TSRI scientists give new superpowers to lifesaving antibiotic

May 30, 2017

Scientists at The Scripps Research Institute (TSRI) have given new superpowers to a lifesaving antibiotic called vancomycin, an advance that could eliminate the threat of antibiotic-resistant infections for years to come. The researchers, led by Dale Boger, co-chair of TSRI’s Department of Chemistry, discovered a way to structurally modify vancomycin to make an already-powerful version of the antibiotic even more potent.

“Doctors could use this modified form of vancomycin without fear of resistance emerging,” said Boger, whose team announced the finding today in the journal Proceedings of the National Academy of Sciences.

The original form of vancomycin is an ideal starting place for developing better antibiotics. The antibiotic has been prescribed by doctors for 60 years, and bacteria are only now developing resistance to it. This suggests bacteria already have a hard time overcoming vancomycin’s original “mechanism of action,” which works by disrupting how bacteria form cell walls.

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Boger called vancomycin “magical” for its proven strength against infections, and previous studies by Boger and his colleagues at TSRI had shown that it is possible to add two modifications to vancomycin to make it even more potent. “With these modifications, you need less of the drug to have the same effect,” Boger said.

The new study shows that scientists can make a third modification–which interferes with a bacterium’s cell wall in a new way–with promising results. Combined with the previous modifications, this alteration gives vancomycin a 1,000-fold increase in activity, meaning doctors would need to use less of the antibiotic to fight infection.

The discovery makes this version of vancomycin the first antibiotic to have three independent mechanisms of action. “This increases the durability of this antibiotic,” said Boger. “Organisms just can’t simultaneously work to find a way around three independent mechanisms of action. Even if they found a solution to one of those, the organisms would still be killed by the other two.”

Tested against Enterococci bacteria, the new version of vancomycin killed both vancomycin-resistant Enterococci and the original forms of Enterococci.

The next step in this research is to design a way to synthesize the modified vancomycin using fewer steps in the lab, as the current method takes 30 steps. But Boger calls this the “easy part” of the project, compared with the challenge of designing the molecule in the first place.

Even if the process isn’t streamlined, Boger believes the new vancomycin’s lifesaving powers make its production valuable. “Antibiotics are total cures for bacterial infections,” said Boger. “Making this molecule is important, even by the current approach, if the failure of antibiotics continues.”

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Scripps scientists make important advance in HIV vaccine design

May 29, 2017

Scientists at The Scripps Research Institute (TSRI) have made another important advance in HIV vaccine design. The development was possible thanks to previous studies at TSRI showing the structures of a protein on HIV’s surface, called the envelope glycoprotein. The scientists used these structures to design a mimic of the viral protein from a different HIV subtype, subtype C, which is responsible for the majority of infections worldwide.

The new immunogen is now part of a growing library of TSRI-designed immunogens that could one day be combined in a vaccine to combat many strains of HIV.

“All of this research is going toward finding combinations of immunogens to aid in protecting people against HIV infection,” said TSRI Professor Ian Wilson, Hanson Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

The research, published recently in the journal Immunity, was led by Wilson and TSRI Professor of Immunology Richard Wyatt, who also serves as Director of Viral Immunology for the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI.

The new study was published alongside a second study in Immunity, led by scientists at the Karolinska Institute in Stockholm, which showed that the vaccine candidate developed in the TSRI-led study can elicit neutralizing antibodies in non-human primates.
“Together, the two studies reiterate how structure-based immunogen design can advance vaccine development,” said Wyatt.

Caption: The new study shows the structure of an important HIV protein, called the envelope glycoprotein, on a common strain of the virus. (Image courtesy Javier Guenaga.)

Caption: The new study shows the structure of an important HIV protein, called the envelope glycoprotein, on a common strain of the virus. (Image courtesy Javier Guenaga.)

Solving the Clade C Structure

HIV mutates rapidly, so there are countless strains of HIV circulating around the world. Of these strains, scientists tend to focus on the most common threats, called clades A, B and C.

Like a flu vaccine, an effective HIV vaccine needs to protect against multiple strains, so researchers are designing a set of immunogens that can be given sequentially or as a cocktail to people so their immune systems can prepare for whatever strain they come up against.

In 2013, TSRI scientists, led by Wilson and TSRI Associate Professor Andrew Ward, determined the structure of a clade A envelope glycoprotein, which recognizes host cells and contains the machinery that HIV uses to fuse with cells. Because this is the only antibody target on the surface of HIV, an effective HIV vaccine will have to trigger the body to produce antibodies to neutralize the virus by blocking these activities.

Building on the previous original research, the scientists in the new study set out to solve the structure of the clade C glycoprotein and enable the immune system to fight clade C viruses.

“Clade C is the most common subtype of HIV in sub-Saharan Africa and India,” explained study co-first author Javier Guenaga, an IAVI collaborator working at TSRI. “Clade C HIV strains are responsible for the majority of infections worldwide.”

The scientists faced a big challenge: the clade C envelope glycoprotein is notoriously unstable, and the molecules are prone to falling apart.

Guenaga needed the molecules to stay together as a trimer so his co-author Fernando Garces could get a clear image of the clade C glycoprotein’s trimeric structure. To solve this problem, Guenaga re-engineered the glycoprotein and strengthened the interactions between the molecules. “We reinforced the structure to get the soluble molecule to assemble as it is on the viral surface,” Guenaga said.

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The project took patience, but it paid off. “Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage,” said Garces. “Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen.”

With these efforts, the glycoprotein could then stay together in solution the same way it remains together on the virus itself. The researchers then captured a high-resolution image of the glycoprotein using a technique called x-ray crystallography.
The researchers finally had a map of the clade C glycoprotein.

Vaccine Candidate Shows Promise

In a companion study, the scientists worked with a team at the Karolinska Institute to test an immunogen based on Guenaga’s findings. The immunogen was engineered to appear on the surface of a large molecule called a liposome—creating a sort of viral mimic, like a mugshot of the virus.

This vaccine candidate indeed prompted the immune system to produce antibodies that neutralized the corresponding clade C HIV strain when tested in non-human primates.

“That was great to see,” said Guenaga. “This study showed that the immunogens we made are not artificial molecules—these are actually relevant for protecting against HIV in the real world.”

In addition to Wyatt, Wilson and Guenaga, the study, “Glycine substitution at helix-to-coil transitions facilitates the structural determination of a stabilized subtype C HIV envelope glycoprotein,” included co-first author Fernando Garces, Natalia de Val, Viktoriya Dubrovskaya and Brett Higgins of TSRI; Robyn L. Stanfield of TSRI and IAVI; Barbara Carrette of IAVI; and Andrew Ward of TSRI, IAVI and the Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID) at TSRI.

This work was supported by the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD; grants OPP1084519 and OPP1115782), CHAVI-ID (grant UM1 AI00663) and the National Institutes of Health (grants P01 HIVRAD AI104722, R56 AI084817 and U54 GM094586).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs.

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Sri Lanka's flood survivors threatened by dengue, disease: aid workers

By Nita Bhalla

NEW DELHI (Thomson Reuters Foundation) – Thousands of survivors of devastating floods and landslides in Sri Lanka are at risk of potentially fatal diseases such as dengue fever, charities warned on Monday as the death toll from the disaster continued to rise.

Torrential rains over the last four days have sparked widespread flooding and triggered landslides in southwestern parts of the Indian Ocean island. At least 177 people have died and almost half a million others have had their lives disrupted.

As search and rescue teams look for more than 100 people who remain missing, and Sri Lanka’s military in boats and helicopters struggle to reach marooned villagers with food and clean water, charities are warning of a looming health threat.

“The threat of water-borne diseases is a big concern with over 100,000 people displaced from their homes, many of whom are staying in damp, crowded conditions,” Chris McIvor, head of Save the Children Sri Lanka, told the Thomson Reuters Foundation.

“I’m particularly worried we could start seeing even more dengue cases because of the floods, as stagnant water provides the perfect breeding ground for mosquitoes. It’s the last thing needed by communities that have already lost so much.”

Outbreaks of diseases such as dengue fever and cholera, and illnesses like diarrhea and dysentery, are often a threat in the aftermath of floods due to water-logging, say experts.

Dengue is common in South Asia, especially during the monsoon season which runs from June to September, and if untreated, it can kill.

Sri Lanka’s ministry of disaster management says almost 558,000 people from 15 of the country’s 25 districts have been hit by the disaster. Villages and towns have been inundated, thousands of homes damaged and agriculture land swamped.

Around 75,000 people in the worst-affected districts have been relocated to temporary shelters.

The Sri Lanka authorities have called for international assistance to help with search and rescue efforts, and have also appealed for aid ranging from boats, generators and mobile toilets to mosquito nets, clothes and clean drinking water.

But aid workers say reaching survivors remains a challenge. Entire communities remain marooned, living out in the open as their homes have been destroyed, with roads submerged under water or blocked by landslides.

“Getting in to these communities is of the highest priority right now so we can find out exactly what the needs are and respond,” said McIvor.

“At the same time more rains are predicted since we are only at the start of the south west monsoon season, so the situation could worsen even more over the coming days and weeks.”

(Reporting by Nita Bhalla @nitabhalla, Editing by Belinda Goldsmith; Please credit the Thomson Reuters Foundation, the charitable arm of Thomson Reuters, that covers humanitarian news, women’s rights, trafficking, property rights, climate change and resilience. Visit news.trust.org)


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Bulgaria to conduct food product checks amid quality concerns

Bulgaria said on Saturday it would conduct checks on different food products of multinational companies sold in the Balkan state and compare them with food sold in richer western European countries, amid concerns over quality.

Consumer groups have complained that popular brands use poorer-quality ingredients in products sold in central and eastern Europe than in countries like Germany and Austria.

However, they have had little recourse to complain because the European Union only requires that the packaging contain a clear list of all ingredients.

Bulgaria’s Minister of Agriculture, Food and Forestry Rumen Porozhanov said experts had already purchased chocolate, dairy and meat products, non-alcoholic beverages, juices and baby foods from Germany and Austria and would make the quality checks after buying the identical products in Bulgaria.

“Next week we will buy identical products that are sold on the Bulgarian market by the big chains and then the analysis will start,” Porozhanov said after a government meeting.

“We have a united vision of conducting such measures with the countries of the Visegrad Four,” he added, referring to Poland, Slovakia, the Czech Republic and Hungary which have already criticized several global food companies on the issue.

The eastern European countries want to lobby within the EU to stop companies from offering identical brands and packaging but different lists of ingredients in the “old” and “new” EU member states.

(Reporting by Angel Krasimirov; Editing by Gareth Jones)


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FFR-CT Accuracy; TnT Assay 'Sense and Sensitivity'; Chocolate Lessens Afib?

Computed tomography–derived fractional flow reserve (FFR-CT) accuracy varies across the spectrum of disease severity as compared with invasive FFR, with the most accurate results found in the upper or lower ranges of cardiac ischemia, a systematic review of five studies with 536 patients reported in JAMA Cardiology.

“In this study, for vessels with FFR-CT values above 0.90, 97.9% met the invasive FFR guideline criterion for deferral (FFR>0.80). At the other end of the spectrum, for vessels with FFR-CT values below 0.60, 86.4% met the invasive FFR guideline criterion for stenting (FFR≤0.80),” the researchers wrote. “In between, FFR-CT gave less certainty as to whether the invasive FFR will meet the stenting criterion.

“Finally, due to the significant scatter and poor numeric match of FFR-CT and invasive FFR values below the 0.80 treatment threshold, the proposed extended application of FFR-CT to virtual stenting and noninvasive revascularization planning currently seems implausible.”

An accompanying editor’s note called for larger prospective studies assessing the clinical outcomes of avoiding or performing angiography in patients with CT-FFR values in the intermediate range. Meanwhile, “clinical judgment is even more paramount.”

Other challenges are the limited guidance for outpatient evaluation of stable chest pain, lack of data that the use of FFR-CT improves patient outcomes, and the “considerable” add-on price of FFR-CT ($1,500), another editorial noted.

Chocolate and Afib

Chocolate has been associated with heart health in as many varieties as, well, a box of chocolates. Now researchers have added atrial fibrillation (Afib) to that list.

Reporting in Heart, the population-based prospective Danish Diet, Cancer, and Health Study showed a roughly 20% lower risk of clinically apparent Afib or flutter with weekly chocolate intake and 10% reduced risk with a few servings a month compared with less than once-a-month indulgence.

However, an accompanying editorial cautioned about possible confounding, as chocolate eaters in the study were healthier and more highly educated and the study did not account for Afib risk factors like kidney disease and sleep apnea.

“Regardless of the limitations of the Danish chocolate study, the findings are interesting and warrant further consideration, especially given the importance of identifying effective prevention strategies,” the editorialists concluded. “Perhaps what is bad for the pancreas is good for the atria.”

Chronic Steroids Hurt Heart

Male weightlifters who have used anabolic steroids for periods that add up to at least 2 years have poorer heart function and harder arteries, not all of which recover after stopping, researchers reported in a study of 140 such men.

Chronic steroid users had relatively reduced left ventricular systolic function, with a mean ejection fraction of 52% versus 63% among nonusers, and poorer diastolic function (early relaxation velocity 9.3 versus 11.1 cm/second). Both were worse in current than in former users. Steroid users also had significantly more coronary artery plaque, with a dose-response association to lifetime amount used.

“It is critical that clinicians become aware of the long-term risks of anabolic steroid use on the heart. Most people relate anabolic steroids to cheating among athletes and fail to realize that there is a large population of men who have developed dependence upon these drugs, but who are not readily visible. The oldest members of this population are only now reaching middle age,” study co-author Harrison Pope, Jr., MD, director of the Biological Psychiatry Laboratory of McLean Hospital, a Harvard Medical School affiliate in Belmont, Mass., said in a news release for the Circulation paper.

High-Sensitivity Troponin

For chest pain diagnosis in the emergency department, introduction of high-sensitivity troponin T (hs-TnT) might have led to fewer truly at-risk patients discharged home, according to a registry-based study from 16 Swedish hospitals reported in the Journal of the American College of Cardiology.

Major cardiac events (MACE) were less common in the 30 days after direct discharge with a diagnosis of unspecified chest pain when patients had been evaluated with hs-TnT versus use of a conventional assay before routine hs-TnT use at the treating hospital (0.6% versus 0.9%, OR 0.7). Those briefly admitted based on hs-TnT were more likely to have MACE after discharge than when evaluated with a conventional assay (7.2% versus 3.4%, OR 2.18).

“Considering the change in risk factor profiles for discharged and admitted patients with chest pain, together with the very small amount of missed cases in the current study, evaluation with the hs-TnT assay appears to be of great help in the ED when deciding whether a patient can be sent home or not,” the researchers concluded.

An accompanying editorial noted the importance of understanding the clinical effect of this test, given the recent FDA approval of the hs-TNT assay.

The editorial cautioned, however, about attributing causality: “While the findings … do support that absolute differences in MACE incidence exist before and after introduction of the hs-TnT assay, they also show that these differences vanish when age, sex, diabetes mellitus, hyperlipidemia, hypertension, and ED visit date are accounted for.”

In Other News

The vibrating technology used to break up kidney stones appeared safe for breaking up coronary artery calcification via a lithoplasty balloon system in early results reported at the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) meeting in Paris.

2017-05-26T12:00:00-0400

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Alzheimer's Deaths Jump 55 Percent: CDC

News Picture: Alzheimer's Deaths Jump 55 Percent: CDCBy Steven Reinberg
HealthDay Reporter

Latest Alzheimers News

THURSDAY, May 25, 2017 (HealthDay News) — As more baby boomers age, deaths from Alzheimer’s disease have jumped 55 percent, and in a quarter of those cases the heavy burden of caregiving has fallen on loved ones, U.S. health officials report.

“Alzheimer’s disease is a public health problem that affects not only people with Alzheimer’s disease, but also the people who provide care to them, which is often family members,” said report author Christopher Taylor. He’s an epidemiologist at the National Center for Chronic Disease Prevention and Health Promotion.

The number of Americans over 65 is growing rapidly, and age is the greatest risk factor for Alzheimer’s disease, Taylor noted.

One Alzheimer’s expert described the news as dire.

“This is an enormous problem that is only growing, it’s only going to get worse — we are staring at a tsunami of Alzheimer’s disease,” said Keith Fargo, director of scientific programs and outreach at the Alzheimer’s Association.

Fargo added that the 55 percent increase in Alzheimer’s deaths is an “adjusted number” that levels age differences in the population. “When you do the math on the unadjusted numbers, the death rate actually increased 83 percent from 1999 to 2014,” he said.

And, more Alzheimer’s sufferers are dying at home. During the 16 years covered by the study (1999-2014), that number increased from 14 percent to 25 percent, according to the report.

“With more people dying at home, there is an increased need for caregivers, because in the late stages of Alzheimer’s. patients are completely dependent on caregivers. At home, a lot of times it’s done by friends and family,” Taylor said.

This suggests that many of these caregivers would benefit from more support, including education and other services, he said.

The increase in Alzheimer’s deaths is occurring for several reasons, Taylor said. They include an aging population and better diagnosis of the disease. Also, Alzheimer’s is being listed more often on death certificates as a cause of death, he said.

Alzheimer’s disease is a fatal type of dementia and the sixth leading cause of death in the United States. It accounted for nearly 4 percent of all deaths in 2014. Alzheimer’s is the fifth leading cause of death among people aged 65 and older, according to the report.

Fargo said it’s alarming that fewer people with Alzheimer’s are passing away in nursing homes. He speculated that many people cannot afford nursing home care.

“Nursing home care is not paid by Medicare. People think it is, but it’s not, and it costs $80,000 to $90,000 per year for a person to be in a nursing home,” Fargo said. “So, I have to wonder if part of the issue is an economic issue.”

During the course of the disease, Alzheimer’s patients pass through a dementia phase, but they ultimately end up bedridden, Fargo said.

“For every person with Alzheimer’s there are three people providing care for them,” he said. “We know that caregivers for Alzheimer’s are more likely to have depression, anxiety and they spend more on their own health care each year because of the physical toll that it takes.”

Alzheimer’s is the most expensive disease in the United States, Fargo said. “Out of every 5 Medicare dollars, 2 of them are spent on someone who has Alzheimer’s disease or another dementia — that’s just not sustainable.”

The first priority is to find a cure, Fargo said. “There is tremendous optimism in the scientific community that we can and will do that,” he said.

Key findings in the report, which was published May 26 in the U.S. Centers for Diseaase Control and Prevention’s Morbidity and Mortality Weekly Report, include:

  • The death rate from Alzheimer’s increased 55 percent — from nearly 17 per 100,000 people in 1999 to slightly more than 25 per 100,000 in 2014.
  • Most Alzheimer’s patients die in a nursing home or long-term care facility, but that number has dropped from 68 percent in 1999 to 54 percent in 2014.
  • Counties with the highest Alzheimer’s death rates are mostly in the Southeast. Clusters are also seen in the Midwest and on the West Coast.

To come to their conclusions, the CDC researchers culled state and county death certificate data from the National Vital Statistics System.

One specialist said the number of deaths from Alzheimer’s will continue to climb, and the financial burden will eventually become untenable.

“There has been an increased effort to list Alzheimer’s disease rather than earlier traditions of listing only more proximate causes of death such as cardiac arrest,” said Dr. Sam Gandy, director of the Center for Cognitive Health at Mount Sinai Hospital in New York City.

So, an increase in Alzheimer’s disease as a cause of death, and especially in home deaths, is being seen, he explained.

“This probably also reflects true increased cases of death due to Alzheimer’s disease due to aging of the baby boom, the peak of which is yet to come. By 2050, at the current pace, Alzheimer’s disease alone will consume the entire Medicare budget,” Gandy said.

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SOURCES: Christopher Taylor, Ph.D., epidemiologist, National Center for Chronic Disease Prevention and Health Promotion, U.S. Centers for Disease Control and Prevention; Sam Gandy, M.D., Ph.D., director, Center for Cognitive Health, Mount Sinai Hospital, New York City; May 26, 2017, Morbidity and Mortality Weekly Report

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Molina Healthcare, A Top Obamacare Insurer, Investigates Breach Of Patients’ Data

Molina Healthcare, a major insurer in Medicaid and state exchanges across the country, has shut down its online patient portal as it investigates a potential data breach that may have exposed sensitive medical information.

The company said Friday that it closed the online portal for medical claims and other customer information while it examined a “security vulnerability.” It’s not clear how many patient records might have been exposed and for how long. The company has more than 4.8 million customers in 12 states and Puerto Rico.

“We are in the process of conducting an internal investigation to determine the impact, if any, to our customers’ information and will provide any applicable notifications to customers and/or regulatory authorities,” Molina said in a statement Friday. “Protecting our members’ information is of utmost importance.”

Brian Krebs, a well-known cybersecurity expert who runs the Krebs on Security website, said he notified the company of the potential breach earlier this month and wrote about it on his website Thursday. Molina said it was already aware of the security vulnerability when contacted.

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Until recently, Krebs said, Molina “was exposing countless patient medical claims to the entire internet without requiring any authentication.”

Krebs said the information he saw online included patients’ names, addresses, dates of birth and information on their medical procedures and medications.

“It’s unconscionable that such a basic, security 101 flaw could still exist at a major health care provider,” Krebs said. “This information is more sensitive than credit card data, but it seems less protected.”

Krebs said he received an anonymous tip in April from a Molina member who stumbled upon the problem when trying to view his medical claim online. The tipster found that by changing a single number in the website address he could then view other patient claims, according to Krebs.

Krebs said the Molina member showed him screenshots of his own medical records and how when he changed the web address slightly it then displayed records of another patient. On Friday, the Molina website told customers that the online portal was “under maintenance.”

Health care companies, hospitals and other providers must report data breaches to U.S. officials. Molina emphasized that it was still investigating the matter so had not yet reported it. Federal regulators can levy significant fines for violations under the Health Insurance Portability and Accountability Act, also known as HIPAA.

Many security experts question the ability of health care companies and providers to safeguard vast troves of electronic medical records and other sensitive data, particularly at a time when cybercriminals are targeting medical information.

Molina, based in Long Beach, Calif., posted $17.8 billion in annual revenue last year.

Molina made news earlier this month with the surprise firing of its top two executives, who are sons of the company’s founder. Both CEO J. Mario Molina and his brother, finance chief John Molina, were ousted. The company’s board said Molina’s disappointing financial performance led to the management change.

Molina has grown more prominent during the rollout of the Affordable Care Act, as Medicaid expanded and state insurance exchanges launched. The company serves more than 1 million people through Obamacare exchanges across several states. It has nearly 69,000 enrollees in the Covered California exchange, or about 5 percent of the market.

This story was produced by Kaiser Health News, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

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