Continuous Glucose Monitoring Use in Clinical Trials for On-Market Diabetes Drugs

To the best of our knowledge, there are no published data on the historical and recent use of CGM in clinical trials of pharmacological agents used in the treatment of diabetes. We analyzed 2,032 clinical trials of 40 antihyperglycemic therapies currently on the market with a study start date between 1 January 2000 and 31 December 2019. According to ClinicalTrials.gov, 119 (5.9%) of these trials used CGM. CGM usage in clinical trials has increased over time, rising from <5% before 2005 to 12.5% in 2019. However, it is still low given its inclusion in the American Diabetes Association’s latest guidelines and known limitations of A1C for assessing ongoing diabetes care.

The availability of reliable continuous glucose monitoring (CGM) systems has proven to be a major innovation in diabetes management and research. Most current CGM systems are approved for 7- to 14-day use and use a wire-tipped glucose oxidase sensor inserted in subcutaneous tissue to monitor glucose concentrations in interstitial fluid. One implanted CGM system is approved for longer-term use (90–180 days); it operates with fluorescence-based technology. CGM sensors record a glucose data point every 1–15 minutes (depending on the system), collecting far more granular data and information on glycemic patterns than self-monitoring of blood glucose (SMBG) alone. Real-time CGM or intermittently scanned CGM systems send data continuously or intermittently to dedicated receivers or smartphones, whereas professional CGM systems provide retrospective data, either blinded or unblinded, for analysis and can be used to identify patterns of hypo- and hyperglycemia. Professional CGM can be helpful to evaluate patients when other CGM systems are not available to the patient or the patient prefers a blinded analysis or a shorter experience with unblinded data.In the 20 years since CGM systems first became available to people with diabetes, technological improvements, particularly pertaining to accuracy and form factor, have made CGM increasingly viable for both patient use and clinical investigation (1,2). Average sensor MARD (mean absolute relative difference; a summary accuracy statistic) has decreased from >20 to <10% (3–10), including two systems that do not require fingerstick calibrations and three that are approved to be used for insulin dosing (11). Concurrently, size, weight, and cost of CGM systems have all decreased, while user-friendliness and convenience have increased (12).To encourage use of CGM-derived data, researchers and clinicians have worked to develop a standard set of glycemic metrics beyond A1C. In 2017, two international groups of leading diabetes clinical and research organizations published consensus definitions for key metrics, including clinically relevant glycemic cut points for hypoglycemia (<70 and <54 mg/dL), hyperglycemia (>180 and >250 mg/dL), and time in range (TIR; 70–180 mg/dL) (13,14).CGM-derived metrics provide far greater precision and granularity than is possible with SMBG or A1C data alone (Table 1), enabling clinicians and investigators to better represent inter- and intraday glycemic differences with metrics such as TIR, glycemic variability, and time in hypoglycemia and hyperglycemia (15). Crucially, CGM also allows for the accurate measurement and detection of nocturnal glycemia (16). The use of these metrics enables a more comprehensive understanding of glycemic management that can facilitate individualized treatment for people with diabetes or prediabetes. Although A1C is a useful estimate of mean glucose over the previous 2–3 months, especially when evaluating population health, it is important to include other glycemic outcomes in clinical trials. Furthermore, there is emerging evidence suggesting that TIR predicts the development of microvascular complications at least as well as A1C (17,18).TABLE 1Benefits of CGM Compared With A1C Alone in Assessing Glycemia

Variable clinical presentation of lysosomal beta-mannosidosis in patients with null mutations

Beta-mannosidosis is an autosomal recessive lysosomal storage disease resulting from a deficiency of the lysosomal enzyme beta-mannosidase. The clinical manifestations of this disease in reported human cases are very heterogeneous ranging from relatively mild to moderately severe. This is in contrast with the severe prenatal onset seen in ruminant beta-mannosidosis. In humans, mental retardation, hearing loss, frequent infections, and behavioral problems are relatively common. Dysmorphology and skeletal involvement such as those seen in ruminants are unusual. The purpose of this study is to determine the range of clinical expression in human beta-mannosidosis resulting from null mutations. We determined that the beta-mannosidase gene consists of 17 exons. Intron-based PCR primers were designed and used to amplify each of the exons in genomic DNA isolated from patient fibroblasts. We identified two patients with null mutations. Results of the analysis showed that one patient was heterozygous for nonsense mutations G334T (E83X) in exon 2 and C1363T (Q426X) in exon 10, resulting in truncation of the deduced peptide sequence from 879 to 82 and 425 amino acids, respectively. The second patient was homozygous for a deletion mutation in exon 11 (1541delAT). This deletion causes a reading frame shift and 26 out of frame amino acids before a stop codon occurs in exon 12, resulting in truncation of the deduced peptide sequence from 879 to 510 amino acids. Because disease presentation in these patients with null mutations is very variable, ranging from mild to severe, we conclude that beta-mannosidosis in humans may indeed be milder than typical of other lysosomal storage disorders.     

Distribution of Burkholderia cepacia complex species among isolates recovered from persons with or without cystic fibrosis

We analyzed Burkholderia cepacia complex isolates recovered from 1,218 cystic fibrosis (CF) patients and 90 patients without CF. Although all B. cepacia complex species were found, some were rarely identified. The distribution of species differed between the CF and non-CF populations and appears to be changing over time among CF patients.     

Vaccination with streptococcal extracellular cysteine protease (interleukin-1β convertase) protects mice against challenge with heterologous group A streptococci

Virtually all clinical isolates of group A streptococci secrete a highly conserved extracellular cysteine protease that cleaves human fibronectin and vitronectin, and converts IL-1β precursor to biologically active IL-1β. Based on the high degree of gene conservation within the species and its role in host pathogenicity, it was postulated that antibodies to the cysteine protease would confer protective immunity against S. pyogenes infection. To test this hypothesis, Swiss CD1 mice were intraperitoneally administered either saline, rabbit IgG, or IgG from rabbits immunized with the protease, and challenged with a highly virulent (minimum lethal dose 10 cfu) clinical isolate of S. pyogenes expressing a heterologous cysteine protease. The results indicate that mice administered IgG from rabbits immunized with purified cysteine protease had significantly enhanced survival when compared with mice given either non-specific rabbit IgG (log rank test; χ²; p = 0.0195) or saline (log rank test; χ²; p = 0.0002). Moreover, mice actively immunized with the cysteine protease had a significantly longer time to death than the control group (log rank test; χ²; p = 0.0418). The results show that the cysteine protease elicits non-type-specific immunity to challenge with heterologous S. pyogenes.     

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Glucose Ingestion Attenuates Interleukin-6 Release from Contracting Skeletal Muscle in Humans

To examine whether glucose ingestion during exercise affects the release of interleukin-6 (IL-6) from the contracting limb, seven men performed 120 min of semi-recumbent cycling on two occasions while ingesting either 250 ml of a 6.4 % carbohydrate (GLU trial) or sweet placebo (CON trial) beverage at the onset of, and at 15 min intervals throughout, exercise. Muscle biopsies obtained before and immediately after exercise were analysed for glycogen and IL-6 mRNA expression. Blood samples were simultaneously obtained from a brachial artery and a femoral vein prior to and during exercise and leg blood flow was measured by thermodilution in the femoral vein. Net leg IL-6 release, and net leg glucose and free fatty acid (FFA) uptake, were calculated from these measurements. The arterial IL-6 concentration was lower (   P < 0.05  ) after 120 min of exercise in GLU, but neither intramuscular glycogen nor IL-6 mRNA were different when comparing GLU with CON. However, net leg IL-6 release was attenuated (   P < 0.05  ) in GLU compared with CON. This corresponded with an enhanced (   P < 0.05  ) glucose uptake and a reduced (   P < 0.05  ) FFA uptake in GLU. These results demonstrate that glucose ingestion during exercise attenuates leg IL-6 release but does not decrease intramuscular expression of IL-6 mRNA.     

Neutrophil mobilization and clearance in the bone marrow

The bone marrow is the site of neutrophil production, a process that is regulated by the cytokine granulocyte colony‐stimulating factor (G‐CSF). Mature neutrophils are continually released into the circulation, with an estimated 10 11 neutrophils exiting the bone marrow daily under basal conditions. These leucocytes have a short half‐life in the blood of ～6·5 hr, and are subsequently destroyed in the spleen, liver and indeed the bone marrow itself. Additionally, mature neutrophils are retained in the bone marrow by the stromal cell‐derived factor (SDF‐1α)/chemokine (C‐X‐C motif) receptor 4 (CXCR4) chemokine axis and form the bone marrow reserve. Following infection or inflammatory insult, neutrophil release from the bone marrow reserve is substantially elevated and this process is mediated by the co‐ordinated actions of cytokines and chemokines. In this review we discuss the factors and molecular mechanisms regulating the neutrophil mobilization and consider the mechanisms and functional significance of neutrophil clearance via the bone marrow.     

Brain responses associated with the Valsalva maneuver revealed by functional magnetic resonance imaging

The Valsalva maneuver, a test frequently used to evaluate autonomic function, recruits discrete neural sites. The time courses of neural recruitment relative to accompanying cardiovascular and breathing patterns are unknown. We examined functional magnetic resonance imaging signal changes within the brain to repeated Valsalva maneuvers and correlated these changes with physiological trends. In 12 healthy subjects (age, 30-58 yr), a series of 25 volumes (20 gradient echo echo-planar image slices per volume) was collected using a 1.5-Tesla scanner during a 60-s baseline and 90-s challenge period consisting of three Valsalva maneuvers. Regions of interest were examined for signal intensity changes over baseline and challenge conditions in cardiorespiratory-related regions. In addition, whole brain correlations between signal intensity and heart rate and airway load pressure were performed on a voxel-by-voxel basis. Significant signal changes, correlated with the time course of load pressure and heart rate, emerged within multiple areas, including the amygdala and hippocampus, insular and lateral frontal cortices, dorsal pons, dorsal medulla, lentiform nucleus, and fastigial and dentate nuclei of the cerebellum. Signal intensities peaked early in the Valsalva maneuver within the hippocampus and amygdala, later within the dorsal medulla, pons and midbrain, and deep cerebellar nuclei, and last within the lentiform nuclei and the lateral prefrontal cortex. The ventral pontine signals increased during the challenge, but not in a fashion correlated to load pressure or heart rate. Sites showing little or no correlation included the vermis and medial prefrontal cortex. These data suggest an initiating component arising in rostral brain areas, a later contribution from cerebellar nuclei, basal ganglia, and lateral prefrontal cortex, and a role for the ventral pons in mediating longer term processes.     

Quality of life profiles and their association with clinical and demographic characteristics and physical activity in people with a stoma: a latent profile analysis

Quality of Life Research - Quality of life can be negatively impacted by the formation of a stoma and is influenced by a number of factors. Research to date treats people with a stoma as a...