Apolipoprotein A-IV Concentrations and Clinical Outcomes In A Large CKD Cohort
ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
KEY FINDINGS: The data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
BACKGROUND: Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD. Study aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.
DETAILS: This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m2 or an eGFR >60 ml/min/1.73m2 in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders. Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01).
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Source: Schwaiger, J. P., Kollerits, B., Steinbrenner, I., et al. (2022). Apolipoprotein A-IV Concentrations And Clinical Outcomes In A Large Chronic Kidney Disease Cohort: Results from the GCKD Study. Journal of Internal Medicine. 2022; 291(5): 622-636. Published: May, 2022. DOI: 10.1111/joim.13437.
Oral Linezolid Compared With Benzathine Penicillin G for Treatment of Early Syphilis in Adults (Trep-AB Study) in Spain
The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.
Summary
A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial
[Posted 8/Apr/2024]
AUDIENCE: Infectious Disease, Family Medicine
KEY FINDINGS: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.
BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG).
DETAILS: Authors did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. Authors recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2.4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49.8 to 86.2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87.7 to 100.0) in the BPG group (treatment difference -29.6, 95% CI -50.5 to -8.8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5.8 to 35.8 in the linezolid group vs five [17%] of 30, 5.6 to 34.7, in the BPG group). No serious adverse events were reported during follow-up.
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Source: Ubals, M., Nadal-Baron, P., Arando, M., et al. (2024). Oral Linezolid Compared With Benzathine Penicillin G for Treatment of Early Syphilis in Adults (Trep-AB Study) in Spain: A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial. The Lancet. 2024; 24(4): 404-416. Published: April, 2024. DOI: 10.1016/S1473-3099(23)00683-7.
GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia
GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
KEY FINDINGS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia.
DETAILS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen.
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Source: Honkanen E. A., Rönkä J., Pekkonen E., et al. (2024). GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia. Journal of Neurology, Neurosurgery & Psychiatry. 2024; 95(4): 300-308. Published: April, 2024. DOI: 10.1136/jnnp-2023-331668.
Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies
HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
KEY FINDINGS: HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
BACKGROUND: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans.
DETAILS: The study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to TSC2 variants, 5 individuals with focal cortical dysplasia type IIA (FCD IIA) due to genetic variants in MTOR, AKT3, and PIK3CA, and 10 individuals with FCD IIB due to variants in TSC1, MTOR, RHEB, DEPDC5, or NPRL3). Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues (p < 0.0001) compared with those in controls, regardless of genetic cause or variant allele frequency. Elevated HCN4 was not observed in controls or individuals with non-mTOR-related focal epilepsy due to pathogenic variants in ATP1A3, SLC35A2, or FGFR1.
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Source: Coleman, M., Pinaes-Garcia, P., Stephenson, S. E., et al. (2024). Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies. Neuro Genetics. 2024; 10(2). Published: March, 2024. DOI: 10.1212/NXG.0000000000200135.
Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis
By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.
KEY FINDINGS: By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.
BACKGROUND: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.
DETAILS: Authors performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). Authors also conducted immunofluorescence staining and functional experiments to examine the mechanism. Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.
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Source: Li, R., Liu, X., Huang, X., et al. (2024). Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis. Gut. 2024; 73(3): 470-484 .Published: March, 2024. DOI: 10.1136/gutjnl-2023-330243.
Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant
This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
KEY FINDINGS: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
BACKGROUND: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.
DETAILS: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.
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Source: Baskar, D., Polavarapu, K., Preethish-kumar, V., et al. (2024). Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant. Neuro Genetics. 2024; 10(1): Published: February, 2024. DOI: 10.1212/NXG.000000000020012.
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