Lineage BA.2 dominated the Omicron SARS-CoV-2 epidemic wave in the Philippines.

The Omicron severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant led to a dramatic global epidemic wave following detection in South Africa in November 2021. The BA.1 Omicron lineage was dominant and responsible for most SARS-CoV-2 outbreaks in countries around the world during December 2021-January 2022, while other Omicron lineages, including BA.2, accounted for the minority of global isolates. Here, we describe the Omicron wave in the Philippines by analysing genomic data. Our results identify the presence of both BA.1 and BA.2 lineages in the Philippines in December 2021, before cases surged in January 2022. We infer that only the BA.2 lineage underwent sustained transmission in the country, with an estimated emergence around 18 November 2021 (95 per cent highest posterior density: 6-28 November), while despite multiple introductions, BA.1 transmission remained limited. These results suggest that the Philippines was one of the earliest areas affected by BA.2 and reiterate the importance of whole genome sequencing for monitoring outbreaks.

Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis.

BACKGROUND: To enable intravascular detection of inflammation in atherosclerosis, we developed a near-infrared fluorescence (NIRF) catheter-based strategy to sense cysteine protease activity during vascular catheterization. METHODS AND RESULTS: The NIRF catheter design was based on a clinical coronary artery guidewire. In phantom studies of NIRF plaques, blood produced only a mild (<30%) attenuation of the fluorescence signal compared with saline, affirming the favorable optical properties of the NIR window. Catheter evaluation in vivo used atherosclerotic rabbits (n=11). Rabbits received an injection of a cysteine protease-activatable NIRF imaging agent (Prosense750; excitation/emission, 750/770 nm) or saline. Catheter pullbacks through the blood-filled iliac artery detected NIRF signals 24 hours after injection of the probe. In the protease agent group, the in vivo peak plaque target-to- BACKGROUND: <0.05). Ex vivo fluorescence reflectance imaging corroborated these results (target-to- BACKGROUND: <0.01). In the protease group only, saline flush-modulated NIRF signal profiles further distinguished atheromata from normal segments in vivo (P<0.01). Good correlation between the in vivo and ex vivo plaque target-to- BACKGROUND: =0.82, P<0.01). Histopathological analyses demonstrated strong NIRF signal in plaques only from the protease agent group. NIRF signals colocalized with immunoreactive macrophages and the cysteine protease cathepsin B. CONCLUSIONS: An intravascular fluorescence catheter can detect cysteine protease activity in vessels the size of human coronary arteries in real time with an activatable NIRF agent. This strategy could aid in the detection of inflammation and high-risk plaques in small arteries.

Predictive factors for in-stent late loss and coronary lesion progression in patients with type 2 diabetes mellitus randomized to rosiglitazone or placebo.

BACKGROUND: Type 2 diabetics (DM2) are at increased risk for restenosis as well as nonculprit coronary artery lesion (NCCL) progression. Rosiglitazone (RSG) favorably modifies many of the altered biologic processes in DM2, although recent reports have questioned its safety. We conducted a double-blind randomized trial to assess the effects of RSG versus placebo on in-stent late lumen loss (LL) and angiographic progression of NCCL. METHODS: A total of 65 DM2 were randomized to RSG (4 mg/d) (n = 32) or placebo (n = 33) at the time of stenting and underwent clinical and laboratory analysis at 1 and 4 months and 8-month angiography (n = 46 patients). Rapid angiographic progression (RAP) was defined as > or =20% diameter reduction of preexisting NCCL by quantitative coronary angiography, or a new narrowing > or =30%. RESULTS: Mean LL in RSG (n = 33 lesions) was not different from that of placebo (0.62 +/- 0.59 vs 0.70 +/- 0.67, P = NS). Seven (13.5%) of 52 NCCLs have RAP in RSG versus 9 (16.1%) of 56 in placebo (P = NS). High-sensitivity C-reactive protein (hs-CRP) was the only predictor of RAP. Patients with a 120-day hs-CRP > or =75th percentile had an OR of 7.35 (95% CI 2.35-23) for RAP versus those below. Although RSG treatment also lowered log (hs-CRP) at 4 months (RSG 0.10 +/- 0.37 vs placebo 0.26 +/- 0.49, P = .06), it did not decrease the likelihood of plaque progression while also raising LDL and N-terminal brain naturetic peptide. CONCLUSIONS: Rosiglitazone appears not to lower LL or reduce angiographic progression of NCCL in DM2 and had complex effects on markers of cardiac risk.

Site-specific targeting of nanoparticle prednisolone reduces in-stent restenosis in a rabbit model of established atheroma.

OBJECTIVE: TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids. METHODS AND RESULTS: Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03). CONCLUSIONS: TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

The significance of preclinical evaluation of sirolimus-, paclitaxel-, and zotarolimus-eluting stents.

Comparative preclinical histologic studies remain the most effective method for assessing the healing characteristics of vascular stents. The 2 most commonly used animal models to assess vascular responses to stent implantation are the porcine coronary artery and the rabbit iliac artery. Neither model alone is comparable to the human response to the implantation of a drug-eluting stent (DES). In the rabbit model at 28 days, the pathologies of the zotarolimus-eluting stent (ZES), the paclitaxel-eluting stent (PES), the sirolimus-eluting stent (SES), and a bare metal stent (BMS) were assessed. There was less inflammation with the ZES than with the SES or PES, and there were uncovered struts with the SES and PES but not with the ZES and BMS. In the pig model at 30, 90, and 180 days, the pathologies of the ZES, SES, and BMS were assessed. At 30 days, the thickness of neointima and the grade of inflammation were less with the SES than with the ZES and BMS, but at 90 and 180 days, the measures increased for the SES and were greater than those with the ZES and BMS, whereas the measures for the ZES and BMS did not change over time. In the rabbit model, the endothelialization of overlapping the SES, PES, and ZES was assessed. There was significantly greater endothelialization in the area above stent struts in the overlapping segment for the ZES than for the SES (p = 0.028). The level of endothelialization for the PES was less than that for the ZES, but the difference was not significant. Because arterial healing is multifactorial, it is extremely important that the next generation of DESs undergo preclinical testing in pig and rabbit models to examine endothelialization, inflammation, release kinetics, and neointimal reduction to establish the safety of these devices in humans.

Time course of stent endothelialization after intravascular radiation therapy in rabbit iliac arteries.

BACKGROUND: Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown. METHODS AND RESULTS: Seventy-two rabbit iliac arteries underwent stent implantation and were treated with gamma-radiation using 192Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66+/-0.07 and 0.66+/-0.04 mm2, respectively) compared with controls (1.01+/-0.11 mm2, P<0.05) and at 6 months with 30 Gy (0.75+/-0.09 versus 1.28+/-0.26 mm2 in controls, P<0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92+/-4% of the control stented segment was covered with endothelial cells, whereas only 37+/-4% and 37+/-8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95+/-2%, 32+/-12%, and 29+/-13%; and at 6 months, 98+/-2%, 40+/-8%, and 35+/-12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium. CONCLUSIONS: Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.

Everolimus-eluting stents improve vascular response in a diabetic animal model.

BACKGROUND: Preclinical evaluation of the vascular response of drug-eluting stents is limited especially in the setting of diabetes mellitus preventing the evaluation of changes in drug-eluting stent design and eluted drugs after clinical use. METHODS AND RESULTS: Cultured human aortic endothelial cells were used to assess the differences between sirolimus and its analog, everolimus, in the setting of hyperglycemia on various cellular functions necessary for endothelial recovery. A diabetic rabbit model of iliac artery stenting was used to compare histological and morphometric characteristics of the vascular response to everolimus-eluting, sirolimus-eluting, and bare metal stent placement. Under hyperglycemic conditions, sirolimus impaired human aortic endothelial cell barrier function, migration, and proliferation to a greater degree compared with everolimus. In our in vivo model of diabetes mellitus, endothelialization at 28 days was significantly lower and endothelial integrity was impaired in sirolimus-eluting stent compared with both everolimus-eluting and bare metal stents. Neointimal area, uncovered struts, and fibrin deposition were significantly higher in sirolimus-eluting compared with everolimus-eluting and bare metal stents. CONCLUSIONS: Use of everolimus-eluting stent results in improved vascular response in our preclinical models of diabetes mellitus.

Differential healing responses in polymer- and nonpolymer-based sirolimus-eluting stents.

OBJECTIVES: We compared the healing and inflammatory responses of polymer-free bare-metal stents (BMS), polymer-free sirolimus-eluting stents (SES) and polymer-free sirolimus-eluting stents plus estradiol (SES+ED) to Cypher drug-eluting stents (CDES) in a rabbit model of overlapping stent placement. BACKGROUND: Inflammatory responses to polymers and delayed healing remain important safety issues associated with CDES. Whether nonpolymeric stents that elute sirolimus or sirolimus and estradiol provoke less inflammation and heal better is unknown. METHODS: Twenty-eight rabbits received 2 overlapping stents in each iliac artery: SES, SES+ED, BMS, or CDES, and vessels were harvested at 28 days for histology and scanning electron microscopy. RESULTS: Although similar at nonoverlapping segments, neointimal thickness within the overlap site of CDES was significantly less than in SES, SES+ED, and BMS (0.07 +/- 0.04 mm vs. 0.16 +/- 0.03 mm, 0.14 +/- 0.03 mm, and 0.15 +/- 0.03 mm, p < 0.0001). Endothelialization was greater in SES, SES+ED, and BMS compared with CDES in nonoverlapping sections (80.0 +/- 5.0% vs. 95.3 +/- 5.0%, 97.5 +/- 2.5%, and 96.7 +/- 3.8%; p = 0.0028) and overlapping sections (85.8 +/- 2.9% vs. 90.8 +/- 6.3%, 89.2 +/- 6.3%, and 48.3 +/- 2.9%; p < 0.0001). The number of luminal eosinophils was also less in overlapping sections of SES, SES+ED, and BMS versus CDES but was similar in nonoverlapping sections. CONCLUSIONS: Polymer-free stents coated with SES or SES+ED result in less robust neointimal suppression but markedly improved arterial healing compared with CDES in the rabbit model.