptions occurred in 146 patients (16.5%), with 95 (65.1%) rescheduling once, 27 (18.5%) twice, and 24 (16.4%) three or more times. Among 90 patients who underwent HFA regularly, 50 (55.6%) experienced worse-than-expected MD values and 12 (13.3%) deteriorated by 2 dB or more. Longer interruptions and high intraocular pressure before interruption worsened the MD values by 2 dB or more. CONCLUSION: Patients with glaucoma with visit interruptions due to the pandemic should be monitored for the progression of visual field impairment.

Clinical Features and Prognostic Factors in Anti-Myelin Oligodendrocyte Glycoprotein Antibody Positive Optic Neuritis.

In order to review the clinical features of anti-myelin oligodendrocyte glycoprotein antibody positive optic neuritis (MOGON), we investigated the clinical characteristics, visual function, optical coherence tomography findings, and magnetic resonance imaging of 31 patients (44 eyes). MOGON was more common in middle age without sex difference and was characterised by pain on eye movement and optic disc swelling. Magnetic resonance imaging lesions tended to be long with inflammation around the optic nerve sheath; longer lesions were associated with worse visual acuities at onset. Recurrence was significantly associated with retinal nerve fibre layer thinning, and thus, it is important to reduce recurrence as much as possible.

A Japanese Case of Leber's Hereditary Optic Neuropathy with the m.13051G>A Pathogenic Variant.

Leber's hereditary optic neuropathy (LHON) is one of the hereditary optic neuropathies and is principally caused by three frequent mitochondria deoxyribonucleic acid (DNA) pathogenic variants (m.11778 G>A, m.3460 G>A, and m.14484T>C). These pathogenic variants account for 90% of LHON cases, with rare pathogenic variants accounting for the remaining cases. We report the first Japanese case of LHON with the m.13051 G>A pathogenic variant, which is a rare primary pathogenic variant of LHON. A 24-year-old woman developed subacute visual loss in both eyes over several months. The best corrected visual acuity (BCVA) was 6/120 in her right eye (OD) and 6/7.5 in her left eye (OS). A relative afferent pupillary defect was not detected. Humphrey visual field testing revealed a central scotoma OD and a temporal paracentral scotoma OS. Fundus examination showed the presence of a pale optic disc OD and optic disc swelling with peripapillary microangiopathy OS. Orbital magnetic resonance imaging showed no abnormal findings. As the mitochondrial DNA gene testing demonstrated the m.13051 G>A pathogenic variant, the patient was diagnosed with LHON. Subsequently, her BCVA worsened to 6/600 in each eye, followed by a nearly plateau-like progression thereafter. This mutation has been primarily reported in Europe but has not yet been confirmed in the Asian region. This case also indicates the importance of examining the whole mitochondrial DNA gene for pathogenic variants in cases where one of the three major pathogenic variants has not been not detected.

Switching to Brimonidine/Ripasudil Fixed Combination from Brimonidine + Ripasudil.

Purpose: A fixed-combination eye drop has several advantages over combination therapy, however, the intraocular pressure (IOP)-lowering efficacy and safety of the newly available brimonidine + ripasudil fixed-combination (BRFC) eye drops after switching from brimonidine + ripasudil is yet to be established. Therefore, this study aimed to retrospectively investigate the 6-month safety, usability, and IOP-lowering efficacy of BRFC switched from brimonidine and ripasudil. Patients and Methods: Overall, 69 patients with primary open-angle glaucoma (69 eyes) receiving brimonidine + ripasudil were enrolled in this study. Brimonidine + ripasudil was discontinued, and treatment was switched to BRFC without a washout period. The IOP was compared before and at 3 and 6 months after switching to BRFC. The side effects, discontinued cases, and usability (a questionnaire survey) were also investigated. Results: The IOP was not significantly different after switching to BRFC (15.1 ± 3.3 mmHg at baseline, 15.9 ± 3.6 mmHg after 3 months, and 14.6 ± 3.3 mmHg after 6 months). Adverse reactions occurred in four patients (5.8%): allergic conjunctivitis, two patients; irritation, one patient; and blurred vision, one patient. Treatment was discontinued in five (7.2%) patients owing to allergic conjunctivitis, two patients; increased IOP, two patients; and blurred vision, one patient. In the questionnaire survey, 68 patients with eye pain, 67 with itching, 64 with conjunctival hyperemia, 64 with irritation, and 62 with blurred vision reported no change or improved conditions. Additionally, in response to the question regarding preferences for pre-treatment and fixed combinations, 14 participants (20.2%) favored pre-treatment, while 53 (76.8%) preferred fixed combinations. Conclusion: The IOP was maintained for 6 months, with satisfactory safety and comfort of use, with BRFC switched from brimonidine and ripasudil.

Efficacy of an eHealth self-management program in reducing irritable bowel syndrome symptom severity: a randomized controlled trial.

This study aimed to verify whether an eHealth-based self-management program can reduce irritable bowel syndrome (IBS) symptom severity. An open-label simple randomized controlled trial was conducted that compared an intervention group (n = 21) participating in an eHealth self-management program, which involved studying IBS-related information from an established self-help guide followed by in-built quizzes, with a treatment-as-usual group (n = 19) that, except for pharmacotherapy, had no treatment restrictions. Participants were female Japanese university students. The eHealth group received unlimited access to the self-management program for 8 weeks on computers and mobile devices. The primary outcome, participants' severity of IBS symptoms assessed using the IBS-severity index (IBS-SI), and the secondary outcomes of participants' quality of life, gut bacteria, and electroencephalography alpha and beta power percentages were measured at baseline and 8 weeks. A significant difference was found in the net change in IBS-SI scores between the eHealth and treatment-as-usual groups, and the former had significantly lower IBS-SI scores following the 8-week intervention than at baseline. Moreover, there was a significant difference in the net change in phylum Cyanobacteria between the eHealth and treatment-as-usual groups. Thus, the eHealth-based self-management program successfully reduced the severity of IBS symptoms.

Haemodynamic effects of acute intravenous landiolol in Takotsubo cardiomyopathy with dynamic left ventricular outflow tract obstruction.

Takotsubo cardiomyopathy (TCM) leads to serious left ventricular outflow tract (LVOT) obstruction with cardiogenic shock in 6%-20% of cases. The onset of LVOT obstruction, coupled with mitral regurgitation resulting from systolic anterior motion of mitral valve leaflets, can lead to haemodynamic instability in addition to severely impaired systolic function. We describe three patients who experienced chest discomfort following emotional stress. These patients displayed pronounced abnormalities on ECGs, insignificant obstructive coronary disease and haemodynamic instability due to LVOT obstruction. The infusion of landiolol, a short-acting beta blocker, was effective in releasing the gradient. Dynamic outflow obstruction is the major predictor of haemodynamic collapse. We suggested that an early identification of this complication in hypotensive patients with suspected TCM could be of utmost importance to optimise the therapeutic approach in the acute setting.

Diagnostic and Cost Efficiency of the 0-h/1-h Rule-out and Rule-in Algorithm for Patients With Chest Pain in the Emergency Department.

BACKGROUND: This study investigated the economic impact of the European Society of Cardiology (ESC) clinical practice guideline recommendation of using the 0-h/1-h rule-out and rule-in algorithm with high-sensitivity cardiac troponin assays (0/1-h algorithm) to triage patients presenting with chest pain.Methods and Results: This post hoc cost-effectiveness evaluation (DROP-ACS; UMIN000030668) used deidentified electronic medical records from health insurance claims from 2 diagnostic centers in Japan. A cost-effectiveness analysis was conducted with 472 patients with care provided following the 0/1-h algorithm (Hospital A) and 427 patients following point-of-care testing (Hospital B). The clinical outcome of interest was all-cause mortality or subsequent myocardial infarction within 30 days of the index presentation. The sensitivity and specificity for the clinical outcome were 100% (95% confidence interval [CI] 91.1-100%) and 95.0% (95% CI 94.3-95.0%), respectively, in Hospital A and 92.9% (95% CI 69.6-98.7%) and 89.8% (95% CI 89.0-90.0%), respectively, in Hospital B. If the diagnostic accuracy of the 0/1-h algorithm was implemented in Hospital B, it is expected that the number of urgent (<24-h) coronary angiograms would decrease by 50%. Incorporating this assumption, implementing the 0/1-h algorithm could potentially reduce medical costs by JPY4,033,874 (95% CI JPY3,440,346-4,627,402) in Hospital B (JPY9,447 per patient; 95% CI JPY 8,057-10,837 per patient). CONCLUSIONS: The ESC 0/1-h algorithm was efficient for risk stratification and for reducing medical costs.

One-Year Outcome of Patients with Chest Pain in the Rule-Out Group According to the 0-Hour/1-Hour Algorithm.

The European Society of Cardiology recommends the 0/1-hour algorithm for risk stratification of patients with suspected non-ST-elevation myocardial infarction as class I, level B; however, there are few reports on the long-term prognosis, resulting in a rule-out group. We aimed to determine whether implementation of the 0-hour/1-hour algorithm is safe and effective in emergency department (ED) patients with possible acute coronary syndrome (ACS) through a 1-year follow-up period. Our study analyzed the 1-year follow-up data from a prospective pre-post study of 1106 ED patients with possible ACS from 4 hospitals in Japan and Taiwan. Patients were 18 years or older. Accrual occurred for 1 year after implementing the 0-1-hour algorithm from November 2014 to December 2018. Overall, 520 patients were stratified into the rule-out group. Major advanced cardiovascular events (all-cause death, acute myocardial infarction [AMI], stroke, unstable angina, and revascularization) at 1-year were determined using data from health records and phone calls. The 0-1-hour algorithm stratified 47.0% of patients in the rule-out group. Over the 1-year follow-up period (follow-up rate = 86.9%), cardiovascular death and subsequent AMI did not occur in the rule-out group. Among the 27 patients who underwent the procedure within 30 days post-index visit, 3 patients (0.7%) had a stroke, 6 patients (1.3%) died of non-cardiovascular cause, and 30 patients (6.7%) underwent coronary revascularization within 1 year. At the 1-year follow-up, implementation of the 0-hour/1-hour algorithm was associated with very low rates of adverse event among patients in the rule-out group.

Calcitonin Related Polypeptide Alpha Mediates Oral Cancer Pain.

Oral cancer patients suffer pain at the site of the cancer. Calcitonin gene related polypeptide (CGRP), a neuropeptide expressed by a subset of primary afferent neurons, promotes oral cancer growth. CGRP also mediates trigeminal pain (migraine) and neurogenic inflammation. The contribution of CGRP to oral cancer pain is investigated in the present study. The findings demonstrate that CGRP-immunoreactive (-ir) neurons and neurites innervate orthotopic oral cancer xenograft tumors in mice. Cancer increases anterograde transport of CGRP in axons innervating the tumor, supporting neurogenic secretion as the source of CGRP in the oral cancer microenvironment. CGRP antagonism reverses oral cancer nociception in preclinical oral cancer pain models. Single-cell RNA-sequencing is used to identify cell types in the cancer microenvironment expressing the CGRP receptor components, receptor activity modifying protein 1 Ramp1 and calcitonin receptor like receptor (CLR, encoded by Calcrl). Ramp1 and Calcrl transcripts are detected in cells expressing marker genes for Schwann cells, endothelial cells, fibroblasts and immune cells. Ramp1 and Calcrl transcripts are more frequently detected in cells expressing fibroblast and immune cell markers. This work identifies CGRP as mediator of oral cancer pain and suggests the antagonism of CGRP to alleviate oral cancer pain.

Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.

INTRODUCTION: This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues. METHODS: A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews. RESULTS: BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation. CONCLUSION: As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy. TRIAL REGISTRATION NUMBER: jRCTs051190125.

Patients with glaucoma who require further reduction in intraocular pressure while undergoing monotherapy with prostaglandin analogue ophthalmic solution have been prescribed two enhanced treatment options: 0.1% brimonidine/0.5% timolol fixed combination ophthalmic solution (BTFC) and 1% dorzolamide/0.5% timolol fixed combination ophthalmic solution (DTFC). The Aibeta Crossover Study Group in Japan compared the efficacy and tolerability of fixed combinations of BTFC versus DTFC when an additional fixed combination ophthalmic solution was prescribed in patients with open-angle glaucoma or ocular hypertension who had been treated with prostaglandin analogue monotherapy. We recruited 110 patients previously treated with prostaglandin analogue monotherapy at 20 clinical centers in Japan, then randomly assigned them to two alternative treatment groups: the BTFC to DTFC group or the DTFC to BTFC group, as an adjunctive therapy to prostaglandin analogues for total of 16 weeks. We compared the reduction in intraocular pressure, occurrence of side effects, eye discomfort after instillation, and patient preference between BTFC versus DTFC instillations. The intraocular pressure reduction of BTFC instillation was comparable to that of DTFC instillation, showing non-inferiority to DTFC (3.55 mmHg vs. 3.60 mmHg; P < 0.0001, mixed-effects model). Both eye drops caused few side effects; however, patients felt greater eye discomfort with DTFC than with BTFC (P < 0.0001). Because of less eye irritation, more patients preferred BTFC (P < 0.0001) over DTFC. We can recommend using BTFC for patients who feel eye discomfort with DTFC­prostaglandin analogue combination therapy.

A Case of Herpes Zoster Ophthalmicus With Multiple Delayed Ocular Complications.

Herpes zoster ophthalmicus (HZO) presents a variety of ocular complications, most of which occur simultaneously as skin lesions. We report a case of HZO with delayed onset of multiple ocular complications. A 72-year-old man developed HZO, blepharitis, iritis, and conjunctivitis in the left eye, which resolved after topical ocular treatment and systemic acyclovir administration. However, six weeks after the first onset of the rash, the patient came to our hospital because of recurrent blepharitis, iritis, scleritis, conjunctivitis, eye pain, ptosis, and blurred vision in the left eye. Best corrected visual acuity (BCVA) in the left eye had decreased to hand motion, and the Goldmann visual field test showed only mild residual peripheral vision on the lateral side. Intraocular pressure showed 25 mmHg in the left eye and inflammation in the anterior chamber with paralytic mydriasis. Orbital magnetic resonance imaging (MRI) showed the contrast effects with the lacrimal gland, superior ophthalmic vein, supraorbital nerve, optic nerve, and around optic nerve sheath. The patient was diagnosed with optic neuritis, optic perineuritis, ptosis, paralytic mydriasis, trigeminal neuralgia, lacrimal gland inflammation, blepharitis, iritis, scleritis, and ocular hypertension after HZO, and three courses of steroid pulse therapy were administered. Thereafter, BCVA improved to 0.3 in the left eye, with improvement in central vision, and MRI lesions and other symptoms also improved. The patient has had no complications or recurrence of HZO. HZO can cause a variety of ocular complications. Since autoimmune mechanisms might be involved, combined immunotherapy should be considered.

A Case of Impending Central Retinal Vein Occlusion Associated With Antiphospholipid Antibody Syndrome Complicated by Paracentral Acute Intermediate Layer Maculopathy.

We report a case of impending central retinal vein occlusion (CRVO) due to antiphospholipid syndrome (APS) complicated by paracentral acute middle maculopathy (PAMM). A 42-year-old man with no medical history acutely presented with blurred vision in his right eye. The best-corrected visual acuity was 20/20 in the right eye, but the Goldman visual field test showed a dark spot over the superior nasal region of the right eye. Fundus examination showed dilated and tortuous retinal veins of the right eye with delayed filling of the inferior retinal veins on fluorescein angiography. Optical coherence tomography (OCT) showed a hyperreflective lesion confined to the inner nuclear layer (INL), consistent with PAMM. After several weeks, his symptoms improved, and the dilated retinal vein and the INL hyperreflexia on OCT were reduced. Multiple positive findings for anti-cardiolipin antibodies were confirmed; therefore, he was diagnosed with APS and treated with aspirin. If the impending CRVO is associated with visual impairment, the complication of PAMM should be considered. In the presence of retinal vasculopathy without atherosclerotic factors, APS should be considered.

Personalized diagnosis in suspected myocardial infarction.

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

Comprehensive study of metabolic changes induced by a ketogenic diet therapy using GC/MS- and LC/MS-based metabolomics.

OBJECTIVE: The ketogenic diet (KD), a high-fat and low-carbohydrate diet, is effective for a subset of patients with drug-resistant epilepsy, although the mechanisms of the KD have not been fully elucidated. The aims of this observational study were to investigate comprehensive short-term metabolic changes induced by the KD and to explore candidate metabolites or pathways for potential new therapeutic targets. METHODS: Subjects included patients with intractable epilepsy who had undergone the KD therapy (the medium-chain triglyceride [MCT] KD or the modified Atkins diet using MCT oil). Plasma and urine samples were obtained before and at 2-4 weeks after initiation of the KD. Targeted metabolome analyses of these samples were performed using gas chromatography-tandem mass spectrometry (GC/MS/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). RESULTS: Samples from 10 and 11 patients were analysed using GC/MS/MS and LC/MS/MS, respectively. The KD increased ketone bodies, various fatty acids, lipids, and their conjugates. In addition, levels of metabolites located upstream of acetyl-CoA and propionyl-CoA, including catabolites of branched-chain amino acids and structural analogues of γ-aminobutyric acid and lactic acid, were elevated. CONCLUSIONS: The metabolites that were significantly changed after the initiation of the KD and related metabolites may be candidates for further studies for neuronal actions to develop new anti-seizure medications.