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.

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.

Renal Artery Stent Placement: Indications and Results.

Although revascularization of renal artery stenosis (RAS) from fibromuscular dysplasia (FMD) generally yields satisfying outcomes, traditional approaches to revascularization for atherosclerotic renal artery stenosis (ARAS) have been suboptimal because of the invasiveness, relatively high perioperative morbidity and mortality rates of surgery, and the low rates of technical success and long-term patency with percutaneous renal balloon angioplasty (PTA). Endovascular stents have been deployed for failed PTA (unsatisfactory results or complications) and treatment of restenotic lesions. Compared to PTA, primary stenting of ostial ARAS gives superior technical success rates greater than 95% and improved long-term patency. Curing hypertension after RAS revascularization is rare (< 10%). Improved control with fewer medications is a more realistic goal. Renal function as judged by serum creatinine improves in 20% to 30%, stabilizes in 40% to 60%, and deteriorates in 20% to 30% of patients whose renal function is impaired initially. One study demonstrated successful stenting slowed the rate of progression of renal failure in 89% of patients whose serum creatinine was less than 400 mol/L. Complications of renal artery stenting may be substantial, though procedure-related mortality is low. Patient selection for renal revascularization remains controversial. Those with renovascular disease and uncontrolled hypertension, progressive renal failure, or recurrent flash pulmonary edema should be carefully considered for renal artery stenting in experienced centers.

Safety, efficacy, and durability of carotid artery stenting for restenosis following carotid endarterectomy: a multicenter study.

PURPOSE: To present the results of a multicenter registry established to collect data on carotid stent procedures in patients with restenosis following carotid endarterectomy. METHODS: The procedural details, outcomes, and late follow-up results were collected from 14 centers in the United States. Thirty-day and late stroke and death rates were analyzed. RESULTS: Three hundred and thirty-eight patients (201 men; 71 +/- 8 years) underwent carotid stenting in 358 arteries. The average duration from carotid endarterectomy was 5.5 +/- 7.3 years. Sixty-one percent of the patients were asymptomatic. The overall 30-day stroke and death rate was 3.7%. The minor stroke rate was 1.7% (6/358), and the major nonfatal stroke rate was 0.8% (3/358). The fatal stroke rate was 0.3% (1/358), and the nonstroke-related death rate was 0.9% (3/338). There was 1 (0.3%) fatal and 1 (0.3%) nonfatal stroke during the follow-up period. The overall 3-year rate of freedom from all fatal and nonfatal strokes was 96% +/- 1% (+/- SE). CONCLUSIONS: Carotid artery stenting can be performed in patients with restenosis following carotid endarterectomy with 30-day complication rates comparable to those of most published studies on repeat carotid endarterectomy. Results of late follow-up suggest that this technique is durable and efficacious.

Global experience in cervical carotid artery stent placement.

The purpose of this article is to review and update the current status of carotid artery stent placement in the world. Surveys to major interventional centers in Europe, North and South America, and Asia were initially completed in June 1997. Subsequent information from these 24 centers in addition to 12 new centers has been obtained to update the information. The survey asked the various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 5,210 procedures involving 4,757 patients. There was a technical success of 98.4% with 5,129 carotid arteries treated. Complications that occurred during the carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 134 transient ischemic attacks (TIAs) for a rate of 2.82%. Based on the total patient population, there were 129 minor strokes with a rate of occurrence of 2.72%. The total number of major strokes was 71 for a rate of 1.49%. There were 41 deaths within a 30-day postprocedure period resulting in a mortality rate of 0.86%. The combined minor and major strokes and procedure-related death rate was 5.07%. Restenosis rates of carotid stenting have been 1.99% and 3.46% at 6 and 12 months, respectively. The rate of neurologic events after stent placement has been 1.42% at 6-12-month follow-up. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative for vascular surgery, especially for patients that are high risk for standard carotid endarterectomy. The periprocedure risks for major and minor strokes and death are generally acceptable at this early stage of development and have not changed significantly since the first survey results. Cathet. Cardiovasc. Intervent. 50:160-167, 2000.

Current global status of carotid artery stent placement.

Our purpose was to review the current status of carotid artery stent placement throughout the world. Surveys were sent to major interventional centers in Europe, North and South America, and Asia. Information from peer-reviewed journals was also included and supplemented the survey. The survey asked various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. Of the centers which were sent surveys, 24 responded. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 2,048 cases, with a technical success of 98.6%. Complications that occurred during carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 63 minor strokes, with a rate of occurrence of 3.08%. The total number of major strokes was 27, for a rate of 1.32%. There were 28 deaths within a 30-day postprocedure period, resulting in a mortality rate of 1.37%. Restenosis rates of carotid stenting have been 4.80% at 6 mo. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative to vascular surgery, especially for patients that are at high risk for standard carotid endarterectomy. The periprocedural risks for major and minor strokes and death are generally acceptable at this early stage of development.

Histopathology of in-stent restenosis in patients with peripheral artery disease.

BACKGROUND: Clinical studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of in-stent restenosis. However, pathological data regarding this issue are limited. Specifically, direct evidence of proliferative activity in tissues excised from stenotic stents has not been previously reported. METHODS AND RESULTS: Tissue specimens were retrieved by directional atherectomy from 10 patients in whom in-stent restenosis complicated percutaneous revascularization of peripheral artery disease. Analysis of cellular composition was performed quantitatively after cell-specific immunostaining. For specimens preserved in methanol (7 of 10), cellular proliferation was evaluated by use of antibodies to proliferating cell nuclear antigen (PCNA), cyclin E, and cdk2. TUNEL staining for apoptosis was performed on 8 paraformaldehyde-preserved specimens. Each of the 10 specimens contained extensive foci of hypercellularity composed predominantly of SMCs (mean+/-SEM, 59.3+/-3.0%). Evidence of ongoing proliferative activity was documented in all 7 methanol-preserved specimens: 24.6+/-2.3% of SMCs were PCNA-positive, 24.8+/-3.1% were cyclin E-positive, and 22.5+/-2.2% were cdk2-positive. Apoptotic cells were detected in all 8 specimens that had been appropriately preserved to permit DNA nick-end labeling. Macrophages and leukocytes were identified in each of the 10 specimens but accounted for a proportionately smaller number of cells (14.5+/-1.9% and 9.5+/-1.4%, respectively). Organized thrombus was observed in 6 of the 10 specimens. CONCLUSIONS: These findings support the notion that in-stent restenosis results from SMC hyperplasia and suggest that adjunctive therapies designed to inhibit SMC proliferation may further enhance the utility of endovascular stents.

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.

Elevated levels of basic fibroblast growth factor in patients with limb ischemia.

Basic fibroblast growth factor (bFGF), a prototypic member of a family of heparin-binding growth factors, is angiogenic both in vitro and in vivo. Increased levels and activity of bFGF have been documented in a variety of diseases, including tumors. We sought to determine whether bFGF might be similarly elevated in patients with clinical evidence of limb ischemia. Serum was obtained at the time of percutaneous revascularization from patients with symptomatic peripheral vascular disease (46 procedures were performed on 40 patients). An enzyme-linked immunoassay specific for bFGF was used (limit of detection, 1 pg/ml; range in normal subjects, 0 to 5 pg/ml). Among the 40 patients (28 men, 12 women, mean age 70 years) studied, elevated circulating bFGF (> or = 10 pg/ml) was detected in 36 samples (78%); levels ranged from 10 to 310 pg/ml (mean +/- SEM = 62 +/- 12). In 16 (89%) of 18 patients with both rest pain and nonhealing ischemic ulcers, serum bFGF levels were elevated up to 30 times normal values. In conclusion, circulating levels of bFGF are elevated in patients with vascular insufficiency and may reflect a physiologic response to limb ischemia.

Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb.

BACKGROUND: Preclinical findings suggest that intra-arterial gene transfer of a plasmid which encodes for vascular endothelial growth factor (VEGF) can improve blood supply to the ischaemic limb. We have used the method in a patient. METHODS: Our patient was the eighth in a dose-ranging series. She was aged 71 with an ischaemic right leg. We administered 2,000 micrograms human plasmid phVEGF165 that was applied to the hydrogel polymer coating of an angioplasty balloon. By inflating the balloon, plasmid DNA was transferred to the distal popliteal artery. FINDINGS: Digital subtraction angiography 4 weeks after gene therapy showed an increase in collateral vessels at the knee, mid-tibial, and ankle levels, which persisted at a 12-week view. Intra-arterial doppler-flow studies showed increased resting and maximum flows (by 82% and 72%, respectively). Three spider angiomas developed on the right foot/ankle about a week after gene transfer; one lesion was excised and revealed proliferative endothelium, the other two regressed. The patient developed oedema in her right leg, which was treated successfully. INTERPRETATION: Administration of endothelial cell mitogens promotes angiogenesis in patients with limb ischaemia.

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.

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.

Focal compensatory enlargement of human arteries in response to progressive atherosclerosis. In vivo documentation using intravascular ultrasound.

BACKGROUND: Previous postmortem studies have demonstrated compensatory enlargement of atherosclerotic arteries in animal models and patients. Conclusions regarding these changes were drawn based on a comparison of the dimensions of diseased arteries in one group of subjects with the dimensions of normal arteries in another group. This method admits potential confounding variables, such as demographics and other disease states, which might also have an impact on arterial size. METHODS AND RESULTS: Using intravascular ultrasound, we studied a total of 62 paired, adjacent normal and diseased sites in the superficial femoral arteries of 20 patients undergoing peripheral vascular interventions. Morphological assessment was performed using a computer-based image analysis system. Measurements were made of the cross-sectional area of the arterial lumen, the atherosclerotic plaque, and the outer border of the artery. These dimensions were then compared to determine the effects of progressive atherosclerosis on arterial morphology. Luminal cross-sectional area decreased from 21.1 +/- 2.2 mm2 in normal segments to 16.7 +/- 0.8 mm2 (P = .0001) in adjacent atherosclerotic segments. Similarly, minimal luminal diameter decreased from 5.7 +/- 0.2 to 5.0 +/- 0.1 mm2, and maximal luminal diameter decreased from 6.2 +/- 0.2 to 5.7 +/- 0.2 mm2. At these same sites, total arterial area was 32.9 +/- 1.6 and 37.9 +/- 1.9 mm2 (P = .0001) in normal and diseased segments, respectively. Minimal and maximal arterial diameters demonstrated similar increases (7.3 +/- 0.2 to 7.7 +/- 0.2 mm2 [P = .0015] and 7.6 +/- 0.2 to 8.3 +/- 0.2 mm2 [P = .0001], respectively). Regression analysis disclosed correlation of the cross-sectional area of plaque to the total arterial area (R = .70, P = .0001). CONCLUSIONS: Human arteries enlarge in response to progressive atherosclerosis. This compensatory mechanism results in an increase in arterial size that is proportionate to the cross-sectional area of plaque that has accumulated in the vessel. Intravascular ultrasound demonstrates that this process is focal compensatory enlargement at discrete sites of atherosclerotic narrowing immediately adjacent to more normal areas in which arterial size is smaller.