Human metabolism: pathways and clinical aspects

Metabolism describes the series of chemical reactions that are concerned with the provision of energy to biological systems. They may be divided into reactions involved in energy yield (catabolism: demand exceeds supply), and energy storage (anabolism: supply exceeds demand). Regulation of these pathways is critical for homeostasis, and derangements in metabolism are seen in a wide variety of pathological processes. Understanding metabolism is key to the treatment of many diseases, notably diabetes, as well as underpinning clinical nutritional support.     

Effect of obstructive sleep apnoea on retinal microvascular function: a randomised controlled trial

Graefe's Archive for Clinical and Experimental Ophthalmology - Retinal microvascular endothelial dysfunction is thought to be of importance in the development of ocular vascular diseases....     

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Radiation dose reduction in CT-guided cryoablation of renal tumors

PURPOSEWe aimed to evaluate the effect on the radiation dose to the patient by reducing the tube current during the placement of the ablation needles (reduced dose group) compared with the patient doses delivered when scanning at the standard fully diagnostic level (full dose group) in computed tomography (CT)-guided percutaneous cryoablation.METHODSWe conducted a retrospective study of 103 patients undergoing cryoablation in a tertiary cancer center. Overall, 62 patients were scanned with standard exposure parameters (full dose group) set on a 64-slice multidetector CT scanner, while 41 patients were scanned on a reduced dose protocol. Dose levels were retrieved from the hospital picture and archiving communication system including the volumetric CT dose index (CTDIvol), total dose length product (DLP), length of cryoablation procedure, number of cryoablation needles and patient size. Wilcoxon Mann-Whitney (rank-sum) tests were used to compare the median DLP, CTDIvol and skin dose between the two groups.RESULTSMedian total DLP for the full dose group was 6025 mGy·cm (1909–13353 mGy·cm) compared with 3391 mGy·cm (1683–6820 mGy·cm) for the reduced dose group. The reduced dose group had a 44% reduction in total DLP and 42% reduction in total CTDIvol (p < 0.001). The estimated skin doses were 384 mGy for the full dose group and 224 mGy for the reduced dose group (42% reduction) (p < 0.001). At 12-month follow-up, the technical success for the full dose (n=62) was 97% with 2 patients requiring a further cryoablation treatment for residual tumor. The technical success for the reduced dose group (n=41) was 100%.CONCLUSIONCT dose reduction technique during image-guided cryoablation treatment of renal tumors can achieve significant radiation dose reduction whilst maintaining sufficient image quality.

Renal cell carcinoma is the most common kidney cancer and has a rising incidence (1–4), with obesity and smoking being major risk factors (5–8).Image-guided ablation offers a more minimally invasive option compared with surgery and the current evidence base shows that it is a safe and effective treatment for T1a tumors, with a low rate of complications (9–11). The major advantage of cryoablation over other modalities is the ability to accurately visualize the iceball and therefore zone of ablation on intraprocedural imaging, either with computed tomography (CT) or magnetic resonance imaging (MRI) (12, 13). However, renal cryoablation involves the placement of more ablation probes and can have almost three times the radiation exposure compared with CT-guided radiofrequency ablation procedures (14).In addition to this substantial radiation dose per cryoablation, estimated to be between 32 and 39.7 mSv, the follow-up CT imaging will also add to the total radiation burden (15, 16). Whilst this level of radiation dose and associated stochastic risk may be a lesser concern in the older patients, greater consideration needs to be given to younger patients (<50 years old) and in patients requiring lifelong follow-up imaging, in particular those with hereditary diseases such as Von Hippel-Lindau syndrome (15). To our knowledge, the potential for reducing radiation dose for cryoablation patients.The principle aim of this study was to evaluate the effect on the radiation dose to the patient by reducing the tube current during the placement of the ablation needles (reduced dose group) compared with the patient doses delivered when scanning at the standard fully diagnostic level (full dose group) in CT-guided percutaneous cryoablation.     

Epithelial ovarian cancer risk: A review of the current genetic landscape

Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.     

Embryonic skull development in the gecko,Tarentola annularis (Squamata: Gekkota: Phyllodactylidae)

Tarentola annularis is a climbing gecko with a wide distribution in Africa north of the equator. In the present paper, we describe the development of the osteocranium of this lizard, from the first appearance of the cranial elements up to the point of hatching. This is based on a combination of histology and cleared and stained specimens. This is the first comprehensive account of gekkotan pre-hatching skull development based on a comprehensive series of embryos, rather than a few selected stages. Given that Gekkota is now widely regarded as representing the sister group to other squamates, this account helps to fill a significant gap in the literature. Moreover, as many authors have considered features of the gekkotan skull and skeleton to be indicative of paedomorphosis, it is important to know whether this hypothesis is supported by delays in the onset of cranial ossification. In fact, we found the sequence of cranial bone ossification to be broadly comparable to that of other squamates studied to date, with no significant lags in development.     

Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4⁺ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection.METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4⁺ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment.RESULTS. Frequencies of Mtb-specific IFN-γ⁺CD4⁺ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38⁺IFN-γ⁺, HLA-DR⁺IFN-γ⁺, and Ki-67⁺IFN-γ⁺, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4⁺ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure.TRIAL REGISTRATION. Registration is not required for observational studies.FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.