Ketogenic metabolic therapy in conjunction with standard treatment for glioblastoma: A case report.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. The standard of care consists of surgical resection and concurrent chemoradiation, followed by adjuvant temozolomide chemotherapy. This protocol is associated with a median survival of 12-15 months, and <5% of patients survive >3 years. Ketogenic metabolic therapy (KMT) targets cancer cell metabolism by restricting glucose availability and evoking differential stress resistance and sensitization, which may augment the standard treatments and lead to therapeutic benefit. The present study reports the case of a 64-year-old woman with isocitrate dehydrogenase (IDH)-wildtype GBM who pursued the standard treatment protocol in conjunction with an intensive, multimodal KMT program for 3 years. The KMT program consisted of a series of prolonged (7-day, fluid-only) fasts, which were specifically timed to maximize the tolerability and efficacy of the standard treatments, combined with a time-restricted ketogenic diet on all other days. During the first and second treatment years the patient sustained a glucose ketone index (GKI) of 1.65 and 2.02, respectively, which coincided with complete clinical improvement, a healthy body-mass index and a high quality of life, with no visible progressive tumour detected on imaging at the end of the second year. In the setting of the death of an immediate family member leading to increased life stress, slightly relaxed KMT adherence, and a higher GKI of 3.20, slow cancer progression occurred during the third year. The adverse effects attributed to KMT were mild. Despite the limitations of this case report, it highlights the feasibility of implementing the standard treatment protocol for GBM in conjunction with an intensive, long-term, multimodal and specifically timed KMT program, the potential therapeutic efficacy of which may depend upon achieving as low a GKI as possible.

Infectious Diseases in a Changing Climate.

This JAMA Insights in the Climate Change and Health series discusses the importance of clinicians having awareness of changes in the geographic range, seasonality, and intensity of transmission of infectious diseases to help them diagnose, treat, and prevent these diseases.

Choosing patients over placebos: oral transitional therapy vs. IV-only therapy for bacteraemia and infective endocarditis.

BACKGROUND: The belief that antibiotics must be administered intravenously (IV) to treat bacteraemia and endocarditis has its origins 70 years ago and has engrained itself in the psyche of the medical community and the public at large. This has led to hesitancy in adopting evidence-based strategies utilizing oral transitional therapy for the treatment of these infections. We aim to reframe the narrative around this debate, focusing on patient safety over vestigial psychology. OBJECTIVES: This narrative review summarizes the current state of the literature regarding the use of oral transitional therapy for the treatment of bacteraemia and infective endocarditis, focusing on studies comparing it to the traditional, IV-only approach. SOURCES: Relevant studies and abstracts from PubMed reviewed in April 2023. CONTENT: Treating bacteraemia with oral transitional therapy has been studied in 9 randomized controlled trials (RCTs), totalling 625 patients, as well as numerous large, retrospective cohorts, including 3 published in the last 5 years alone, totalling 4763 patients. We identified 3 large, retrospective cohort studies; one quasi-experimental, pre-post study, and 3 RCTs of patients with endocarditis, totalling 748 patients in the retrospective cohorts and 815 patients in prospective, controlled studies. In all these studies, no worse outcomes were observed in the oral transitional therapy arm as compared with IV-only therapy. The main difference has consistently been longer durations of inpatient hospitalization and increased risk of catheter-related adverse events like venous thrombosis and line-associated blood stream infections in the IV-only groups. IMPLICATIONS: There are ample data showing that choosing oral therapy reduces hospital stay and has fewer adverse events for patients than IV-only therapy, all with similar or better outcomes. In selected patients, choosing IV-only therapy may serve more as an anxiolytic "placebo" for the patient and provider rather than a necessity for treating the actual infection.

Relationships between native and non-native speech perception.

Individuals differ in their ability to perceive and learn unfamiliar speech sounds, but we lack a comprehensive theoretical account that predicts individual differences in this skill. Predominant theories largely attribute difficulties of non-native speech perception to the relationships between non-native speech sounds/contrasts and native-language categories. The goal of the current study was to test whether the predictions made by these theories can be extended to predict individual differences in naive perception of non-native speech sounds or learning of these sounds. Specifically, we hypothesized that the internal structure of native-language speech categories is the cause of difficulty in perception of unfamiliar sounds such that learners who show more graded (i.e., less categorical) perception of sounds in their native language would have an advantage for perceiving non-native speech sounds because they would be less likely to assimilate unfamiliar speech tokens to their native-language categories. We tested this prediction in two experiments in which listeners categorized speech continua in their native language and performed tasks of discrimination or identification of difficult non-native speech sound contrasts. Overall, results did not support the hypothesis that individual differences in categorical perception of native-language speech sounds is responsible for variability in sensitivity to non-native speech sounds. However, participants who responded more consistently on a speech categorization task showed more accurate perception of non-native speech sounds. This suggests that individual differences in non-native speech perception are more related to the stability of phonetic processing abilities than to individual differences in phonetic category structure. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Can the Future of ID Escape the Inertial Dogma of Its Past? The Exemplars of Shorter Is Better and Oral Is the New IV.

Like all fields of medicine, Infectious Diseases is rife with dogma that underpins much clinical practice. In this study, we discuss 2 specific examples of historical practice that have been overturned recently by numerous prospective studies: traditional durations of antimicrobial therapy and the necessity of intravenous (IV)-only therapy for specific infectious syndromes. These dogmas are based on uncontrolled case series from >50 years ago, amplified by the opinions of eminent experts. In contrast, more than 120 modern, randomized controlled trials have established that shorter durations of therapy are equally effective for many infections. Furthermore, 21 concordant randomized controlled trials have demonstrated that oral antibiotic therapy is at least as effective as IV-only therapy for osteomyelitis, bacteremia, and endocarditis. Nevertheless, practitioners in many clinical settings remain refractory to adopting these changes. It is time for Infectious Diseases to move beyond its history of eminent opinion-based medicine and truly into the era of evidenced-based medicine.

Time-restricted ketogenic diet in amyotrophic lateral sclerosis: a case study.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD.

Time-Restricted Ketogenic Diet in Huntington's Disease: A Case Study.

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder with limited treatment options. Substantial evidence implicates mitochondria dysfunction in brain and skeletal muscle in the pathogenesis of HD. Metabolic strategies, such as fasting and ketogenic diets, theoretically enhance brain and muscle metabolism and mitochondria function, which may improve the clinical symptoms of HD. We report the case of a 41-year-old man with progressive, deteriorating HD who pursued a time-restricted ketogenic diet (TRKD) for 48 weeks. Improvements were measured in his motor symptoms (52% improvement from baseline), activities of daily living (28% improvement), composite Unified HD Rating Scale (cUHDRS) score (20% improvement), HD-related behavior problems (apathy, disorientation, anger, and irritability improved by 50-100%), and mood-related quality of life (25% improvement). Cognition did not improve. Weight remained stable and there were no significant adverse effects. This case study is unique in that a patient with progressive, deteriorating HD was managed with a TRKD, with subsequent improvements in his motor symptoms, activities of daily living, cUHDRS score, most major HD-related behavior problems, and quality of life. Our patient remains dedicated to his TRKD, which continues to provide benefit for him and his family.

SARS-CoV-2 cycle threshold (Ct) values predict future COVID-19 cases.

AIM: Anticipating local surges in COVID-19 cases has predominantly been based on observation of increasing cases. We sought to determine if temporal trends in SARS-CoV-2 Cycle threshold (Ct) values from clinical testing were predictive of future cases. METHODS: Data were collected from a large, safety-net hospital in Los Angeles, California. Ct values for all SARS-CoV-2 detections by the GeneXpert system (Cepheid) between October 2020 to March 2021 were analyzed. RESULTS: A total of 2,114 SARS-CoV-2-positive samples were included. Cases increased dramatically in December 2020, peaking the first week of January, before returning to pre-surge numbers by mid-February. Ct values fell during this same period, with values in December and January (25.6 ± 7.8 and 27±7.9, respectively) significantly lower than those of the other months (30±9.3 to 37.7 ± 6.3). Average weekly Ct values for all patients negatively correlated with the number of tests run two weeks in the future (r= -0.74, p<0.0001), whereas Ct values for asymptomatic patients negatively correlated most strongly with total number of tests performed one month later (r= -0.88, p<0.0001). Predictive modeling using these Ct values correctly predicted whether cases would increase or decrease 65% of the time for a subsequent surge (May-July 2021). CONCLUSIONS: During the largest COVID-19 surge in Los Angeles to date, we observed significantly lower Ct values (representing higher levels of viral RNA) suggesting that increased transmission of COVID-19 was temporarily associated with higher viral loads. Decreasing Ct values appear to be a leading indicator for predicting future COVID-19 cases, which can facilitate improved hospital-level surge planning.

Clinical application of nano-targeting for enhancing chemotherapeutic efficacy and safety in cancer management.

Despite improvements in treatment, cancer remains a leading cause of death worldwide. While chemotherapy is effective, it also damages healthy tissue, leading to severe, dose-limiting side effects that can impair efficacy and even contribute to chemoresistance. Nano-based drug-delivery systems can potentially target the delivery of chemotherapy to improve efficacy and reduce adverse effects. A number of nanocarriers have been investigated for the delivery of chemotherapy, and many of the most promising agents have advanced to clinical trials. This review examines the safety and efficacy of nanoformulated chemotherapeutic agents in clinical trials, with particular emphasis on anthracyclines, taxanes and platinum compounds. It also briefly discusses the role nano-targeting might play in the prevention and treatment of chemoresistance.

Metabolics risk factors in a New Zealand glioblastoma cohort.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive form of glioma. There is growing recognition that mitochondrial metabolism plays a role in cancer development. Metabolic syndrome is a risk factor for several cancers; however, the prevalence in GBM patients in New Zealand (NZ) is unknown. We hypothesized that patients with GBM would show a higher prevalence of metabolic syndrome compared to the general NZ population and that metabolic syndrome may be associated with worsened overall survival (OS) in GBM. METHODS: We performed a retrospective analysis in 170 patients diagnosed and treated for GBM between 2005 and 2020. Clinical and biochemical data were collected with regard to 5 metabolic criteria. OS was determined from the date of initial surgical diagnosis to the date of death or date of data acquisition. RESULTS: Of 170 patients, 31 (18.2%) met the diagnostic criteria for metabolic syndrome. The prevalence of metabolic syndrome in our cohort did not significantly differ from that of the general NZ population. However, OS in patients with metabolic syndrome was significantly worse compared to patients without metabolic syndrome (8.0 vs 13.0 months, P = .016). Patients who received a lower dexamethasone dose had significantly better survival outcomes (15.0 vs 5.0 months, P < .01). Differences in OS did not differ by gender or ethnicity. CONCLUSIONS: We have shown that metabolic syndrome is associated with reduced OS in a NZ cohort of GBM patients. This finding further strengthens the possibility that a metabolic pathogenesis may underpin GBM. However, prospective clinical trials are needed.

Fosfomycin vs Ertapenem for Outpatient Treatment of Complicated Urinary Tract Infections: A Multicenter, Retrospective Cohort Study.

BACKGROUND: We sought to determine the comparative efficacy of fosfomycin vs ertapenem for outpatient treatment of complicated urinary tract infections (cUTIs). METHODS: We conducted a multicenter, retrospective cohort study involving patients with cUTI treated with outpatient oral fosfomycin vs intravenous ertapenem at 3 public hospitals in Los Angeles County between January 2018 and September 2020. The primary outcome was resolution of clinical symptoms 30 days after diagnosis. RESULTS: We identified 322 patients with cUTI treated with fosfomycin (n = 110) or ertapenem (n = 212) meeting study criteria. The study arms had similar demographics, although patients treated with ertapenem more frequently had pyelonephritis or bacteremia while fosfomycin-treated patients had more retained catheters, nephrolithiasis, or urinary obstruction. Most infections were due to extended-spectrum ß-lactamase-producing E. coli and Klebsiella pneumoniae, 80%-90% of which were resistant to other oral options. Adjusted odds ratios for clinical success at 30 days, clinical success at last follow-up, and relapse were 1.21 (95% CI, 0.68-2.16), 0.84 (95% CI, 0.46-1.52), and 0.94 (95% CI, 0.52-1.70) for fosfomycin vs ertapenem, respectively. Patients treated with fosfomycin had significant reductions in length of hospital stay and length of antimicrobial therapy and fewer adverse events (1 vs 10). Fosfomycin outcomes were similar irrespective of duration of lead-in intravenous (IV) therapy or fosfomycin dosing interval (daily, every other day, every third day). CONCLUSIONS: These results would support the conduct of a randomized controlled trial to verify efficacy. In the meantime, they suggest that fosfomycin may be a reasonable stepdown from IV antibiotics for cUTI.

Effect of mortality from COVID-19 on inpatient outcomes.

When hospitals first encountered coronavirus disease 2019 (COVID-19), there was a dearth of therapeutic options and nearly 1 in 3 patients died from the disease. By the summer of 2020, as deaths from the disease declined nationally, multiple single-center studies began to report declining mortality of patients with COVID-19. To evaluate the effect of COVID-19 on hospital-based mortality, we searched the Vizient Clinical Data Base for outcomes data from approximately 600 participating hospitals, including 130 academic medical centers, from January 2017 through December 2020. More than 32 million hospital admissions were included in the analysis. After an initial spike, mortality from COVID-19 declined in all regions of the country to under 10% by June 2020 and remained constant for the remainder of the year. Despite this, inpatient, all-cause mortality has increased since the beginning of the pandemic, even those without respiratory failure. Inpatient mortality has particularly increased in elderly patients and in those requiring intubation for respiratory failure. Since June 2020, COVID-19 kills one in every 10 patients admitted to the hospital with this diagnosis. The addition of this new disease has raised overall hospital mortality especially those who require intubation for respiratory failure.

Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative.

BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Oral Is the New IV. Challenging Decades of Blood and Bone Infection Dogma: A Systematic Review.

BACKGROUND: We sought to determine if controlled, prospective clinical data validate the long-standing belief that intravenous (IV) antibiotic therapy is required for the full duration of treatment for 3 invasive bacterial infections: osteomyelitis, bacteremia, and infective endocarditis. METHODS: We performed a systematic review of published, prospective, controlled trials that compared IV-only to oral stepdown regimens in the treatment of these diseases. Using the PubMed database, we identified 7 relevant randomized controlled trials (RCTs) of osteomyelitis, 9 of bacteremia, 1 including both osteomyelitis and bacteremia, and 3 of endocarditis, as well as one quasi-experimental endocarditis study. Study results were synthesized via forest plots and funnel charts (for risk of study bias), using RevMan 5.4.1 and Meta-Essentials freeware, respectively. RESULTS: The 21 studies demonstrated either no difference in clinical efficacy, or superiority of oral versus IV-only antimicrobial therapy, including for mortality; in no study was IV-only treatment superior in efficacy. The frequency of catheter-related adverse events and duration of inpatient hospitalization were both greater in IV-only groups. DISCUSSION: Numerous prospective, controlled investigations demonstrate that oral antibiotics are at least as effective, safer, and lead to shorter hospitalizations than IV-only therapy; no contrary data were identified. Treatment guidelines should be modified to indicate that oral therapy is appropriate for reasonably selected patients with osteomyelitis, bacteremia, and endocarditis.

Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease.

BACKGROUND: Brain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients. METHODS: We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects. RESULTS: We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild. CONCLUSIONS: This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia. TRIAL REGISTRATION: This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202 . The trial was registered on August 28, 2018.

Epithelial TLR4 Signaling Activates DUOX2 to Induce Microbiota-Driven Tumorigenesis.

BACKGROUND & AIMS: Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease. We have described the critical role of innate immune signaling via Toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitis-associated neoplasia. METHODS: Inflammatory bowel disease and colorectal cancer data sets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (H2O2) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-knockout mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice. RESULTS: Activation of epithelial TLR4 was associated with up-regulation of DUOX2 and NOX1 in inflammatory bowel disease and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H2O2. Epithelial H2O2 was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased H2O2 production and tumorigenesis. CONCLUSIONS: Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of H2O2. The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial reactive oxygen species and increased development of colitis-associated tumors. The inter-relationship between epithelial reactive oxygen species and tumor-promoting microbiota requires a 2-pronged strategy to reduce the risk of dysplasia in colitis patients.

Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC. METHODS: We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet. RESULTS: Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02). CONCLUSIONS: In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.

Pharmacology, Dosing, and Side Effects of Rifabutin as a Possible Therapy for Antibiotic-Resistant Acinetobacter Infections.

Acinetobacter baumannii has among the highest rates of antibiotic resistance encountered in hospitals. New therapies are critically needed. We found that rifabutin has previously unrecognized hyperactivity against most strains of A. baumannii. Here we review the pharmacology and adverse effects of rifabutin to inform potential oral dosing strategies in patients with A. baumannii infections. Rifabutin demonstrates dose-dependent increases in blood levels up to 900 mg per day, but plateaus thereafter. Furthermore, rifabutin induces its own metabolism after prolonged dosing, lowering its blood levels. Pending future development of an intravenous formulation, a rifabutin oral dose of 900-1200 mg per day for 1 week is a rational choice for adjunctive therapy of A. baumannii infections. This dosage maximizes AUC24 to drive efficacy while simultaneously minimizing toxicity. Randomized controlled trials will be needed to definitively establish the safety and efficacy of rifabutin to treat A. baumannii infections.

Impact of a Ketogenic Diet on Sporadic Inclusion Body Myositis: A Case Study.

Sporadic inclusion body myositis (IBM) is a chronic inflammatory and degenerative muscle disease with limited treatment options; no therapy can alter its natural course. Ketogenic diets are theoretically capable of suppressing inflammation, enhancing cell bioenergetics, alleviating mitochondria dysfunction, and stimulating autophagy, which may be beneficial in IBM. We report the case of a 52-year-old woman with worsening IBM who pursued a modified ketogenic diet for 1 year. Adverse effects were mild and resolved 3 weeks into the diet. Prior to starting her ketogenic diet, despite the use of a walking stick at all times, she was experiencing one to two falls per week as well as swallowing difficulties, musculoskeletal pain, and depression. Moreover, magnetic resonance imaging (MRI) of the bilateral thighs during the year prior to the diet indicated worsening muscle inflammation and a 14% decrease in thigh muscle volume, which corresponded to a 4% decrease in the ratio of thigh muscle to thigh total volume. After 1 year on her ketogenic diet, our patient regained independent walking, and her swallowing difficulties, pain, and depression resolved. She maintained her strength, improved in every test of function, enhanced her quality of life, and lowered her blood creatine kinase. MRI of the bilateral thighs during the year of the diet indicated stabilized muscle inflammation and a 2.9% decrease in thigh muscle volume, which in the context of diet-induced fat loss corresponded to a sustained 1% increase in the ratio of thigh muscle to thigh total volume. This case is unique in that a ketogenic diet was utilized as the primary treatment strategy for a patient with confirmed IBM, culminating in substantial clinical improvement, stabilized muscle inflammation, and a slowed rate of muscle atrophy. Our patient has remained on her ketogenic diet for over 2 years now and continues to enjoy a full and independent life.

Managing Metastatic Thymoma With Metabolic and Medical Therapy: A Case Report.

Thymomas consist of neoplastic thymic cells intermixed with variable numbers of non-neoplastic lymphocytes. Metastatic thymomas are typically managed with non-curative chemotherapy to control tumor-related symptoms; no prolonged survival is expected. Metabolic-based approaches, such as fasting and ketogenic diets, target cancer cell metabolism by creating an increased reliance on ketones while decreasing glucose, glutamine, and growth factor availability, theoretically depriving cancer cells of their metabolic fuels while creating an unfavorable environment for cancer growth, which may be beneficial in metastatic thymoma. We report the case of a 37-year-old woman with myasthenia gravis, diagnosed with an inoperable type AB, stage IVA thymoma, who pursued a metabolic intervention consisting of periodic fasting (7-day, fluid-only fasts every 1-2 months), combined with a modified ketogenic diet on feeding days, for 2 years. Fasting-related adverse effects included cold intolerance, fatigue, and generalized muscle aches, all of which resolved during the second year. She experienced two myasthenia relapses, each associated with profoundly reduced oral intake, marked weight loss, and tumor regression-the first relapse was followed by a 32% decrease in tumor volume over 4 months, the second relapse by a dramatic 96% decrease in tumor volume over 4 months. The second relapse also required prednisone to control the myasthenia symptoms. We hypothesize that 2 years of fasting and ketogenic diet therapy metabolically weakened the neoplastic thymic cell component of the thymoma, "setting the stage" for immune activation and extreme energy restriction to destroy the majority of cancer cells during both relapses, while prednisone-induced apoptosis eradicated the remaining lymphocytic component of the thymoma during the second relapse. This case is unique in that a metabolic-based fasting and ketogenic diet intervention was used as the primary management strategy for a metastatic cancer in the absence of surgery, chemotherapy, or radiotherapy, culminating in a near-complete regression. Nearly 3 years after being diagnosed with inoperable metastatic cancer, our patient shows no signs of disease and leads a full and active life.