Modelling the impact of reopening schools in the UK in early 2021 in the presence of the alpha variant and with roll-out of vaccination against SARS-CoV-2.

Following the resurgence of the COVID-19 epidemic in the UK in late 2020 and the emergence of the alpha (also known as B117) variant of the SARS-CoV-2 virus, a third national lockdown was imposed from January 4, 2021. Following the decline of COVID-19 cases over the remainder of January 2021, the question of when and how to reopen schools became an increasingly pressing one in early 2021. This study models the impact of a partial national lockdown with social distancing measures enacted in communities and workplaces under different strategies of reopening schools from March 8, 2021 and compares it to the impact of continual full national lockdown remaining until April 19, 2021. We used our previously published agent-based model, Covasim, to model the emergence of the alpha variant over September 1, 2020 to January 31, 2021 in presence of Test, Trace and Isolate (TTI) strategies. We extended the model to incorporate the impacts of the roll-out of a two-dose vaccine against COVID-19, with 200,000 daily vaccine doses prioritised by age starting with people 75 years or older, assuming vaccination offers a 95% reduction in disease acquisition risk and a 30% reduction in transmission risk. We used the model, calibrated until January 25, 2021, to simulate the impact of a full national lockdown (FNL) with schools closed until April 19, 2021 versus four different partial national lockdown (PNL) scenarios with different elements of schooling open: 1) staggered PNL with primary schools and exam-entry years (years 11 and 13) returning on March 8, 2021 and the rest of the schools years on March 15, 2020; 2) full-return PNL with both primary and secondary schools returning on March 8, 2021; 3) primary-only PNL with primary schools and exam critical years (years 11 and 13) going back only on March 8, 2021 with the rest of the secondary schools back on April 19, 2021 and 4) part-rota PNL with both primary and secondary schools returning on March 8, 2021 with primary schools remaining open continuously but secondary schools on a two-weekly rota-system with years alternating between a fortnight of face-to-face and remote learning until April 19, 2021. Across all scenarios, we projected the number of new daily cases, cumulative deaths and effective reproduction number R until April 30, 2021. Our calibration across different scenarios is consistent with alpha variant being around 60% more transmissible than the wild type. We find that strict social distancing measures, i.e. national lockdowns, were essential in containing the spread of the virus and controlling hospitalisations and deaths during January and February 2021. We estimated that a national lockdown over January and February 2021 would reduce the number of cases by early March to levels similar to those seen in October 2020, with R also falling and remaining below 1 over this period. We estimated that infections would start to increase when schools reopened, but found that if other parts of society remain closed, this resurgence would not be sufficient to bring R above 1. Reopening primary schools and exam critical years only or having primary schools open continuously with secondary schools on rotas was estimated to lead to lower increases in cases and R than if all schools opened. Without an increase in vaccination above the levels seen in January and February, we estimate that R could have increased above 1 following the reopening of society, simulated here from April 19, 2021. Our findings suggest that stringent measures were integral in mitigating the increase in cases and bringing R below 1 over January and February 2021. We found that it was plausible that a PNL with schools partially open from March 8, 2021 and the rest of the society remaining closed until April 19, 2021 would keep R below 1, with some increase evident in infections compared to continual FNL until April 19, 2021. Reopening society in mid-April, without an increase in vaccination levels, could push R above 1 and induce a surge in infections, but the effect of vaccination may be able to control this in future depending on the transmission blocking properties of the vaccines.

Coronary artery perforations in the contemporary interventional era.

BACKGROUND: Coronary perforations represent a serious complication of percutaneous coronary intervention (PCI). METHODS: We performed a retrospective analysis of documented coronary perforations at Massachusetts General Hospital from 2000 to 2008. Medical records review and detailed angiographic analysis were performed in all patients. RESULTS: Sixty-eight cases of coronary perforation were identified from a total of 14,281 PCIs from March 2000 to March 2008 representing an overall incidence of 0.48%. The study cohort was predominantly male (61.8%), mean age 71+/-11 years with 78% representing acute cases (unstable angina: 36.8%, NSTEMI: 30.9%, STEMI: 10.3%). Coronary artery perforation occurred as a complication of wire manipulation in 45 patients (66.2%) with 88.9% of this group being hydrophilic wires, of coronary stenting in 11 (16.2%), of angioplasty alone in 6 (8.8%), and of rotational atherectomy in 8 (11.8%). The perforation was sealed with an angioplasty balloon alone in 16 patients (23.5%), and with stents in 14 patients (20.6%) (covered stents: 11.8% and noncovered stents: 8.8%). Emergency CABG was performed in 2 patients (2.9%). Five patients (7.4%) developed periprocedural MI. The in-hospital mortality rate was 5.9% in the study cohort. CONCLUSION: Coronary artery perforation as a complication of PCI is still rare as demonstrated in our series with an incidence of 0.48%. The predominant cause of coronary perforations in the current era of PCI is wire injury.

Restenosis of endovascular stents from stent compression.

OBJECTIVES: We sought to determine the basis for restenosis within superficial femoral arteries (SFAs) and hemodialysis conduits treated with balloon-expandable stents. BACKGROUND: Use of stents within coronary and peripheral vessels continues to increase exponentially. The mechanism of restenosis within stents placed at various vascular sites is not well understood. In particular, the implications of deploying a balloon-expandable stent in a compressible site are not well understood. METHODS: After the serendipitous detection of stent deformation during intravascular ultrasound (IVUS) examination of a restenosed dialysis fistula, we evaluated a consecutive series of patients with stents placed in compressible vascular sites, including the SFA (six patients) and hemodialysis fistulae (five patients). Clinical, angiographic and IVUS examinations were performed to evaluate mechanisms of restenosis. RESULTS: Stent compression was identified as the principal cause of restenosis in all dialysis conduits and SFAs. Stent deformity was not reliably identified by angiography; however, IVUS identified compression of two forms: eccentric deformation, implicating two-point compressive force, and complete circumferential encroachment of stent struts around the catheter, suggesting multidirectional compressive force. Despite redilation, secondary restenosis resulting from recurrent compression recurred in most sites. CONCLUSIONS: Restenosis within balloon-expandable endovascular stents may occur as a result of stent compression, a phenomenon readily detected by IVUS, but often not by angiography. These findings have significant implications for the use of balloon-expandable stents within vascular sites subject to extrinsic compression, such as hemodialysis conduits, the adductor canal segment of the SFA and carotid arteries.

Smooth muscle cell outgrowth from human atherosclerotic plaque: implications for the assessment of lesion biology.

OBJECTIVES: The purpose of this study was to determine whether the kinetics of smooth muscle cell outgrowth from in vitro explants of human atherosclerotic tissue is dependent on the nature of the atherosclerotic lesion in vivo. BACKGROUND: The use of techniques for percutaneous in vivo extraction of atherosclerotic plaque has provided the opportunity to study human atheroma-derived smooth muscle cells in culture. However, because of cell selection and changes in phenotype, in vitro findings may not always reflect the biologic properties of the vessel wall, particularly if cells are in culture for prolonged periods. In contrast, studies with nonhuman cells have suggested that the rate at which cells grow out of tissue explants is closely related to the status of the cells in vivo. METHODS: Atherosclerotic tissue from 41 lesions, including primary plaques (from peripheral arteries and venous bypass conduits) and restenotic lesions (from peripheral arteries and venous conduits) were divided into a total of 1,596 fragments and placed in culture on fibronectin-coated wells. Explant outgrowth was scored over the ensuing 1 month to determine the prevalence and time course of smooth muscle cell outgrowth and the total cellular accumulation. RESULTS: Explant fragments from 40 (98%) of the 41 lesions yielded an outgrowth of smooth muscle cells, confirmed by immunocytochemistry. The mean proportion of adherent explant fragments yielding outgrowth, per lesion, was 69 +/- 4% and was higher in restenotic tissue (81 +/- 3%) than in primary tissue (56 +/- 6%, p < 0.001). For primary lesions, initiation of outgrowth was half-maximal by 8.7 +/- 0.4 days; for restenotic explants, initiation of outgrowth was considerably faster (half-maximal by 5.9 +/- 0.6 days, p < 0.001). Similarly, accumulation of smooth muscle cells around an explant was significantly greater for restenotic lesions (2,791 +/- 631 cells/explant) than for primary lesions (653 +/- 144 cells/explant, p < 0.01). Labeling of first-passage cells with [3H]-thymidine indicated that cells from restenotic lesions had a 1.3-fold greater incorporation rate than did cells from primary lesions (p < 0.05). CONCLUSIONS: Smooth muscle cells may be reliably cultivated by explant outgrowth from a variety of human atherosclerotic plaque types obtained intraoperatively or percutaneously. The kinetics of outgrowth from restenotic tissue is distinctly different from that of outgrowth from primary tissue, suggesting a relation between the in vitro outgrowth behavior and the biology of the lesion in vivo. Assessment of smooth muscle cell outgrowth from human atherosclerotic plaque may thus represent a practical and reliable means to investigate the biologic behavior, including growth characteristics, of individual atherosclerotic lesions from human subjects. This technique may also offer a suitable assay system for evaluating therapies designed to inhibit lesion proliferation.

Catheter-based intravascular ultrasound discriminates bicuspid from tricuspid valves in adults with calcific aortic stenosis.

A catheter-based intravascular ultrasound transducer was used to study aortic valve morphology in adults with calcific aortic stenosis. Examination of 14 postmortem specimens disclosed that intravascular ultrasound consistently identified the number of cusps or the presence of a calcified median raphe in the conjoined cusp, or both, and thereby distinguished a calcified bicuspid from a calcified tricuspid aortic valve. These postmortem findings were then employed to identify valvular morphology in 15 patients undergoing diagnostic cardiac catheterization or balloon aortic valvuloplasty, or both. Reproduction of criteria established in vitro allowed discrimination of congenital valvular morphology in all 15 patients, including 7 in whom assessment by intravascular ultrasound was confirmed by subsequent pathologic examination. Identification of aortic valvular morphology by intravascular ultrasound has potential therapeutic implications for patients considered to be candidates for operative or nonoperative aortic valvuloplasty.

Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease.

The age-adjusted prevalence of peripheral arterial disease (PAD) in the U.S. population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease (PAD) include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may be used to successfully revascularize the limbs of certain patients with PAD. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and/or healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients. The purpose of this clinical protocol is to document the safety of therapeutic angiogenesis achieved in this case by percutaneous catheter-based delivery of the gene encoding vascular endothelial growth factor (VEGF) in patients with PAD; and, as secondary objectives, investigate the bioactivity of this strategy to relieve rest pain and heal ischemic ulcers of the lower extremities. The rationale for this human protocol is based upon preclinical studies performed in a rabbit model of hindlimb ischemia. These studies are described in detail below and in the manuscripts enclosed in the Appendix to this proposal. In brief, a single intra-arterial bolus of VEGF recombinant human protein, delivered percutaneously to the ischemic limb via an intravascular catheter, resulted in angiographic, hemodynamic, physiologic, and histologic evidence of augmented collateral artery development. Subsequently, similar results were achieved using an angioplasty catheter with a hydrogel-coated balloon to deliver 400 micrograms of a plasmid containing the cDNA for VEGF to the internal iliac artery in the same animal model. Accordingly, we propose to administer arterial gene (VEGF) therapy to patients with rest pain and/or ischemic leg ulcers considered not to be candidates for conventional revascularization techniques. The dose of plasmid to be administered will be progressively escalated beginning with 500 micrograms for the first four patients, 1000 micrograms for the following six patients, 2000 micrograms for the third group of six patients, and 400 micrograms for the fourth group of six patients.

Combined physiologic and anatomic assessment of percutaneous revascularization using a Doppler guidewire and ultrasound catheter.

Previous investigations have established the utility of intravascular ultrasound (IVUS) examination for the evaluation of arterial dimensions and qualitative changes following percutaneous revascularization. More recently, the feasibility of obtaining intravascular physiology findings before and/or after percutaneous revascularization by use of an intravascular Doppler Flowire (Cardiometrics) has been demonstrated. Accordingly, we investigated the feasibility of using this combined physiologic/anatomic approach to evaluate individuals undergoing percutaneous revascularization of stenotic or occluded coronary and peripheral arteries. A total of 76 patients were evaluated using the Flowire to guide an IVUS catheter. Revascularization of coronary and peripheral vascular stenoses and/or occlusions was achieved in these patients by balloon angioplasty, directional atherectomy, excimer laser angioplasty, and thrombolytic therapy, alone or in combination. Physiologic findings obtained with the Flowire reinforced conclusions regarding morphologic severity of candidate stenoses and anatomic adequacy of revascularization following IVUS examination. In certain ambiguous cases, information gained by one modality clarified information obtained with the other. Finally, one modality may also serve as an alternative when logistics preclude the serial use of both. The preliminary experience obtained in this feasibility trial confirmed that IVUS and the Flowire may be combined to assess both candidate lesions as well as postprocedural patency in patients undergoing percutaneous revascularization. The combination of anatomic and physiologic data available from IVUS and Flowire provides a far more sensitive and possibly more accurate analysis of the adequacy of revascularization than has been possible by angiography alone. The extent to which such a detailed investigation is required to optimize interventional therapy on a routine basis is the subject of subsequent investigations.

Three-dimensional reconstruction of human carotid arteries from images obtained during noninvasive B-mode ultrasound examination.

Previous investigators have demonstrated that B-mode ultrasonography can provide high resolution images of the carotid arteries. When combined with Doppler flow measurements, quantitative estimates of luminal narrowing may also be obtained. B-mode imaging is limited, however, in its ability to provide a composite view of the vessel wall, lumen and plaque. Spatial relations between structures visualized in individual frames must be inferred from repeated transducer passes over the designated site, or repeated review of recorded images, followed by a "mind's eye" reconstruction. Three-dimensional (3-D) reconstruction of serially recorded cross-sectional images from current B-mode systems represents a possible solution to this limited spatial display that preserves detail regarding vessel wall pathology. Accordingly, computer-based automated 3-D reconstruction was used to generate a tangible format with which to assess and compare serially and transcutaneously recorded 2-dimensional (2-D) B-mode images of the carotid arteries. One or more timed sweep recordings of the 2-D B-mode examination were obtained from 5 patients for 3-D reconstruction. In all cases, satisfactory 3-D reconstruction was accomplished in three 3-D formats: cylindrical, sagittal and lumen cast. Sagittal 3-D reconstruction provided information regarding pathologic alterations within the arterial wall. Experience with the cylindrical mode suggests that this 3-D format, particularly when the reconstructed vascular segment is hemisected, is optimally suited for those cases in which direct inspection of luminal topography is of special interest. The lumen cast display, used with a recently validated edge-detection algorithm, may enhance the use of B-mode ultrasound for assessment of luminal cross-sectional area.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual balloon technique for valvuloplasty of aortic stenosis in adults.

A dual balloon technique was studied in 16 patients with aortic stenosis in whom results with a single balloon (up to 20 mm, 5.5 cm or 25 mm, 3.0 cm in diameter and length, respectively) were judged to be suboptimal. Dual balloon valvuloplasty was performed using 2 balloons advanced and inflated simultaneously across the stenotic aortic valve orifice. For the group as a whole, the average peak transvalvular gradient was reduced from 79 +/- 8 to 57 +/- 7 mm Hg (mean +/- standard error) using a single balloon (p less than 0.0005), and reduced further to 36 +/- 4 mm Hg using dual balloons (p less than 0.0005 compared with single balloon results). Similarly, calculated aortic valve orifice area was increased from 0.45 +/- 0.04 to 0.57 +/- 0.05 cm2 using a single balloon (p less than 0.0005), and further increased to 0.77 +/- 0.06 cm2 using dual balloons (p less than 0.0005). Dual balloon dilation caused no complications directly attributable to the use of 2 balloons, including no exacerbation of aortic regurgitation. These results suggest that dual balloon valvuloplasty is safe and efficacious in selected patients with aortic stenosis.

Pericardiocentesis under two-dimensional echocardiographic guidance in loculated pericardial effusion.

Pericardiocentesis to relieve tamponade from a loculated pericardial effusion in patients following cardiac surgery is greatly aided by two-dimensional echocardiographic imaging guidance. This technique delineates the fluid distribution and the site of adhesions, defines the path for introduction of an aspiration needle, alerts to the possibility of myocardial contact, and helps in positioning the drainage catheter. Two-dimensional echocardiographic imaging can be performed at the patient's bedside, and the images are easy to interpret. This technique simplifies pericardiocentesis and helps to avoid complications.

Results of a prospective, randomized trial of surgery versus thrombolysis for occluded lower extremity bypass grafts.

PURPOSE: The purpose of this study was to prospectively evaluate the treatment of patients with occluded lower extremity bypass grafts, comparing surgical revascularization with catheter-directed thrombolysis. MATERIALS AND METHODS: One hundred twenty-four patients (68% male and 32% female) with lower limb bypass graft occlusion (46 autogenous and 78 prosthetic) were prospectively randomized to surgery (n = 46) or intra-arterial catheter-directed thrombolysis (n = 78) with recombinant tissue plasminogen activator (rt-PA) 0.1 mg/kg/h modified to 0.05 mg/kg/h for up to 12 hours, or urokinase (UK) 250,000 U bolus followed by 4,000 U/min for 4 hours, then 2,000 U/min for up to 36 hours. A composite clinical outcome including death, amputation, ongoing/recurrent ischemia, and major morbidity was analyzed on an intent-to-treat basis at 30 days and 1 year. RESULTS: The average duration of graft occlusion was 34.0 days, with 58 (48%) presenting with acute ischemia (0 to 14 days) and 64 (52%) with chronic ischemia (> 14 days). Thirty-nine percent randomized to lysis failed catheter placement and required surgical revascularization. Overall, there was a better composite clinical outcome at 30 days (P = 0.023) and 1 year (P = 0.04) in the surgical group compared with lysis, due predominately to a reduction in ongoing/recurrent ischemia, most notable in autogenous grafts. However, following successful catheter placement, patency was restored by lysis in 84%, and 42% had a major reduction in their planned operation. One-year results of successful lysis compared favorably with the best surgical procedure, which was new graft placement. Acutely ischemic patients (0 to 14 days) randomized to lysis demonstrated a trend toward a lower major amputation rate at 30 days (P = 0.074) and significantly at 1 year (P = 0.026) compared with surgical patients, while those with > 14 days ischemia showed no difference in limb salvage but higher ongoing/recurrent ischemia in lytic patients (P < 0.001). Patients with occluded prosthetic grafts had greater major morbidity than did those with occluded autogenous grafts (P < 0.02). CONCLUSIONS: Proper catheter positioning currently limits the potential of catheter-directed thrombolysis for lower extremity bypass graft occlusion. Patients with graft occlusion > 14 days have a significantly better outcome when treated surgically, with a new bypass being the best surgical option. However, in patients with acute limb ischemia (< 14 days) successful thrombolysis of occluded lower extremity bypass grafts improves limb salvage and reduces the magnitude of the planned surgical procedure. Patients with occluded prosthetic grafts suffer more major morbid events compared with occluded autogenous grafts.

Therapeutic angiogenesis in critical limb and myocardial ischemia.

Research in animal models of ischemia has shown that administration of angiogenic growth factors, either as a recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries; a strategy termed "therapeutic angiogenesis." In animal models and clinical trials, the best studied cytokines with angiogenic activity are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with critical limb ischemia demonstrated resolution of rest pain and/or improved limb integrity, increased pain-free walking time and ankle-brachial index, newly visible collateral vessels by digital subtraction angiography, and qualitative evidence of improved distal flow by magnetic resonance imaging. Initial clinical trials in patients with end-stage coronary artery disease using direct myocardial injection via thoracotomy resulted in large increases in exercise time and marked reductions in anginal symptoms, as well as objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein, and have not shown significant improvement in exercise time or angina compared to placebo. Larger scale placebo-controlled studies of gene transfer using catheter-based endocardial delivery are in progress. Future clinical studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors, as well as the requirement for endothelial progenitor cell or stem cell supplementation, to provide effective and safe therapeutic angiogenesis for patients with critical limb ischemia and chronic myocardial ischemia who are not candidates for conventional revascularization procedures.