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Contact-tracing programs in two areas hit hardest by buy antibiotics best online cipro are working. Catherine Lee, a community health representative, talks with a man at his home on the Navajo Nation. The nation has nearly 200 contact tracers spread across numerous health-care agencies.Jim Thompson/Albuquerque best online cipro Journal On a mild morning in April at Arizona’s Whiteriver Indian Hospital, Dr. Ryan Close tested nasal swabs from two members of an eight-person household on the Fort Apache Reservation northwest of Phoenix.

About half of the family had a runny nose and cough and had lost their sense of taste and smell — all symptoms of buy antibiotics — and, by late morning, the two tests had come back positive. Close’s contact-tracing work began.For Close best online cipro and his team, each day begins like this. With a list of new buy antibiotics cases — new sources that may have spread the cipro. The 35 or so people on the team must rapidly test people, isolate the infected and visit the homes of any who may have best online cipro been exposed.

Again, and again. Recently, though, their cases have declined, due in part to something rare, at least in the United States. An effective contact-tracing and testing best online cipro plan. Both the White Mountain Apache and nearby Navajo Nation experienced some of the country’s worst rates, yet both began to curb their cases in mid-June and mid-July, respectively, due to their existing health department resources and partnerships, stringent public health orders, testing and robust contact tracing.

€œWe've seen a significant decline in cases on the reservation at the same time that things were on fire for the rest of the state,” said Close, an epidemiologist and physician at Whiteriver Indian Hospital, an Indian Health best online cipro Service facility. Tracing disease transmission from buy antibiotics is crucial to slowing its spread, but successful contact tracing has proven challenging for communities that lack the funds, community cooperation, personnel or supplies for rapid testing. The White Mountain Apache Tribe of Fort Apache and the Navajo Nation, however, have been growing a contact-tracing army, setting them apart from other tribes during the cipro. As tribal communities best online cipro brace for multiple waves of buy antibiotics, public health experts from the two nations have already successfully adapted contact-tracing programs.

The White Mountain Apache and the Navajo Nation “were hit hardest early on, and so they have had a little bit more time and opportunity to put these systems into place,” said Laura Hammitt, director of the infectious disease and prevention program at Johns Hopkins Center for American Indian Health, which is working with the Centers for Disease Control to develop a guide for tribal governments to train and grow their own contact-tracing workforces.Across the country, tribes are employing a number of public health measures — closing reservations to nonresidents, setting curfews, providing free testing and aid to families and Indigenous language translations of public health guidelines — but few are actively contact tracing. Contact tracing requires fast and systematic testing and trained personnel best online cipro. In March, Close trained eight Whiteriver Indian Hospital staffers, but the number has since grown to around 35, serving some 12,000 tribal citizens and residents. The relatively small team takes advantage of the firmly closed reservation boundaries and rapid testing to find and isolate new cases.

buy antibiotics cases were dropping in Fort Apache, which stayed closed, as the state best online cipro neared its caseload peak in mid-June after the governor lifted stay-at-home orders, becoming one of the country’s worst antibiotics hotspots. Catherine Lee, a community health representative, talks with a man at his home on the Navajo Nation. The nation has nearly 200 contact tracers spread across numerous health-care agencies.Jim Thompson/Albuquerque Journal While most contact-tracing best online cipro programs rely on phone calls to learn patient history, assess symptoms, encourage isolation and trace other contacts, the Whiteriver team relies on home visits. €œI (can) come to your house to assess you, do a case investigation, or to inform you that you are a contact,” Close said.

€œThe benefit of that is that, if you were ill-appearing, they can evaluate you right there.” Tracers can also determine whether other household members are symptomatic, checking temperatures and oxygen saturation, while health-care providers can check breathing with a stethoscope. The Whiteriver Hospital can turn around a buy antibiotics test in a single day, a process best online cipro that takes days or weeks at other public health institutions.“We’re not just trying to flatten the curve. We’re trying to actually completely contain this cipro.”The Navajo Nation has succeeded in slowing the spread of the new antibiotics, even though the reservation spans three states — New Mexico, Arizona and Utah — so teams must coordinate across several jurisdictions. The nation has nearly 200 contact tracers spread across numerous health-care best online cipro agencies.

With scores of Indigenous communities to monitor over a huge geographic area, phone calls are its primary investigative tool. The Navajo Nation is setting its sights high. €œWe’re not just trying to flatten the curve,” said Sonya Shin, who leads tracing investigations for the Nation, best online cipro “We’re trying to actually completely contain this cipro.”Still, critics say it is not enough. The most effective tracing relies on mass testing to catch asymptomatic people as well as those with symptoms.

Due to best online cipro a limited supply of tests, most tribes, like most states, can only test symptomatic people, so the number of cases is inevitably undercounted. €œContact tracing does not mean a damn thing unless you have really good tests, and you’re testing everybody,” said Rudolf Rÿser (Cree/Oneida), executive director of the Center for World Indigenous Studies. €œNot just the people showing the symptoms, but everybody, whether they are Indian or non-Indian, in your area — you have to catch them all.”Kalen Goodluck is a contributing editor at High Country News. Email him at [email protected] or submit best online cipro a letter to the editor.Follow @kalengoodluck Get our Indigenous Affairs newsletter ↓ Thank you for signing up for Indian Country News, an HCN newsletter service.

Look for it in your email each month. Read more More from buy antibiotics19.

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August 28, how to get cipro without prescription 2020Contact. Office of CommunicationsPhone. 202-693-1999U.S.

Department of Labor Issues Revised Final Beryllium StandardsFor Construction and Shipyards WASHINGTON, DC - The U.S. Department of Labor's Occupational Safety and Health Administration (OSHA) today published a final rule revising the beryllium standards for construction and shipyards. The final rule includes changes designed to clarify the standards and simplify or improve compliance.

These changes maintain protection for workers while ensuring that the standard is well understood and compliance is simple and straightforward. The final rule amends the following paragraphs in the beryllium standards for construction and shipyards. Definitions, Methods of Compliance, Respiratory Protection, Personal Protective Clothing and Equipment, Housekeeping, Hazard Communication, Medical Surveillance, and Recordkeeping.

OSHA has removed the Hygiene Areas and Practices paragraph from the final standards because the necessary protections are provided by existing OSHA standards for sanitation. The effective date of the revisions in this final rule is September 30, 2020. OSHA began enforcing the new permissible exposure limits in the 2017 beryllium standards for construction and shipyards in May 2018.

OSHA will begin enforcing the remaining provisions of the standards on September 30, 2020. The final standard will affect approximately 12,000 workers employed in nearly 2,800 establishments in the construction and shipyard industries. The final standards are estimated to yield $2.5 million in total annualized cost savings to employers.

Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA's role is to help ensure these conditions for America's working men and women by setting and enforcing standards, and providing training, education, and assistance. For more information, visit www.osha.gov.

The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States. Improve working conditions. Advance opportunities for profitable employment.

And assure work-related benefits and rights. # # # U.S. Department of Labor news materials are accessible at http://www.dol.gov.

The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).August 27, 2020U.S. Department of Labor Announces ActionsTo Assist Americans Impacted By Hurricane Laura WASHINGTON, DC – The U.S.

Department of Labor today announced actions it is taking to assist Americans in states affected by Hurricane Laura. In response to the anticipated needs of those living in states in the path of Hurricane Laura, the Department and its agencies are taking the following actions. The Occupational Safety and Health Administration (OSHA) has actively engaged with the U.S.

Department of Homeland Security, the Federal Emergency Management Administration, the Environmental Protection Agency, and other federal agencies and is prepared to provide assistance. The Wage and Hour Division (WHD) will be prioritizing all calls in the affected areas to continue to provide uninterrupted service to workers and employers. The Employment and Training Administration (ETA) is prepared to provide Disaster Dislocated Worker Grants to help affected states address workforce needs.

The disbursement of funds will be determined as needs are assessed by state and local partners. ETA is also prepared to assist in administering Disaster Unemployment Assistance. The Employee Benefits Security Administration (EBSA) will coordinate with other federal agencies, including the U.S.

Department of Treasury, the IRS and the Pension Benefit Guaranty Corp. On the release of compliance guidance for employee benefit plans, and plan participants and beneficiaries in response to Hurricane Laura. General information on disaster relief under the Employee Retirement Income Security Act (ERISA) is available on EBSA's website at Disaster Relief Information for Employers and Advisers and Disaster Relief Information for Workers and Families, or by contacting EBSA online or by calling 1-866-444-3272.

The Office of Federal Contract Compliance Programs (OFCCP) issued a Temporary Exemption from certain federal contracting requirements. For a period of three months, from August 27, 2020, to November 27, 2020, new federal contracts to provide relief, clean-up or rebuilding efforts will be exempt from having to develop written affirmative action programs as required by Executive Order 11246. The Mine Safety and Health Administration (MSHA) is responding to Hurricane Laura's impact on mines, and stands ready to respond more generally with specialized equipment and personnel.

And The Veterans' Employment and Training Service (VETS) is working with its grantees to identify further flexibilities and additional funding needs for its programs. VETS staff is prepared to assist employers, members of the National Guard and Reserves and members of the National Disaster Medical System and Urban Search and Rescue who deploy in support of rescue and recovery operations. The Department will continue to monitor developments regarding Hurricane Laura and take additional actions as necessary.

For additional information, please visit the Department's Severe Storm and Flood Recovery Assistance webpage. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure work-related benefits and rights. # # # Media Contact.

Eric Holland, 202-693-4676, holland.eric.w@dol.gov Release Number. 20-1654-NAT U.S. Department of Labor news materials are accessible at http://www.dol.gov.

The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay)..

August 28, best online cipro 2020Contact. Office of CommunicationsPhone. 202-693-1999U.S. Department of Labor Issues Revised Final Beryllium StandardsFor Construction and Shipyards WASHINGTON, DC - The U.S. Department of Labor's Occupational Safety and Health Administration (OSHA) today published a final rule revising the beryllium standards for construction and shipyards.

The final rule includes changes designed to clarify the standards and simplify or improve compliance. These changes maintain protection for workers while ensuring that the standard is well understood and compliance is simple and straightforward. The final rule amends the following paragraphs in the beryllium standards for construction and shipyards. Definitions, Methods of Compliance, Respiratory Protection, Personal Protective Clothing and Equipment, Housekeeping, Hazard Communication, Medical Surveillance, and Recordkeeping. OSHA has removed the Hygiene Areas and Practices paragraph from the final standards because the necessary protections are provided by existing OSHA standards for sanitation.

The effective date of the revisions in this final rule is September 30, 2020. OSHA began enforcing the new permissible exposure limits in the 2017 beryllium standards for construction and shipyards in May 2018. OSHA will begin enforcing the remaining provisions of the standards on September 30, 2020. The final standard will affect approximately 12,000 workers employed in nearly 2,800 establishments in the construction and shipyard industries. The final standards are estimated to yield $2.5 million in total annualized cost savings to employers.

Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA's role is to help ensure these conditions for America's working men and women by setting and enforcing standards, and providing training, education, and assistance. For more information, visit www.osha.gov. The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure work-related benefits and rights. # # # U.S. Department of Labor news materials are accessible at http://www.dol.gov. The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print.

For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).August 27, 2020U.S. Department of Labor Announces ActionsTo Assist Americans Impacted By Hurricane Laura WASHINGTON, DC – The U.S. Department of Labor today announced actions it is taking to assist Americans in states affected by Hurricane Laura. In response to the anticipated needs of those living in states in the path of Hurricane Laura, the Department and its agencies are taking the following actions. The Occupational Safety and Health Administration (OSHA) has actively engaged with the U.S.

Department of Homeland Security, the Federal Emergency Management Administration, the Environmental Protection Agency, and other federal agencies and is prepared to provide assistance. The Wage and Hour Division (WHD) will be prioritizing all calls in the affected areas to continue to provide uninterrupted service to workers and employers. The Employment and Training Administration (ETA) is prepared to provide Disaster Dislocated Worker Grants to help affected states address workforce needs. The disbursement of funds will be determined as needs are assessed by state and local partners. ETA is also prepared to assist in administering Disaster Unemployment Assistance.

The Employee Benefits Security Administration (EBSA) will coordinate with other federal agencies, including the U.S. Department of Treasury, the IRS and the Pension Benefit Guaranty Corp. On the release of compliance guidance for employee benefit plans, and plan participants and beneficiaries in response to Hurricane Laura. General information on disaster relief under the Employee Retirement Income Security Act (ERISA) is available on EBSA's website at Disaster Relief Information for Employers and Advisers and Disaster Relief Information for Workers and Families, or by contacting EBSA online or by calling 1-866-444-3272. The Office of Federal Contract Compliance Programs (OFCCP) issued a Temporary Exemption from certain federal contracting requirements.

For a period of three months, from August 27, 2020, to November 27, 2020, new federal contracts to provide relief, clean-up or rebuilding efforts will be exempt from having to develop written affirmative action programs as required by Executive Order 11246. The Mine Safety and Health Administration (MSHA) is responding to Hurricane Laura's impact on mines, and stands ready to respond more generally with specialized equipment and personnel. And The Veterans' Employment and Training Service (VETS) is working with its grantees to identify further flexibilities and additional funding needs for its programs. VETS staff is prepared to assist employers, members of the National Guard and Reserves and members of the National Disaster Medical System and Urban Search and Rescue who deploy in support of rescue and recovery operations. The Department will continue to monitor developments regarding Hurricane Laura and take additional actions as necessary.

For additional information, please visit the Department's Severe Storm and Flood Recovery Assistance webpage. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights.

# # # Media Contact. Eric Holland, 202-693-4676, holland.eric.w@dol.gov Release Number. 20-1654-NAT U.S. Department of Labor news materials are accessible at http://www.dol.gov. The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print.

For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay)..

What should my health care professional know before I take Cipro?

They need to know if you have any of these conditions:

  • child with joint problems
  • heart condition
  • kidney disease
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  • seizures disorder
  • an unusual or allergic reaction to ciprofloxacin, other antibiotics or medicines, foods, dyes, or preservatives
  • pregnant or trying to get pregnant
  • breast-feeding

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Your girls’ weekend? cipro side effects fatigue http://piforimpact.com/propecia-cost/. Do you have plans to watch the Husker game with people?. Even if it’s only like one other person?. Did you have your kids’ friends over to play in the cipro side effects fatigue basement?. I ask you these questions because though they may be low-risk to you, they are high-risk to me.

Because my colleagues and I cannot take care of all of you currently needing to be admitted to the hospital. You’re right cipro side effects fatigue. Most people with buy antibiotics do just fine. But, a number of people do not. And if our health care workforce keeps getting stretched to the limits AND many of them keep needing time to quarantine due to buy antibiotics or positive exposures, then we are ALL going to be cipro side effects fatigue in a really dark(er) place.

For example, my institution usually runs 2 general buy antibiotics teams. We are up to 6-7 teams with plans to increase to 10. You know what that also means? cipro side effects fatigue. We will run out of space for non-buy antibiotics patients too. And we may not have enough people to take care of these folks.Please.

Please. Rethink interacting with people outside of your home. I know this exhausting. I’m tired. I miss my old life.

You’re right. I don’t have older kids that need human interaction with others. But please help. I jokingly compare buy antibiotics to an STD. The person you are with may seem “safe,” but you never know where they have been.

And though that’s rather funny, it’s scarily true. Asymptomatic carriers and or people that are positive but don’t have symptoms yet are a real problem. Don’t think negative buy antibiotics test excuses what you’ve done or clears you!. You can still turn positive a day or two later, having exposed people in the meantime. Ugh.Please don’t assume this isn’t about you and that I’m directing this to someone else not you.

Don’t assume you’re doing enough. We all AREN’T doing enough. Take a step back and assume you aren’t doing enough. How you could have done better?. How can you do better starting right now?.

I beg you all to make decisions for your health care providers. My colleagues and I are making sacrifices for you. Please make a sacrifice for us.Allison Ashford is a hospitalist.With the holidays approaching, how can we celebrate with loved ones while reducing risks?. The buy antibiotics cipro is nowhere near over, increasing the risk of transmission during one of the busiest travel and social-gathering periods of the year. The Texas Medical Association (TMA) unveils two new tools from doctors to help people make safe holiday plans.

New podcastTrish Perl, MD, and TMA public health staff member Meredith Vinez address how to reduce your risk for buy antibiotics during the holiday season, in the latest episode of the TMA’s Practice Well podcasts. Dr. Perl is a member of both TMA’s buy antibiotics Task Force and Committee on Infectious Diseases, and chief of the infectious diseases division at UT Southwestern Medical Center in Dallas.“This is the new normal, and until we really see that we have something like a treatment or other measures that are going to prevent transmission, this is going to be our new normal,” Dr. Perl says in the podcast. That means everyone should balance healthy practices with pursuing holiday traditions.Dr.

Perl discusses the dangers of buy antibiotics fatigue, and how wearing face masks, maintaining good hygiene (washing hands frequently), and social distancing can help stop the spread of the cipro. Citing their own family situations, she and Ms. Vinez discuss what people should do if they decide to travel for the holidays, the safest way to travel, and the risks of visiting elderly relatives. The episode also covers how to deal with relatives who aren’t taking buy antibiotics seriously, low risk holiday activities for the kids, potential tweaks to the traditional holiday to family dinners, and how to give back to the community this season. Some of their suggestions include hosting outdoor family gatherings, using disposable plates and utensils, and serving guests rather than passing a bowl of food with a single serving spoon.Dr.

Perl concluded with this reminder. €œStay safe, and everybody remember your three w’s. Wear your mask, watch your distance, and wash your hands!. € To listen to the holiday podcast and other episodes of TMA’s Practice Well podcast, visit us on our website, Apple Podcasts, Spotify, iHeartRadio and Podbean. New infographicThe TMA buy antibiotics Task Force also released a holiday update to its popular buy antibiotics risk assessment chart released in summer, 2020.

But I need you all to just listen for a read this article second.I’m best online cipro scared. For you and for me.I need you all to take a minute and think of the last time that you interacted in-person with someone who does not live in your home. Did you see a friend this weekend?. Did best online cipro you go to the store?.

Did you go inside the gas station?. Did family come in from out of state?. How about best online cipro that wedding shower that you went to?. Your girls’ weekend?.

Do you have plans to watch the Husker game with people?. Even if it’s only like one best online cipro other person?. Did you have your kids’ friends over to play in the basement?. I ask you these questions because though they may be low-risk to you, they are high-risk to me.

Because my colleagues and I cannot take care of all of you currently needing to be admitted to the best online cipro hospital. You’re right. Most people with buy antibiotics do just fine. But, a number of people best online cipro do not.

And if our health care workforce keeps getting stretched to the limits AND many of them keep needing time to quarantine due to buy antibiotics or positive exposures, then we are ALL going to be in a really dark(er) place. For example, my institution usually runs 2 general buy antibiotics teams. We are up to 6-7 teams best online cipro with plans to increase to 10. You know what that also means?.

We will run out of space for non-buy antibiotics patients too. And we may not have enough people to take care of best online cipro these folks.Please. Please. Rethink interacting with people outside of your home.

I know best online cipro this exhausting. I’m tired. I miss my old life. You’re right best online cipro.

I don’t have older kids that need human interaction with others. But please help. I jokingly best online cipro compare buy antibiotics to an STD. The person you are with may seem “safe,” but you never know where they have been.

And though that’s rather funny, it’s scarily true. Asymptomatic carriers and or people that are positive but don’t have symptoms yet are a real best online cipro problem. Don’t think negative buy antibiotics test excuses what you’ve done or clears you!. You can still turn positive a day or two later, having exposed people in the meantime.

Ugh.Please don’t assume this isn’t about you and that I’m directing best online cipro this to someone else not you. Don’t assume you’re doing enough. We all AREN’T doing enough. Take a best online cipro step back and assume you aren’t doing enough.

How you could have done better?. How can you do better starting right now?. I beg you all best online cipro to make decisions for your health care providers. My colleagues and I are making sacrifices for you.

Please make a sacrifice for us.Allison Ashford is a hospitalist.With the holidays approaching, how can we celebrate with loved ones while reducing risks?. The buy antibiotics cipro is nowhere near over, increasing the risk best online cipro of transmission during one of the busiest travel and social-gathering periods of the year. The Texas Medical Association (TMA) unveils two new tools from doctors to help people make safe holiday plans. New podcastTrish Perl, MD, and TMA public health staff member Meredith Vinez address how to reduce your risk for buy antibiotics during the holiday season, in the latest episode of the TMA’s Practice Well podcasts.

Dr. Perl is a member of both TMA’s buy antibiotics Task Force and Committee on Infectious Diseases, and chief of the infectious diseases division at UT Southwestern Medical Center in Dallas.“This is the new normal, and until we really see that we have something like a treatment or other measures that are going to prevent transmission, this is going to be our new normal,” Dr. Perl says in the podcast. That means everyone should balance healthy practices with pursuing holiday traditions.Dr.

Perl discusses the dangers of buy antibiotics fatigue, and how wearing face masks, maintaining good hygiene (washing hands frequently), and social distancing can help stop the spread of the cipro. Citing their own family situations, she and Ms. Vinez discuss what people should do if they decide to travel for the holidays, the safest way to travel, and the risks of visiting elderly relatives.

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€‚ For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Can you buy amoxil Focus Issue on vascular biology and medicine contains a clinical research article entitled ‘The association of amputations and peripheral artery disease in patients cipr certificate with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors. Real-world study’, authored by Sanjoy Paul from the University of Melbourne in Australia, and colleagues.1 Patients with peripheral artery disease (PAD) remain a challenging population to treat, in particular in the attempt to reduce the risk of amputation.2–4 Paul et al. Evaluated the temporal pattern of amputations in cipr certificate type 2 diabetes (T2DM) patients, the risk of amputations by new and older antidiabetic drugs (ADDs), and the interplay of PAD with therapy and amputation risk. Using Centricity Electronic Medical Records from the USA, ∼3 300 000 patients with T2DM were identified. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000–2008 and significantly increased to 12.3 in 2017.

Patients with pre-existing cipr certificate PAD had a more than four-fold higher risk of lower limb amputation (LLA). In propensity score-adjusted pair-wise analyses, the risk of LLA was similar in sodium–glucose co-transporter type-2 inhibitors (SGLT-2is) vs. Glucagon-like peptide 1 receptor agonists (GLP1-RAs), and lower in SGLT-2i vs. Dipeptidyl peptidase-4 cipr certificate inhibitor (DPP-4i) or other ADDs (hazard ratio 0.65 and 0.43, respectively) (Figure 1). The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin.

Figure 1Adjusted risk of amputations and peripheral artery disease (from Paul SK, cipr certificate Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors. Real-world study. See pages 1728–1738).Figure 1Adjusted risk of amputations and peripheral artery disease cipr certificate (from Paul SK, Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors.

Real-world study. See pages 1728–1738).The authors conclude that the risk of amputation in patients treated with SGLT-2is and incretins is not cipr certificate higher compared with other ADDs. In addition, and not surprisingly, pre-existing PAD is the greatest driver of amputation risk. The manuscript is accompanied by an Editorial by Charalambos Vlachopoulos from the University of Athens Medical School in Greece, and colleagues.5 The authors conclude that a considerable number cipr certificate of original studies and analyses have been applied on the canvas of the risk of amputation by SGLT2is that as a whole reduce the contrast of the first randomized trials. While any risk appears to be related specifically to canagliflozin, recent large registries provide reassuring data on the safety of SGLT2is, as long as physicians are aware of this particular complication and monitor their patients closely.

Undoubtedly, we are in need of more data, and the pursuit for proper evaluation of canagliflozin calls for ‘making haste slowly’.Inflammation plays an important role in development of cardiovascular disease (CVD).6–8 The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β (IL-1β) cipr certificate can be targeted therapeutically. In a clinical research article entitled ‘Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality’, Stefan Schunk from the Saarland University Hospital in Homburg/Saar, Germany, and colleagues note that associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.9 The authors explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on an individual participant level in an explorative gene-centric approach without performing multiple testing. The functional relevance of the single nucleotide polymorphism (SNP) for NLRP3 inflammasome activation was evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent cipr certificate intronic NLRP3 variant rs10754555 as affecting NLRP3 gene expression.

Rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of cipr certificate the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease (CAD) was significantly higher as compared with non-carriers, with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g cipr certificate.

Urate, triglycerides, and ApoC3) modulated the association between rs10754555 and mortality.The authors conclude that the NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent CAD, and mortality. This study provides evidence for a substantial role for genetically driven systemic inflammation in cardiovascular disease and highlights the NLRP3 inflammasome as a therapeutic target. The manuscript cipr certificate is accompanied by an Editorial by Christoph J. Binder and Nikolina Papac-Milicevic from the Medical University of Vienna in Austria.10 The authors conclude that the findings of this study provide important evidence for the individual differences in the ability to develop chronic inflammation in the context of metabolic disturbances. This may open up the possibility for more personalized therapeutic approaches by enabling stratification of patients based on their genetically determined inflammatory risk before clinical manifestations occur.The aim of endovascular stent implantation at the time of coronary angioplasty is to prevent acute vessel closure and chronic cipr certificate negative arterial remodelling in patients affected by coronary disease.

However, stents are sensed as a foreign body, leading to immune cell activation, resulting in chronic inflammation and, eventually, in-stent restenosis due to the local proliferation of arterial smooth muscle cells. Mitigating the body’s reaction by improving stent biocompatibility thus represents a major challenge to increase the efficacy of arterial stents and hence the clinical outcome of patients affected by coronary disease.11,12 In a translational research article entitled ‘Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo’, Sergio Diaz-Rodriguez from the Laval University, Québec, Canada, and colleagues evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements, and the in vivo strut coverage and neointimal growth.13 The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leucocyte cipr certificate activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, it has been shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leucocyte homeostasis and arterial healing. Furthermore, it has been shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist.

The authors produced cobalt chromium disks and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable cipr certificate results. They found that CD31-mimetic disks significantly reduced the extent of primary human coronary artery EC and blood platelet/leucocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at cipr certificate 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/time point). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized, with no activated platelets/leucocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared with BMS, appearing as a normal arterial media with absence of thrombosis in contrast to DES.The authors conclude that CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis.

Hence, such coatings cipr certificate seem to improve metal stent biocompatibility. The manuscript is accompanied by an Editorial by Alexandra Lansky from the Yale School of Medicine in New Haven, CT, USA and colleagues.14 The authors conclude that the effect of a CD31-mimetic stent in CAD patients may be blunted due to impaired function of CD31-expressing cells in this patient population. These will be critical benchmarks to more reliably predict whether this breakthrough combination stent technology can provide the incremental safety and effectiveness benefit needed to further advance the management options of our patients with obstructive coronary disease.In another translational research article entitled ‘A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy’, Thorsten Kessler from the Deutsches Herzzentrum München in Germany, and colleagues sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.15 Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of ∼5000 proteins revealed massive proteome remodelling, with cipr certificate more than half of all proteins exhibiting expression differences between injured and non-injured vessels. The authors observed major changes in the composition of the extracellular matrix and cell migration processes.

Among the latter, they identified the cipr certificate classical transient receptor potential channel 6 (Trpc6) as driving neointima formation. This was confirmed in an experimental model. Indeed, Trpc6–/– mice presented reduced neointima formation compared with wild-type mice. In addition, activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased or cipr certificate decreased migratory capacity, respectively. Finally, in a cohort of individuals with angiographic follow-up in >3000 patients, homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49) during a mean follow-up of 217 days.The authors conclude that their study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting.

They present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation. The manuscript is accompanied by an Editorial by Giuseppina Caligiuri from INSERM in Paris and Gregory Franck from the Hôpitaux Universitaires Paris Nord Val-de-Seine in France.16 The authors conclude that further studies are needed in order to specifically address the therapeutic potential of TRCP6 inhibitors cipr certificate in a clinical perspective. If confirmed, a combo device eluting both mTOR inhibitors and TRCP blockers could select the right ‘channels’, affecting the broadest relevant targets and eventually reaching the ‘no-restenosis’ Holy Grail.‘Embolic stroke of undetermined source’ (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. In a State of the Art review article entitled ‘Supracardiac atherosclerosis in embolic stroke cipr certificate of undetermined source. The underestimated source’, George Ntaios from the University of Thessaly in Greece, and colleagues note that when the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients.17 Yet another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch—collectively described as supracardiac atherosclerosis.

There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than was initially perceived. Advanced imaging methods are available to identify plaques cipr certificate which carry high embolic risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials. This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid in identifying plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.Unlike native LDL, modified LDLs such as oxidized, carbamylated, or acetylated LDLs are not recognized by the native LDL receptor (LDL-R). Rather, modified LDL binds to the lectin-like oxidized LDL receptor-1 (LOX-1).8,18,19 In a State of the Art review article cipr certificate entitled ‘Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).

A crucial driver of atherosclerotic cardiovascular disease’, Alexander Akhmedov from the University of Zurich in Switzerland, and colleagues note that LOX-1, a scavenger receptor that promotes endothelial dysfunction by inducing proatherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke.20 In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs. Therefore, understanding the molecular structure and function cipr certificate of LOX-1 is of critical importance. In this review, the authors highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. They also describe recent findings from basic research, delineate their translational value, and discuss the potential cipr certificate of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs (Figure 2).

Figure 2Ligand–receptor interactions (left) and their potential role in various diseases (right). (A) Multiple ligands, including oxLDL, L5, and dysfunctional HDL, have been shown to induce full-length LOX-1 stimulation. Depending on the cell type studied, LOX-1 stimulation activates subcellular signalling pathways that play major roles in the cipr certificate pathogenesis of various cardiovascular diseases. Notably, in human coronary endothelial cells exposed to oxLDL, Del-1 inhibits the LOX-1-dependent up-regulation of endothelial adhesion molecules, thereby representing an interesting endogenous molecule that—at least in part—curtails the detrimental effects mediated by LOX-1. (B) In recent years, the byproduct of LOX-1 cleavage (i.e.

SLOX-1) and the most electronegative LDL subfraction cipr certificate (i.e. L5) have emerged as novel biomarkers, specifically in atherosclerosis-related events, such as myocardial infarction and ischaemic stroke. Furthermore, enhanced LAB activity has been shown to be associated with the incidence of cardiovascular diseases, particularly ischaemic stroke cipr certificate. AGEs, advanced glycation end-products. CRP, C-reactive protein.

Del-1, developmental endothelial locus-1 cipr certificate. HSP70, heat shock protein 70. LAB, LOX-1 ligand containing apoB. LOX-1, lectin-like oxidized LDL receptor-1 cipr certificate. L5, L5 LDL.

NTF, N-terminal cipr certificate fragment. OxLDL, oxidized LDL. SLOX-1, soluble LOX-1. VSMC, vascular smooth muscle cell (from Akhmedov A, Sawamura cipr certificate T, Chen CH, Kraler S, Vdovenko D, Lüscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).

A crucial driver of atherosclerotic cardiovascular disease. See pages 1797–1807).Figure 2Ligand–receptor interactions (left) and their potential role in cipr certificate various diseases (right). (A) Multiple ligands, including oxLDL, L5, and dysfunctional HDL, have been shown to induce full-length LOX-1 stimulation. Depending on the cell type studied, LOX-1 stimulation activates subcellular signalling pathways that cipr certificate play major roles in the pathogenesis of various cardiovascular diseases. Notably, in human coronary endothelial cells exposed to oxLDL, Del-1 inhibits the LOX-1-dependent up-regulation of endothelial adhesion molecules, thereby representing an interesting endogenous molecule that—at least in part—curtails the detrimental effects mediated by LOX-1.

(B) In recent years, the byproduct of LOX-1 cleavage (i.e. SLOX-1) and the most cipr certificate electronegative LDL subfraction (i.e. L5) have emerged as novel biomarkers, specifically in atherosclerosis-related events, such as myocardial infarction and ischaemic stroke. Furthermore, enhanced LAB activity has been shown to be associated with the incidence of cardiovascular diseases, particularly ischaemic stroke. AGEs, advanced glycation end-products cipr certificate.

CRP, C-reactive protein. Del-1, developmental cipr certificate endothelial locus-1. HSP70, heat shock protein 70. LAB, LOX-1 ligand containing apoB. LOX-1, lectin-like oxidized cipr certificate LDL receptor-1.

L5, L5 LDL. NTF, N-terminal fragment. OxLDL, oxidized cipr certificate LDL. SLOX-1, soluble LOX-1. VSMC, vascular smooth muscle cell (from Akhmedov A, Sawamura T, Chen CH, cipr certificate Kraler S, Vdovenko D, Lüscher TF.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). A crucial driver of atherosclerotic cardiovascular disease. See pages 1797–1807).The issue is cipr certificate complemented by two Discussion Forum articles. In a contribution entitled ‘Which biomarker to use, when to start, and how to improve adherence for reducing atherosclerotic cardiovascular disease risk?. €™, Kwang Kon Koh from Gachon University in Korea comments on the contribution ‘2019 vs.

2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cipr certificate cardiovascular disease’ by Martin Bødtker Mortensen from the Aarhus University Hospital in Denmark, and colleagues.21,22 Mortensen et al. Respond in a separate comment.23The editors hope that readers of this issue of the European Heart Journal will find it of interest.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. References1Paul SK, Bhatt DL, cipr certificate Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors. Real-world study.

Eur Heart cipr certificate J 2021;42:1728–1738.2Behrendt CA. Higher long-term mortality after endovascular vs. Open-surgical revascularization of peripheral artery disease in Australia and New Zealand?. Eur Heart J 2021 cipr certificate. Doi:10.1093/eurheartj/ehab143.3Parvar SL, Ngo L, Dawson J, Nicholls SJ, Fitridge R, Psaltis PJ, Ranasinghe I.

Long-term outcomes cipr certificate following endovascular and surgical revascularization for peripheral artery disease. A propensity score-matched analysis. Eur Heart J 2021. Doi. 10.1093/eurheartj/ehab116.4Tseng A, Bhatt S, Girardo M, Liedl D, Wennberg P, Shamoun F.

Complex antithrombotic therapy and bleeding risk in patients with peripheral arterial disease. Eur Heart J 2020;41(Suppl_2):ehaa946.2396.5Vlachopoulos C, Terentes-Printzios D, Tsioufis K. Do SGLT2 inhibitors increase the risk of amputation?. Make haste slowly. Eur Heart J 2021;42:1739–1741.6Lawler PR, Bhatt DL, Godoy LC, Lüscher TF, Bonow RO, Verma S, Ridker PM.

Targeting cardiovascular inflammation. Next steps in clinical translation. Eur Heart J 2021;42:113–131.7Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG. Inflamm-ageing. The role of inflammation in age-dependent cardiovascular disease.

Eur Heart J 2020;41:2974–2982.8Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG. Senescence-induced inflammation. An important player and key therapeutic target in atherosclerosis. Eur Heart J 2020;41:2983–2996.9Schunk SJ, Kleber ME, März W, Pang S, Zewinger S, Triem S, Ege P, Reichert MC, Krawczyk M, Weber SN, Jaumann I, Schmit D, Sarakpi T, Wagenpfeil S, Kramann R, Boerwinkle E, Ballantyne CM, Grove ML, Tragante V, Pilbrow AP, Richards AM, Cameron VA, Doughty RN, Dubé MP, Tardif JC, Feroz-Zada Y, Sun M, Liu C, Ko YA, Quyyumi AA, Hartiala JA, Tang WHW, Hazen SL, Allayee H, McDonough CW, Gong Y, Cooper-DeHoff RM, Johnson JA, Scholz M, Teren A, Burkhardt R, Martinsson A, Smith JG, Wallentin L, James SK, Eriksson N, White H, Held C, Waterworth D, Trompet S, Jukema JW, Ford I, Stott DJ, Sattar N, Cresci S, Spertus JA, Campbell H, Tierling S, Walter J, Ampofo E, Niemeyer BA, Lipp P, Schunkert H, Böhm M, Koenig W, Fliser D, Laufs U, Speer T. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021;42:1742–1756.10Papac-Milicevic N, Binder CJ. Can a single genetic variant explain residual cardiovascular risk by modifying NLRP3 expression?. Eur Heart J 2021;42:1757–1759.11Giacoppo D, Alfonso F, Xu B, Claessen B, Adriaenssens T, Jensen C, Pérez-Vizcayno MJ, Kang DY, Degenhardt R, Pleva L, Baan J, Cuesta J, Park DW, Schunkert H, Colleran R, Kukla P, Jiménez-Quevedo P, Unverdorben M, Gao R, Naber CK, Park SJ, Henriques JPS, Kastrati A, Byrne RA. Paclitaxel-coated balloon angioplasty vs. Drug-eluting stenting for the treatment of coronary in-stent restenosis.

A comprehensive, collaborative, individual patient data meta-analysis of 10 randomized clinical trials (DAEDALUS study). Eur Heart J 2020;41:3715–3728.12Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis. What have we learned and where are we going?. The Andreas Grüntzig Lecture ESC 2014.

Eur Heart J 2015;36:3320–3331.13Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, Gallet R, Choqueux C, Even G, Sayah N, Chaubet F, Nicoletti A, Ghaleh B, Feldman LJ, Mantovani D, Caligiuri G. Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo. Eur Heart J 2021;42:1760–1769.14Lansky A, Chun H, Pietras C, Hussain Y. Refining drug-eluting stent technologies. From engineering to basic science.

Eur Heart J 2021;42:1770–1772.15Wierer M, Werner J, Wobst J, Kastrati A, Cepele G, Aherrahrou, Sager HB, Erdmann J, Dichgans M, Flockerzi V, Civelek M, Dietrich A, Mann M, Schunkert H, Kessler T. A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy. Eur Heart J 2021;42:1733–1785.16Caligiuri G, Frack G. Hitting the right channels to spread a ‘no-restenosis’ message to vascular wall cells. Eur Heart J 2021;42:1786–1788.17Ntaios G, Wintermark M, Michel P.

Supracardiac atherosclerosis in embolic stroke of undetermined source. The underestimated source. Eur Heart J 2021;42:1789–1796.18Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, Daemen MJ, Demer LL, Hegele RA, Nicholls SJ, Nordestgaard BG, Watts GF, Bruckert E, Fazio S, Ference BA, Graham I, Horton JD, Landmesser U, Laufs U, Masana L, Pasterkamp G, Raal FJ, Ray KK, Schunkert H, Taskinen MR, van de Sluis B, Wiklund O, Tokgozoglu L, Catapano AL, Ginsberg HN. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Pathophysiological, genetic, and therapeutic insights.

A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41:2313–2330.19Lüscher TF. Understanding and preventing atherosclerosis. From bench to bedside. Eur Heart J 2019;40:323–327.20Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Lüscher TF.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). A crucial driver of atherosclerotic cardiovascular disease. Eur Heart J 2021;42:1797–1807.21Koh KK. Which biomarker to use, when to start, and how to improve adherence for reducing atherosclerotic cardiovascular disease risk?. Eur Heart J 2021;42:1808.22Mortensen MB, Nordestgaard BG.

2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease. Eur Heart J 2020;41:3005–3015.23Mortensen MB, Nordestgaard BG. Examine low-density lipoprotein, remnants, and lipoprotein(a) in parallel in high risk patients. Eur Heart J 2021;42:1809–1810.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email. Journals.permissions@oup.com.Comment on ‘Statin treatment and muscle symptoms.

Series of randomised, placebo controlled n-of-1 trials’ published in the British Medical Journal (DOI. Http://dx.doi.org/10.1136/bmj.n135).Key pointsStatinWISE (Statin Web-based Investigation of Side Effects)1 was a series of institutionally funded, randomized, double-blind, placebo-controlled n-of-1 trials, recruiting 200 participants from general practices across 50 sites in the UK to establish the effect of statins on muscle symptoms. Participants, who were taking any type of statin at any dose before trial enrolment, had recently stopped or were considering stopping treatment with statins because of muscle symptoms. Exclusion criteria were previously raised levels of serum alanine aminotransferase (≥3 times the upper limit of normal). Persistent, generalized, unexplained muscle pain.

Levels of creatine kinase ≥5 times the upper limit of normal. Any contraindication to atorvastatin treatment.The overall length of the trial was 1 year for each participant and comprised six 2-month treatment periods (three of placebo, three of atorvastatin 20 mg daily) in a randomly allocated order. At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale. The primary outcome compared symptom scores (score 0 = no symptoms, 5 = moderate symptoms, and 10 = worst possible symptoms) in the statin and placebo periods. Three months after the end of the final treatment period, participants were asked whether they had, or intended to restart treatment with statins.Of the 200 participants, 151 (76%) provided one or more visual analogue scale measurements in both a statin and a placebo period and were included in the primary analysis.

No statistically significant difference in muscle symptom scores was found between the statin and placebo periods [mean ± SD. 1.7 ± 2.6 vs. 1.8 ± 2.7. Mean difference statin minus placebo −0.1. 95% confidence interval (CI) −0.4 to 0.1.

P = 0.40]. Atorvastatin showed no significant effect on development of muscle symptoms overall with an odds ratio (OR) of 1.11 (99% CI, 0.62–1.99). Nor was there any effect on muscle symptoms that could not be attributed to another cause (OR, 1.22. 95% CI, 0.77–1.94).Of the 80 withdrawals during the study for any reason, 42% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Withdrawals because of intolerable muscle symptoms were 9% during a statin period and 7% during a placebo period.

Two-thirds of those completing the six treatment periods (74/113 participants) reported restarting long-term statin treatment. CommentThe European Atherosclerosis Society Consensus Panel and other groups established that there is evidence for causality for only three statin-related adverse effects. Muscle side effects, new-onset diabetes, and transient elevations of liver enzymes, with muscle symptoms being the most common complaint during statin treatment.2 Systematic reviews and meta-analyses of randomized controlled trials (RCTs) have confirmed the safety of statins, showing that the risk of myopathy and its progression to severe rhabdomyolysis are rare, and suggesting that symptomatic adverse events may be misattributed to statins.3–5 Indeed, the association between muscle symptoms and statins has suffered the bias of observational studies, reinforced by media reports. Patients taking statins expect to experience adverse effects, and therefore reporting of symptoms in statin users may be higher than in a comparable population not on statins. This phenomenon, known as the ‘nocebo’ effect, often leads to patients discontinuing treatment, exposing them to an increased risk of cardiovascular events.6In the present study, patients who had previously faced severe muscle symptoms on a statin reported similar muscle symptom prevalence or severity during blinded statin or placebo periods.

Also, there were no differences for the effect of muscle symptoms on several aspects of daily life between statin and placebo periods. Thus, the study adds to the evidence from SAMSON,7 a recent trial with similar design, and from RCTs like ODYSSEY ALTERNATIVE8 and GAUSS-39 showing that a significant number of people who have problems with muscle pain associated with statins are experiencing a ‘nocebo’ effect, and that re-challenge with statins can be tolerated by most patients.StatinWISE, however, has several limitations. (i) the lack of creatine kinase measurement did not allow establishing what proportion of participants had symptoms associated with biochemical signs of muscle damage. (ii) the trial results may not apply to higher doses of atorvastatin or other statins, as only the effects of atorvastatin 20 mg were assessed. (iii) most importantly, 86 of the original 200 participants did not complete the whole trial, 49 of whom did not provide sufficient data to contribute to the primary analysis.

Furthermore, withdrawals due to intolerable muscle symptoms were not significantly different between statin (9%) and placebo (7%) periods, but StatinWISE was not powered to detect a difference in such withdrawals. (iv) the study participants may not be representative of all those who believe they experience side effects with statins. On one hand, the study may have selected people who were less susceptible to the ‘nocebo’ effect. On the other hand, the majority (70%) of study participants had a history of cardiovascular disease, and they may have had a higher commitment to statin therapy than those in primary prevention. And (v) the 2-month treatment period should be long enough to allow washout between different treatments and avoid the carry-over of symptoms between statin and placebo periods.

However, while muscle pain/weakness typically occurs within 4–6 weeks after starting statin treatment, the onset may be delayed months or years.10Despite these limitations, these findings underscore the need for clinicians to acknowledge their patients’ muscle symptoms on statin therapy and, using a StatinWISE-like approach, ensure that as many as possible continue on a statin to reduce their cardiovascular risk.Conflict of interest. G.L. Received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programmes of the Italian Cardiovascular Network. C.P.

Received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, Eli Lilly, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission. He chairs the Scientific Advisory Board of the International Aspirin Foundation. References1Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, Shakur-Still H, Roberts I, Prowse D, Goldacre B, van Staa T, MacDonald TM, Armitage J, Wimborne J, Melrose P, Singh J, Brooks L, Moore M, Hoffman M, Smeeth L, on behalf of the StatinWISE Trial Group. Statin treatment and muscle symptoms. Series of randomised, placebo controlled n-of-1 trials.

BMJ 2021;372:n135.2Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms. Impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012–1022.3Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy.

Lancet 2016;388:2532–2561.4Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, Collins R, Sever P, ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). A randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017;389:2473–2481.5Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL2nd, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell PB, Brinton EA, Pollak A, Braun LT, Welty FK, American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health. Council on Cardiovascular Disease in the Young.

Council on Clinical Cardiology. Stroke Council. Statin safety and associated adverse events. A scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2019;39:e38–e81.6Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group.

2019 ESC/EAS Guidelines for the management of dyslipidaemias. Lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.7Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly S, Cegla J, Stride C, Sever P, Norton C, Thom SAM, Shun-Shin MJ, Francis DP. N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med 2020;383:2182–2184.8Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, Gipe D.

Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients. Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8:554–561.9Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceška R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA, for the GAUSS-3 Investigators. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance. The GAUSS-3 randomized clinical trial.

JAMA 2016;315:1580–1590.10Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation 2013;127:96–103. Published on behalf of the European Society of Cardiology. All rights reserved.

© The Author(s) 2021. For permissions, please email. Journals.permissions@oup.com..

€‚ For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on vascular biology and medicine contains a clinical research article entitled ‘The association of amputations and peripheral artery disease in patients best online cipro with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors. Real-world study’, authored by Sanjoy Paul from the University of Melbourne in Australia, and colleagues.1 Patients with peripheral artery disease (PAD) remain a challenging population to treat, in particular in the attempt to reduce the risk of amputation.2–4 Paul et al. Evaluated the temporal pattern of amputations in type 2 diabetes (T2DM) patients, the risk of amputations by new and older antidiabetic drugs (ADDs), and the interplay of PAD with therapy and amputation risk best online cipro.

Using Centricity Electronic Medical Records from the USA, ∼3 300 000 patients with T2DM were identified. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000–2008 and significantly increased to 12.3 in 2017. Patients with pre-existing PAD best online cipro had a more than four-fold higher risk of lower limb amputation (LLA).

In propensity score-adjusted pair-wise analyses, the risk of LLA was similar in sodium–glucose co-transporter type-2 inhibitors (SGLT-2is) vs. Glucagon-like peptide 1 receptor agonists (GLP1-RAs), and lower in SGLT-2i vs. Dipeptidyl peptidase-4 inhibitor (DPP-4i) or other ADDs (hazard ratio 0.65 and 0.43, best online cipro respectively) (Figure 1).

The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Figure 1Adjusted risk of best online cipro amputations and peripheral artery disease (from Paul SK, Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors.

Real-world study. See pages 1728–1738).Figure 1Adjusted risk of amputations and peripheral artery disease (from Paul SK, Bhatt DL, Montvida best online cipro O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors.

Real-world study. See pages best online cipro 1728–1738).The authors conclude that the risk of amputation in patients treated with SGLT-2is and incretins is not higher compared with other ADDs. In addition, and not surprisingly, pre-existing PAD is the greatest driver of amputation risk.

The manuscript is accompanied by an Editorial by Charalambos Vlachopoulos from the University of Athens Medical School in Greece, best online cipro and colleagues.5 The authors conclude that a considerable number of original studies and analyses have been applied on the canvas of the risk of amputation by SGLT2is that as a whole reduce the contrast of the first randomized trials. While any risk appears to be related specifically to canagliflozin, recent large registries provide reassuring data on the safety of SGLT2is, as long as physicians are aware of this particular complication and monitor their patients closely. Undoubtedly, we are in need of more data, and the pursuit for proper evaluation of canagliflozin calls for ‘making haste slowly’.Inflammation plays an important role in development of cardiovascular disease (CVD).6–8 The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models.

Components of the NLRP3 inflammasome pathway such as interleukin-1β best online cipro (IL-1β) can be targeted therapeutically. In a clinical research article entitled ‘Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality’, Stefan Schunk from the Saarland University Hospital in Homburg/Saar, Germany, and colleagues note that associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.9 The authors explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on an individual participant level in an explorative gene-centric approach without performing multiple testing. The functional relevance of the single nucleotide polymorphism (SNP) for NLRP3 inflammasome activation was evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs).

Genetic analyses identified the highly prevalent intronic NLRP3 variant rs10754555 as affecting NLRP3 gene best online cipro expression. Rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher best online cipro NLRP3 inflammasome activation in isolated human PBMCs.

In carriers of the rs10754555 variant, the prevalence of coronary artery disease (CAD) was significantly higher as compared with non-carriers, with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g best online cipro.

Urate, triglycerides, and ApoC3) modulated the association between rs10754555 and mortality.The authors conclude that the NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent CAD, and mortality. This study provides evidence for a substantial role for genetically driven systemic inflammation in cardiovascular disease and highlights the NLRP3 inflammasome as a therapeutic target. The manuscript is accompanied by an best online cipro Editorial by Christoph J.

Binder and Nikolina Papac-Milicevic from the Medical University of Vienna in Austria.10 The authors conclude that the findings of this study provide important evidence for the individual differences in the ability to develop chronic inflammation in the context of metabolic disturbances. This may open up the possibility for more personalized therapeutic approaches by enabling stratification of patients based on their genetically determined inflammatory risk before clinical manifestations occur.The aim of endovascular stent implantation at the time of coronary angioplasty is to prevent acute vessel closure best online cipro and chronic negative arterial remodelling in patients affected by coronary disease. However, stents are sensed as a foreign body, leading to immune cell activation, resulting in chronic inflammation and, eventually, in-stent restenosis due to the local proliferation of arterial smooth muscle cells.

Mitigating the body’s reaction by improving stent biocompatibility thus represents a major challenge to increase the efficacy of arterial stents and hence the clinical outcome of patients affected by coronary disease.11,12 In a translational research article entitled ‘Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo’, Sergio Diaz-Rodriguez from the Laval University, Québec, Canada, and colleagues evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements, and the in vivo strut coverage and neointimal growth.13 The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leucocyte activation but impair endothelialization, delaying effective device integration best online cipro into arterial walls. Previously, it has been shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leucocyte homeostasis and arterial healing.

Furthermore, it has been shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The authors produced cobalt chromium disks and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results best online cipro. They found that CD31-mimetic disks significantly reduced the extent of primary human coronary artery EC and blood platelet/leucocyte activation in vitro.

In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and best online cipro microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/time point). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized, with no activated platelets/leucocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared with BMS, appearing as a normal arterial media with absence of thrombosis in contrast to DES.The authors conclude that CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis.

Hence, such coatings seem to improve best online cipro metal stent biocompatibility. The manuscript is accompanied by an Editorial by Alexandra Lansky from the Yale School of Medicine in New Haven, CT, USA and colleagues.14 The authors conclude that the effect of a CD31-mimetic stent in CAD patients may be blunted due to impaired function of CD31-expressing cells in this patient population. These will be critical benchmarks to more reliably predict whether this breakthrough combination stent technology can provide the incremental safety and effectiveness benefit needed to further advance the management options of our patients with obstructive coronary disease.In another translational research article entitled ‘A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy’, Thorsten Kessler from the Deutsches Herzzentrum München in Germany, and colleagues sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.15 Neointima formation was induced by wire injury in mouse femoral arteries.

High-accuracy proteomic measurement of single femoral arteries to a depth of ∼5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences best online cipro between injured and non-injured vessels. The authors observed major changes in the composition of the extracellular matrix and cell migration processes. Among the best online cipro latter, they identified the classical transient receptor potential channel 6 (Trpc6) as driving neointima formation.

This was confirmed in an experimental model. Indeed, Trpc6–/– mice presented reduced neointima formation compared with wild-type mice. In addition, activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased or best online cipro decreased migratory capacity, respectively.

Finally, in a cohort of individuals with angiographic follow-up in >3000 patients, homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49) during a mean follow-up of 217 days.The authors conclude that their study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. They present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation. The manuscript is accompanied by an Editorial by Giuseppina Caligiuri from INSERM in Paris and Gregory Franck from the Hôpitaux Universitaires Paris Nord Val-de-Seine in France.16 The authors conclude that further studies are needed in order to specifically best online cipro address the therapeutic potential of TRCP6 inhibitors in a clinical perspective.

If confirmed, a combo device eluting both mTOR inhibitors and TRCP blockers could select the right ‘channels’, affecting the broadest relevant targets and eventually reaching the ‘no-restenosis’ Holy Grail.‘Embolic stroke of undetermined source’ (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. In a State of the Art best online cipro review article entitled ‘Supracardiac atherosclerosis in embolic stroke of undetermined source. The underestimated source’, George Ntaios from the University of Thessaly in Greece, and colleagues note that when the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients.17 Yet another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch—collectively described as supracardiac atherosclerosis.

There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than was initially perceived. Advanced imaging methods are available to identify plaques which carry high embolic best online cipro risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials.

This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid in identifying plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.Unlike native LDL, modified LDLs such as oxidized, carbamylated, or acetylated LDLs are not recognized by the native LDL receptor (LDL-R). Rather, modified LDL binds to best online cipro the lectin-like oxidized LDL receptor-1 (LOX-1).8,18,19 In a State of the Art review article entitled ‘Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). A crucial driver of atherosclerotic cardiovascular disease’, Alexander Akhmedov from the University of Zurich in Switzerland, and colleagues note that LOX-1, a scavenger receptor that promotes endothelial dysfunction by inducing proatherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke.20 In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation.

LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs. Therefore, understanding the molecular structure and function of LOX-1 is of critical importance best online cipro. In this review, the authors highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs.

They also describe recent findings from basic research, delineate best online cipro their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs (Figure 2). Figure 2Ligand–receptor interactions (left) and their potential role in various diseases (right). (A) Multiple ligands, including oxLDL, L5, and dysfunctional HDL, have been shown to induce full-length LOX-1 stimulation.

Depending on the cell type studied, LOX-1 stimulation activates subcellular signalling pathways that play major roles in best online cipro the pathogenesis of various cardiovascular diseases. Notably, in human coronary endothelial cells exposed to oxLDL, Del-1 inhibits the LOX-1-dependent up-regulation of endothelial adhesion molecules, thereby representing an interesting endogenous molecule that—at least in part—curtails the detrimental effects mediated by LOX-1. (B) In recent years, the byproduct of LOX-1 cleavage (i.e.

SLOX-1) and best online cipro the most electronegative LDL subfraction (i.e. L5) have emerged as novel biomarkers, specifically in atherosclerosis-related events, such as myocardial infarction and ischaemic stroke. Furthermore, enhanced LAB activity has been shown to be associated with the incidence of best online cipro cardiovascular diseases, particularly ischaemic stroke.

AGEs, advanced glycation end-products. CRP, C-reactive protein. Del-1, developmental best online cipro endothelial locus-1.

HSP70, heat shock protein 70. LAB, LOX-1 ligand containing apoB. LOX-1, lectin-like oxidized LDL receptor-1 best online cipro.

L5, L5 LDL. NTF, N-terminal fragment best online cipro. OxLDL, oxidized LDL.

SLOX-1, soluble LOX-1. VSMC, vascular best online cipro smooth muscle cell (from Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Lüscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).

A crucial driver of atherosclerotic cardiovascular disease. See pages best online cipro 1797–1807).Figure 2Ligand–receptor interactions (left) and their potential role in various diseases (right). (A) Multiple ligands, including oxLDL, L5, and dysfunctional HDL, have been shown to induce full-length LOX-1 stimulation.

Depending on the cell type studied, LOX-1 stimulation activates subcellular signalling pathways that play major best online cipro roles in the pathogenesis of various cardiovascular diseases. Notably, in human coronary endothelial cells exposed to oxLDL, Del-1 inhibits the LOX-1-dependent up-regulation of endothelial adhesion molecules, thereby representing an interesting endogenous molecule that—at least in part—curtails the detrimental effects mediated by LOX-1. (B) In recent years, the byproduct of LOX-1 cleavage (i.e.

SLOX-1) and the most electronegative LDL best online cipro subfraction (i.e. L5) have emerged as novel biomarkers, specifically in atherosclerosis-related events, such as myocardial infarction and ischaemic stroke. Furthermore, enhanced LAB activity has been shown to be associated with the incidence of cardiovascular diseases, particularly ischaemic stroke.

AGEs, advanced glycation end-products best online cipro. CRP, C-reactive protein. Del-1, developmental best online cipro endothelial locus-1.

HSP70, heat shock protein 70. LAB, LOX-1 ligand containing apoB. LOX-1, lectin-like best online cipro oxidized LDL receptor-1.

L5, L5 LDL. NTF, N-terminal fragment. OxLDL, oxidized best online cipro LDL.

SLOX-1, soluble LOX-1. VSMC, vascular smooth muscle cell (from Akhmedov A, Sawamura T, Chen best online cipro CH, Kraler S, Vdovenko D, Lüscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).

A crucial driver of atherosclerotic cardiovascular disease. See pages 1797–1807).The issue is complemented by best online cipro two Discussion Forum articles. In a contribution entitled ‘Which biomarker to use, when to start, and how to improve adherence for reducing atherosclerotic cardiovascular disease risk?.

€™, Kwang Kon Koh from Gachon University in Korea comments on the contribution ‘2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease’ by Martin Bødtker Mortensen from the Aarhus University Hospital in Denmark, and colleagues.21,22 best online cipro Mortensen et al. Respond in a separate comment.23The editors hope that readers of this issue of the European Heart Journal will find it of interest.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

References1Paul SK, Bhatt best online cipro DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium–glucose co-transporter type-2 inhibitors. Real-world study.

Eur Heart best online cipro J 2021;42:1728–1738.2Behrendt CA. Higher long-term mortality after endovascular vs. Open-surgical revascularization of peripheral artery disease in Australia and New Zealand?.

Eur Heart J best online cipro 2021. Doi:10.1093/eurheartj/ehab143.3Parvar SL, Ngo L, Dawson J, Nicholls SJ, Fitridge R, Psaltis PJ, Ranasinghe I. Long-term outcomes following endovascular and surgical revascularization for best online cipro peripheral artery disease.

A propensity score-matched analysis. Eur Heart J 2021. Doi.

10.1093/eurheartj/ehab116.4Tseng A, Bhatt S, Girardo M, Liedl D, Wennberg P, Shamoun F. Complex antithrombotic therapy and bleeding risk in patients with peripheral arterial disease. Eur Heart J 2020;41(Suppl_2):ehaa946.2396.5Vlachopoulos C, Terentes-Printzios D, Tsioufis K.

Do SGLT2 inhibitors increase the risk of amputation?. Make haste slowly. Eur Heart J 2021;42:1739–1741.6Lawler PR, Bhatt DL, Godoy LC, Lüscher TF, Bonow RO, Verma S, Ridker PM.

Targeting cardiovascular inflammation. Next steps in clinical translation. Eur Heart J 2021;42:113–131.7Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG.

Inflamm-ageing. The role of inflammation in age-dependent cardiovascular disease. Eur Heart J 2020;41:2974–2982.8Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG.

Senescence-induced inflammation. An important player and key therapeutic target in atherosclerosis. Eur Heart J 2020;41:2983–2996.9Schunk SJ, Kleber ME, März W, Pang S, Zewinger S, Triem S, Ege P, Reichert MC, Krawczyk M, Weber SN, Jaumann I, Schmit D, Sarakpi T, Wagenpfeil S, Kramann R, Boerwinkle E, Ballantyne CM, Grove ML, Tragante V, Pilbrow AP, Richards AM, Cameron VA, Doughty RN, Dubé MP, Tardif JC, Feroz-Zada Y, Sun M, Liu C, Ko YA, Quyyumi AA, Hartiala JA, Tang WHW, Hazen SL, Allayee H, McDonough CW, Gong Y, Cooper-DeHoff RM, Johnson JA, Scholz M, Teren A, Burkhardt R, Martinsson A, Smith JG, Wallentin L, James SK, Eriksson N, White H, Held C, Waterworth D, Trompet S, Jukema JW, Ford I, Stott DJ, Sattar N, Cresci S, Spertus JA, Campbell H, Tierling S, Walter J, Ampofo E, Niemeyer BA, Lipp P, Schunkert H, Böhm M, Koenig W, Fliser D, Laufs U, Speer T.

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J 2021;42:1742–1756.10Papac-Milicevic N, Binder CJ. Can a single genetic variant explain residual cardiovascular risk by modifying NLRP3 expression?.

Eur Heart J 2021;42:1757–1759.11Giacoppo D, Alfonso F, Xu B, Claessen B, Adriaenssens T, Jensen C, Pérez-Vizcayno MJ, Kang DY, Degenhardt R, Pleva L, Baan J, Cuesta J, Park DW, Schunkert H, Colleran R, Kukla P, Jiménez-Quevedo P, Unverdorben M, Gao R, Naber CK, Park SJ, Henriques JPS, Kastrati A, Byrne RA. Paclitaxel-coated balloon angioplasty vs. Drug-eluting stenting for the treatment of coronary in-stent restenosis.

A comprehensive, collaborative, individual patient data meta-analysis of 10 randomized clinical trials (DAEDALUS study). Eur Heart J 2020;41:3715–3728.12Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis.

What have we learned and where are we going?. The Andreas Grüntzig Lecture ESC 2014. Eur Heart J 2015;36:3320–3331.13Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, Gallet R, Choqueux C, Even G, Sayah N, Chaubet F, Nicoletti A, Ghaleh B, Feldman LJ, Mantovani D, Caligiuri G.

Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo. Eur Heart J 2021;42:1760–1769.14Lansky A, Chun H, Pietras C, Hussain Y. Refining drug-eluting stent technologies.

From engineering to basic science. Eur Heart J 2021;42:1770–1772.15Wierer M, Werner J, Wobst J, Kastrati A, Cepele G, Aherrahrou, Sager HB, Erdmann J, Dichgans M, Flockerzi V, Civelek M, Dietrich A, Mann M, Schunkert H, Kessler T. A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy.

Eur Heart J 2021;42:1733–1785.16Caligiuri G, Frack G. Hitting the right channels to spread a ‘no-restenosis’ message to vascular wall cells. Eur Heart J 2021;42:1786–1788.17Ntaios G, Wintermark M, Michel P.

Supracardiac atherosclerosis in embolic stroke of undetermined source. The underestimated source. Eur Heart J 2021;42:1789–1796.18Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, Daemen MJ, Demer LL, Hegele RA, Nicholls SJ, Nordestgaard BG, Watts GF, Bruckert E, Fazio S, Ference BA, Graham I, Horton JD, Landmesser U, Laufs U, Masana L, Pasterkamp G, Raal FJ, Ray KK, Schunkert H, Taskinen MR, van de Sluis B, Wiklund O, Tokgozoglu L, Catapano AL, Ginsberg HN.

Low-density lipoproteins cause atherosclerotic cardiovascular disease. Pathophysiological, genetic, and therapeutic insights. A consensus statement from the European Atherosclerosis Society Consensus Panel.

Eur Heart J 2020;41:2313–2330.19Lüscher TF. Understanding and preventing atherosclerosis. From bench to bedside.

Eur Heart J 2019;40:323–327.20Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Lüscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). A crucial driver of atherosclerotic cardiovascular disease.

Eur Heart J 2021;42:1797–1807.21Koh KK. Which biomarker to use, when to start, and how to improve adherence for reducing atherosclerotic cardiovascular disease risk?. Eur Heart J 2021;42:1808.22Mortensen MB, Nordestgaard BG.

2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease. Eur Heart J 2020;41:3005–3015.23Mortensen MB, Nordestgaard BG.

Examine low-density lipoprotein, remnants, and lipoprotein(a) in parallel in high risk patients. Eur Heart J 2021;42:1809–1810. Published on behalf of the European Society of Cardiology.

All rights reserved. © The Author(s) 2021. For permissions, please email.

Journals.permissions@oup.com.Comment on ‘Statin treatment and muscle symptoms. Series of randomised, placebo controlled n-of-1 trials’ published in the British Medical Journal (DOI. Http://dx.doi.org/10.1136/bmj.n135).Key pointsStatinWISE (Statin Web-based Investigation of Side Effects)1 was a series of institutionally funded, randomized, double-blind, placebo-controlled n-of-1 trials, recruiting 200 participants from general practices across 50 sites in the UK to establish the effect of statins on muscle symptoms.

Participants, who were taking any type of statin at any dose before trial enrolment, had recently stopped or were considering stopping treatment with statins because of muscle symptoms. Exclusion criteria were previously raised levels of serum alanine aminotransferase (≥3 times the upper limit of normal). Persistent, generalized, unexplained muscle pain.

Levels of creatine kinase ≥5 times the upper limit of normal. Any contraindication to atorvastatin treatment.The overall length of the trial was 1 year for each participant and comprised six 2-month treatment periods (three of placebo, three of atorvastatin 20 mg daily) in a randomly allocated order. At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale.

The primary outcome compared symptom scores (score 0 = no symptoms, 5 = moderate symptoms, and 10 = worst possible symptoms) in the statin and placebo periods. Three months after the end of the final treatment period, participants were asked whether they had, or intended to restart treatment with statins.Of the 200 participants, 151 (76%) provided one or more visual analogue scale measurements in both a statin and a placebo period and were included in the primary analysis. No statistically significant difference in muscle symptom scores was found between the statin and placebo periods [mean ± SD.

1.7 ± 2.6 vs. 1.8 ± 2.7. Mean difference statin minus placebo −0.1.

95% confidence interval (CI) −0.4 to 0.1. P = 0.40]. Atorvastatin showed no significant effect on development of muscle symptoms overall with an odds ratio (OR) of 1.11 (99% CI, 0.62–1.99).

Nor was there any effect on muscle symptoms that could not be attributed to another cause (OR, 1.22. 95% CI, 0.77–1.94).Of the 80 withdrawals during the study for any reason, 42% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Withdrawals because of intolerable muscle symptoms were 9% during a statin period and 7% during a placebo period.

Two-thirds of those completing the six treatment periods (74/113 participants) reported restarting long-term statin treatment. CommentThe European Atherosclerosis Society Consensus Panel and other groups established that there is evidence for causality for only three statin-related adverse effects. Muscle side effects, new-onset diabetes, and transient elevations of liver enzymes, with muscle symptoms being the most common complaint during statin treatment.2 Systematic reviews and meta-analyses of randomized controlled trials (RCTs) have confirmed the safety of statins, showing that the risk of myopathy and its progression to severe rhabdomyolysis are rare, and suggesting that symptomatic adverse events may be misattributed to statins.3–5 Indeed, the association between muscle symptoms and statins has suffered the bias of observational studies, reinforced by media reports.

Patients taking statins expect to experience adverse effects, and therefore reporting of symptoms in statin users may be higher than in a comparable population not on statins. This phenomenon, known as the ‘nocebo’ effect, often leads to patients discontinuing treatment, exposing them to an increased risk of cardiovascular events.6In the present study, patients who had previously faced severe muscle symptoms on a statin reported similar muscle symptom prevalence or severity during blinded statin or placebo periods. Also, there were no differences for the effect of muscle symptoms on several aspects of daily life between statin and placebo periods.

Thus, the study adds to the evidence from SAMSON,7 a recent trial with similar design, and from RCTs like ODYSSEY ALTERNATIVE8 and GAUSS-39 showing that a significant number of people who have problems with muscle pain associated with statins are experiencing a ‘nocebo’ effect, and that re-challenge with statins can be tolerated by most patients.StatinWISE, however, has several limitations. (i) the lack of creatine kinase measurement did not allow establishing what proportion of participants had symptoms associated with biochemical signs of muscle damage. (ii) the trial results may not apply to higher doses of atorvastatin or other statins, as only the effects of atorvastatin 20 mg were assessed.

(iii) most importantly, 86 of the original 200 participants did not complete the whole trial, 49 of whom did not provide sufficient data to contribute to the primary analysis. Furthermore, withdrawals due to intolerable muscle symptoms were not significantly different between statin (9%) and placebo (7%) periods, but StatinWISE was not powered to detect a difference in such withdrawals. (iv) the study participants may not be representative of all those who believe they experience side effects with statins.

On one hand, the study may have selected people who were less susceptible to the ‘nocebo’ effect. On the other hand, the majority (70%) of study participants had a history of cardiovascular disease, and they may have had a higher commitment to statin therapy than those in primary prevention. And (v) the 2-month treatment period should be long enough to allow washout between different treatments and avoid the carry-over of symptoms between statin and placebo periods.

However, while muscle pain/weakness typically occurs within 4–6 weeks after starting statin treatment, the onset may be delayed months or years.10Despite these limitations, these findings underscore the need for clinicians to acknowledge their patients’ muscle symptoms on statin therapy and, using a StatinWISE-like approach, ensure that as many as possible continue on a statin to reduce their cardiovascular risk.Conflict of interest. G.L. Received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research.

She is currently involved in the Research Programmes of the Italian Cardiovascular Network. C.P. Received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, Eli Lilly, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission.

He chairs the Scientific Advisory Board of the International Aspirin Foundation. References1Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, Shakur-Still H, Roberts I, Prowse D, Goldacre B, van Staa T, MacDonald TM, Armitage J, Wimborne J, Melrose P, Singh J, Brooks L, Moore M, Hoffman M, Smeeth L, on behalf of the StatinWISE Trial Group. Statin treatment and muscle symptoms.

Series of randomised, placebo controlled n-of-1 trials. BMJ 2021;372:n135.2Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms.

Impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012–1022.3Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy.

Lancet 2016;388:2532–2561.4Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, Collins R, Sever P, ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). A randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.

Lancet 2017;389:2473–2481.5Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL2nd, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell PB, Brinton EA, Pollak A, Braun LT, Welty FK, American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health. Council on Cardiovascular Disease in the Young. Council on Clinical Cardiology.

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