Investigating COVID-19 Vaccine Impact on the Risk of Hospitalisation through the Analysis of National Surveillance Data Collected in Belgium

The national vaccination campaign against SARS-CoV-2 started in January 2021 in Belgium. In the present study, we aimed to use national hospitalisation surveillance data to investigate the recent evolution of vaccine impact on the risk of COVID-19 hospitalisation. We analysed aggregated data from 27,608 COVID-19 patients hospitalised between October 2021 and February 2022, stratified by age category and vaccination status. For each period, vaccination status, and age group, we estimated risk ratios (RR) corresponding to the ratio between the probability of being hospitalised following SARS-CoV-2 infection if belonging to the vaccinated population and the same probability if belonging to the unvaccinated population. In October 2021, a relatively high RR was estimated for vaccinated people > 75 years old, possibly reflecting waning immunity within this group, which was vaccinated early in 2021 and invited to receive the booster vaccination at that time. In January 2022, a RR increase was observed in all age categories coinciding with the dominance of the Omicron variant. Despite the absence of control for factors like comorbidities, previous infections, or time since the last administered vaccine, we showed that such real-time aggregated data make it possible to approximate trends in vaccine impact over time.     

Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.     

Obesity Blunts Microvascular Recruitment in Human Forearm Muscle After a Mixed Meal

OBJECTIVE

Ingestion of a mixed meal recruits flow to muscle capillaries and increases total forearm blood flow in healthy young lean people. We examined whether these vascular responses are blunted by obesity.

RESEARCH DESIGN AND METHODS

We fed eight middle-aged lean and eight obese overnight-fasted volunteers a liquid mixed meal (480 kcal). Plasma glucose and insulin were measured every 30 min, and brachial artery flow and muscle microvascular recruitment (contrast ultrasound) were assessed every 60 min over 2 h after the meal.

RESULTS

By 30 min, plasma glucose rose in both the lean (5.1 ± 0.1 vs. 6.7 ± 0.4 mmol/l, P < 0.05) and the obese groups (5.4 ± 0.2 vs. 6.7 ± 0.4 mmol/l, P < 0.05). Plasma insulin rose (28 ± 4 vs. 241 ± 30 pmol/l, P < 0.05) by 30 min in the lean group and remained elevated for 2 h. The obese group had higher fasting plasma insulin levels (65 ± 8 pmol/l, P < 0.001) and a greater postmeal area under the insulin-time curve (P < 0.05). Brachial artery flow was increased at 120 min after the meal in the lean group (38 ± 6 vs. 83 ± 16 ml/min, P < 0.05) but not in the obese group. Muscle microvascular blood volume rose by 120 min in the lean group (14.4 ± 2.2 vs. 24.4 ± 4.2 units, P < 0.05) but not in the obese group.

CONCLUSIONS

A mixed meal recruits muscle microvasculature in lean subjects, and this effect is blunted by obesity. This impaired vascular recruitment lessens the endothelial surface available and may thereby impair postprandial glucose disposal.Skeletal muscle is a major site for insulin-mediated glucose storage and thereby influences postprandial plasma glucose levels (1). Over the past 15 years it has become increasingly evident that insulin exerts important actions on muscle vasculature as an integral part of its action to increase glucose disposal (2–5). Within muscle the vascular endothelium is the first tissue that insulin encounters. A primary function of the endothelium is to serve as a permeability barrier that restricts transport of macromolecules such as insulin into the interstitial space. In addition to modulating delivery of insulin to muscle cells, the endothelium also directly responds to insulin by increasing production of nitric oxide, a potent vasodilator, and endothelin-1, a potent vasoconstrictor, to regulate muscle blood flow (6,7).Baron and colleagues (2,8,9) hypothesized that insulin increases leg blood flow to facilitate access of glucose and insulin to muscle, thereby increasing glucose disposal. Blocking insulin-induced increases in blood flow reduced insulin-stimulated glucose disposal by ∼30%. Furthermore, this vascular action of insulin was significantly blunted in insulin-resistant obese humans (8).These investigators used a thermodilution method that measured only total limb blood flow and not microvascular responses. Others have measured the effect of insulin on limb blood flow using a variety of methods with divergent findings (10,11). Our laboratories have developed new methods that assess the microvascular action of insulin in muscle (3,5,12,13). We reasoned that microvascular perfusion directly mediates nutrient exchange in muscle (14). We have previously shown that insulin acts on preterminal arterioles (which control microvascular blood flow) more rapidly and at more physiologically relevant insulin concentrations than is the case for resistance arteries (which control total muscle blood flow) (3,5,12).Using contrast-enhanced ultrasound (CEU) and the euglycemic insulin clamp method, we observed that physiological hyperinsulinemia expands the volume of microvasculature perfused in forearm muscle of healthy lean people (4,15) and that this action of insulin is markedly impaired in obese subjects (4). Indeed, we observed a negative correlation between insulin-mediated microvascular recruitment in muscle and BMI (4). Although the clamp technique provides an excellent assessment of the physiological actions of insulin, it does not mimic the changes that typically occur after the ingestion of a mixed meal. With the meal there are changes in blood glucose, amino acids, gut hormones, and parasympathetic/sympathetic tone. Few studies have reported on the effect of a meal on total limb blood flow, and these have yielded conflicting results. Although some investigators reported that the ingestion of a mixed meal (16) or an oral glucose load (17) increased total limb blood flow, others reported no effect (18). These differences may relate to techniques used to measure flow, the types of meals ingested, and differences in the population studied. However, in each of these clinical studies, investigators have measured only total limb blood flow and not microvascular responses.We have recently reported that ingestion of a mixed meal by lean young adults increases total forearm blood flow and increases microvascular flow (19). These vascular responses occurred at a time when plasma insulin was significantly elevated. Whether total muscle blood flow along with muscle microvascular recruitment after the ingestion of a mixed meal is normal or blunted in insulin-resistant obese subjects is unknown, and addressing this issue was the goal of the current study. We used Doppler ultrasound to study total forearm blood flow and CEU to quantify muscle microvascular responses of forearm muscle in healthy lean and otherwise healthy obese age-matched adults in response to a mixed meal. We hypothesized that both total limb blood flow and the microvascular response would be blunted by obesity.     

The oxygen radical generator pyrogallol impairs cardiomyocyte contractile function via a superoxide and p38 MAP kinase-dependent pathway

Oxygen-derived free radicals have been demonstrated to contribute to the pathogenesis of myocardial dysfunction, although the underlying mechanism remains not fully understood. This study was designed to examine the role of the superoxide generator pyrogallol on cardiac contractile function and possible intervention with herbal medicines anisodamine and tetramethylpyrazine (TMP) on pyrogallol-induced cardiac contractile response. Adult rat ventricular myocytes were isolated and stimulated to contract at 0.5 Hz. Mechanical properties were evaluated using an lonOptix system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR₉₀), and maximal velocity of shortening/relengthening (±dL/dt). A 10-min exposure of pyrogallol (0 to 10⁻² M) did not affect cardiac contractile mechanics. However, longer duration of pyrogallol exposure (1, 3, and 6 h) significantly shortened resting cell length, reduced PS and ±dL/dt, and prolonged TPS and TR₉₀ in time- and concentration-dependent manners. The pyrogallol (10⁻⁴ M with 6-h incubation)-induced mechanical defects were prevented by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (1 μM) and superoxide dismutase (SOD, 500 U/mL) with the exception that pyrogallol-induced PS depression was unaffected by SOD. Interestingly, incubation of herbal antioxidants anisodamine (10⁻⁷ M) and TMP (10⁻⁷ M) effectively attenuated the pyrogallol-induced cardiac mechanical defects with the exception of PS unaffected by TMP. Our data demonstrate a direct inhibitory effect of pyrogallol on cardiac contraction, probably in a superoxide- and p38 MAP kinase-dependent manner. The antioxidant medicines anisodamine and TMP may be useful in the treatment of oxygen free radical-induced myocardial dysfunction.     

Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical library screen and antileishmanial activity

The CRK3 cyclin-dependent kinase of Leishmania has been shown by genetic manipulation of the parasite to be essential for proliferation. We present data which demonstrate that chemical inhibition of CRK3 impairs the parasite's viability within macrophages, thus further validating CRK3 as a potential drug target. A microtiter plate-based histone H1 kinase assay was developed to screen CRK3 against a chemical library enriched for protein kinase inhibitors. Twenty-seven potent CRK3 inhibitors were discovered and screened against Leishmania donovani amastigotes in vitro. Sixteen of the CRK3 inhibitors displayed antileishmanial activity, with a 50% effective dose (ED50) of less than 10 microM. These compounds fell into four chemical classes: the 2,6,9-trisubstituted purines, including the C-2-alkynylated purines; the indirubins; the paullones; and derivatives of the nonspecific kinase inhibitor staurosporine. The paullones and staurosporine derivatives were toxic to macrophages. The 2,6,9-trisubstituted purines inhibited CRK3 in vitro, with 50% inhibitory concentrations ranging from high nanomolar to low micromolar concentrations. The most potent inhibitors of CRK3 (compounds 98/516 and 97/344) belonged to the indirubin class; the 50% inhibitory concentrations for these inhibitors were 16 and 47 nM, respectively, and the ED50s for these inhibitors were 5.8 and 7.6 microM, respectively. In culture, the indirubins caused growth arrest, a change in DNA content, and aberrant cell types, all consistent with the intracellular inhibition of a cyclin-dependent kinase and disruption of cell cycle control. Thus, use of chemical inhibitors supports genetic studies to confirm CRK3 as a validated drug target in Leishmania and provides pharmacophores for further drug development.     

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.     

Temperature measurement in pediatrics: a comparison of the rectal method versus the temporal artery method

The purpose of this study was to determine if there is a difference between temperature readings obtained using two different electronic temperature devices: one measuring temporal artery temperature (TAT) and one measuring rectal temperature (RT). A comparative single-group design was used with each participant acting as his or her control. The sample consisted of 47 pediatric patients between 3 and 36 months of age. Data analysis revealed no statistically significant differences between TAT and RT; however, concerns related to statistical significance versus clinical significance are discussed.