Ablation is Associated With Decreased Mortality and Stroke

From www.practiceupdate.com

This study finds that ablation for atrial fibrillation (AF) produces a hazard ratio of 0.59 with a statistical significance of less than 0.0001, i.e., reduces the annual mortality rate by an estimated 31% versus no ablation.  That sounds fantastic.  However, it corresponds to a reduction in estimated annual mortality only from 1.9% to 0.9%, which is important but not fantastic.  Sometimes, hazard ratios make thing sound better than they are.

Nevertheless, the long term implication is important.

To put this in perspective, the controls have a 98.1% probability of surviving for a year versus 99.1% for the ablation group.  Suppose these probabilities do not change over time (they do) and that you come down with AF at age 60.  With ablation, your survival probability over the next 20 years is 0.991^20=0.835=83.5%.  Without ablation it is 0.981^20=0.681=68.1%.  While the difference of 15.4 percentage points is important, it doesn't sound nearly as great as the hazard ratio.
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BACKGROUND

Ablation for atrial fibrillation (AF) is superior to medical therapy for rhythm control. We compared stroke and mortality among patients undergoing ablation for AF to matched controls in a large multiethnic population.

METHODS

Using discharge and surgical records from California nonfederal hospitals, we identified patients who had ablation and principal diagnosis of AF with at least 1 prior hospitalization for AF. We excluded cases with valve disease, open maze, other arrhythmias, or implantable devices. Matched controls were selected based on years of AF diagnosis, age, sex, and being alive the same number of days from the initial AF encounter to the ablation date. Clinical outcomes, including mortality, ischemic stroke, or hemorrhagic stroke, were assessed using a weighted proportional hazard model, adjusting for demographics, prior admissions with AF before the ablation, calendar year, and presence of chronic comorbidities.

RESULTS

There were 4169 ablation cases and 4169 weighted-matched controls; 39% percent of the ablation group was >65 years, 72% men, 84% white; mean follow-up was up to 3.6±0.9 years. In adjusted models, ablation was associated with significantly lower mortality (per patient-years) 0.9% versus 1.9%, hazard ratio=0.59 (P<0.0001; confidence interval: 0.45-0.77); ischemic stroke (>30 days post-ablation ≤5 years), 0.37% versus 0.59%, hazard ratio=0.68 (P=0.04; confidence interval: 0.47-0.97); hemorrhagic stroke 0.11% versus 0.35%, hazard ratio=0.36 (P=0.001; confidence interval: 0.20-0.64) compared with controls.

CONCLUSIONS

In this large population-based study of hospitalized patients with nonvalvular AF, ablation was associated with lower mortality, ischemic stroke, and hemorrhagic stroke compared with controls.

Five-Year Risk of Stroke After TIA or Minor Ischemic Stroke

From www.practiceupdate.com

The results are a little problematic since not all patient sources (sites) were included and not all patients at included sites were followed for the term of the study.
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Background

After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke and other vascular events is not well known. In this follow-up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events.

Methods

We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk.

Results

A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke.

Conclusions

In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years.

Effects of Statins on Coronary Atherosclerotic Plaques

From www.practiceupdate.com
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OBJECTIVES

This study sought to describe the impact of statins on individual coronary atherosclerotic plaques.
BACKGROUND

Although statins reduce the risk of major adverse cardiovascular events, their long-term effects on coronary atherosclerosis remain unclear.

METHODS

We performed a prospective, multinational study consisting of a registry of consecutive patients without history of coronary artery disease who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. Atherosclerotic plaques were quantitatively analyzed for percent diameter stenosis (%DS), percent atheroma volume (PAV), plaque composition, and presence of high-risk plaque (HRP), defined by the presence of ≥2 features of low-attenuation plaque, positive arterial remodeling, or spotty calcifications.

RESULTS

Among 1,255 patients (60 ± 9 years of age; 57% men), 1,079 coronary artery lesions were evaluated in statin-naive patients (n = 474), and 2,496 coronary artery lesions were evaluated in statin-taking patients (n = 781). Compared with lesions in statin-naive patients, those in statin-taking patients displayed a slower rate of overall PAV progression (1.76 ± 2.40% per year vs. 2.04 ± 2.37% per year, respectively; p = 0.002) but more rapid progression of calcified PAV (1.27 ± 1.54% per year vs. 0.98 ± 1.27% per year, respectively; p < 0.001). Progression of noncalcified PAV and annual incidence of new HRP features were lower in lesions in statin-taking patients (0.49 ± 2.39% per year vs. 1.06 ± 2.42% per year and 0.9% per year vs. 1.6% per year, respectively; all p < 0.001). The rates of progression to >50%DS were not different (1.0% vs. 1.4%, respectively; p > 0.05). Statins were associated with a 21% reduction in annualized total PAV progression above the median and 35% reduction in HRP development.

CONCLUSIONS

Statins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features. Statins did not affect the progression of percentage of stenosis severity of coronary artery lesions but induced phenotypic plaque transformation.

The armed citizen

Job strain may increase the risk of atrial fibrillation

From the European Journal of Preventive Cardiology.

Here is a link to the paper.

Here is the abstract.
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Background: Knowledge about the impact of occupational exposures, such as work stress, on the risk of atrial fibrillation is limited. The present study aims to investigate the association between job strain, a measure of work stress, and atrial fibrillation.

Design: Prospective cohort study design and fixed-effect meta-analysis.

Methods: Data from the Swedish Longitudinal Occupational Survey of Health (SLOSH) was utilised for the main analysis, combining self-reported data on work stress at baseline with follow-up data on atrial fibrillation from nationwide registers. Cox proportional hazard regression analyses were used to estimate hazard ratios and 95% confidence intervals (CIs). A fixed-effect meta-analysis was conducted to pool the results from the present study with results from two similar previously published studies.

Results: Based on SLOSH data, job strain was associated with an almost 50% increased risk of atrial fibrillation (hazard ratio 1.48, 95% CI 1.00–2.18) after adjustment for age, sex and education. Further adjustment for smoking, physical activity, body mass index and hypertension did not alter the estimated risk. The meta-analysis of the present and two previously published studies showed a consistent pattern, with job strain being associated with increased risk of atrial fibrillation in all three studies. The estimated pooled hazard ratio was 1.37 (95% CI 1.13–1.67). Conclusion: The results highlight that occupational exposures, such as work stress, may be important risk factors for incident atrial fibrillation.
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The estimated hazard ratio of 1.48 is impressive.  However, the absolute risk is so small that increasing it by 48% still leaves it very small.  According to Table 1 in the paper (assuming I am reading it right), about 1.0 % of the "no strain" people developed atrial fibrillation vs. about 1.3% for the "strain" group.

Gun Control Lies and What to Do About Schools

Here is a link to a talk by John Lott of the Crime Prevention Research Center.  Listen to it if you want to be informed.

You will be shocked at the extent of the false information you are being fed by the media and anti-gun groups.  You will be doubly shocked, if you know anything about data and data analysis, about the likely purposeful misuse of the data and methods of analysis to produce "results" opposite to the facts.

HIV vaccine elicits antibodies in animals that neutralize dozens of HIV strains

From Science Daily.
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An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported today in the journal Nature Medicine by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and their colleagues.

Peter D. Kwong, Ph.D., and John R. Mascola, M.D., led the study. Dr. Kwong is chief of the Structural Biology Section at the NIAID Vaccine Research Center, and Dr. Mascola is the center director.

"NIH scientists have used their detailed knowledge of the structure of HIV to find an unusual site of vulnerability on the virus and design a novel and potentially powerful vaccine," said NIAID Director Anthony S. Fauci, M.D. "This elegant study is a potentially important step forward in the ongoing quest to develop a safe and effective HIV vaccine."

A preliminary human trial of the new vaccine regimen is anticipated to begin in the second half of 2019.

Today's report reflects one of two broad, complementary approaches NIAID is pursuing to develop an HIV vaccine. In one approach, scientists first identify powerful HIV antibodies that can neutralize many strains of the virus, and then try to elicit those antibodies with a vaccine based on the structure of the HIV surface protein where the antibodies bind. In other words, scientists start with the most promising part of the immune response and work to develop a vaccine that will induce it. This method was used to design the vaccine described today.

The other, empiric approach to HIV vaccine development begins by evaluating the most encouraging vaccine candidates for efficacy in people through clinical trials. Then scientists try to build on successful trial results by, for example, examining blood and other clinical specimens from study participants who received the vaccine to identify the most promising parts of the immune response. Researchers subsequently use this information to improve vaccination approaches for future trials. This method was used to develop the HIV vaccine regimen tested in the RV144 clinical trial and the HIV vaccine regimens currently under study in the HVTN 702 and Imbokodo clinical trials.

Over the past several years, HIV researchers have discovered many powerful, naturally occurring antibodies that can prevent multiple HIV strains from infecting human cells in the laboratory. About half of people living with HIV make these so-called "broadly neutralizing" antibodies, but usually only after several years of infection -- long after the virus has established a foothold in the body. Scientists have identified and characterized the sites, or epitopes, on HIV where each known broadly neutralizing antibody binds. Many laboratories around the world are developing HIV vaccine candidates based on the structure of these epitopes with the goal of coaxing the immune systems of HIV-negative people to make protective antibodies after vaccination.

The experimental vaccine described in today's report is based on an epitope called the HIV fusion peptide, identified by NIAID scientists in 2016. The fusion peptide, a short string of amino acids, is part of the spike on the surface of HIV that the virus uses to enter human cells. According to the scientists, the fusion peptide epitope is particularly promising for use as a vaccine because its structure is the same across most strains of HIV, and because the immune system clearly "sees" it and makes a strong immune response to it. The fusion peptide lacks sugars that obscure the immune system's view of other HIV epitopes.

To make the vaccine, the researchers engineered many different immunogens -- proteins designed to activate an immune response. These were designed using the known structure of the fusion peptide. The scientists first assessed the immunogens using a collection of antibodies that target the fusion peptide epitope, and then tested in mice which immunogens most effectively elicited HIV-neutralizing antibodies to the fusion peptide. The best immunogen consisted of eight amino acids of the fusion peptide bonded to a carrier that evoked a strong immune response. To improve their results, the scientists paired this immunogen with a replica of the HIV spike.

The researchers then tested different combinations of injections of the protein plus HIV spike in mice and analyzed the antibodies that the vaccine regimens generated. The antibodies attached to the HIV fusion peptide and neutralized up to 31 percent of viruses from a globally representative panel of 208 HIV strains.

Based on their analyses, the scientists adjusted the vaccine regimen and tested it in guinea pigs and monkeys. These tests also yielded antibodies that neutralized a substantial fraction of HIV strains, providing initial evidence that the vaccine regimen may work in multiple species.

The scientists are now working to improve the vaccine regimen, including making it more potent and able to achieve more consistent outcomes with fewer injections. The researchers also are isolating additional broadly neutralizing antibodies generated by the vaccine in monkeys, and they will assess these antibodies for their ability to protect the animals from a monkey version of HIV. The NIAID scientists will use their findings to optimize the vaccine and then manufacture a version of it suitable for safety testing in human volunteers in a carefully designed and monitored clinical trial.

New approach to immunotherapy leads to complete response in breast cancer patient unresponsive to other treatments

From Science Daily.
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A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. This patient received the treatment in a clinical trial led by Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI's Center for Cancer Research (CCR), and the findings were published June 4, 2018 in Nature Medicine. NCI is part of the National Institutes of Health.

"We've developed a high-throughput method to identify mutations present in a cancer that are recognized by the immune system," Dr. Rosenberg said. "This research is experimental right now. But because this new approach to immunotherapy is dependent on mutations, not on cancer type, it is in a sense a blueprint we can use for the treatment of many types of cancer."

The new immunotherapy approach is a modified form of adoptive cell transfer (ACT). ACT has been effective in treating melanoma, which has high levels of somatic, or acquired, mutations. However, it has been less effective with some common epithelial cancers, or cancers that start in the lining of organs, that have lower levels of mutations, such as stomach, esophageal, ovarian, and breast cancers.

In an ongoing phase 2 clinical trial, the investigators are developing a form of ACT that uses tumor-infiltrating lymphocytes (TILs) that specifically target tumor cell mutations to see if they can shrink tumors in patients with these common epithelial cancers. As with other forms of ACT, the selected TILs are grown to large numbers in the laboratory and are then infused back into the patient (who has in the meantime undergone treatment to deplete remaining lymphocytes) to create a stronger immune response against the tumor.

A patient with metastatic breast cancer came to the trial after receiving multiple treatments, including several chemotherapy and hormonal treatments, that had not stopped her cancer from progressing. To treat her, the researchers sequenced DNA and RNA from one of her tumors, as well as normal tissue to see which mutations were unique to her cancer, and identified 62 different mutations in her tumor cells.

The researchers then tested different TILs from the patient to find those that recognized one or more of these mutated proteins. TILs recognized four of the mutant proteins, and the TILs then were expanded and infused back into the patient. She was also given the checkpoint inhibitor pembrolizumab to prevent the possible inactivation of the infused T cells by factors in the tumor microenvironment. After the treatment, all of this patient's cancer disappeared and has not returned more than 22 months later.

"This is an illustrative case report that highlights, once again, the power of immunotherapy," said Tom Misteli, Ph.D., director of CCR at NCI. "If confirmed in a larger study, it promises to further extend the reach of this T-cell therapy to a broader spectrum of cancers."

Investigators have seen similar results using mutation-targeted TIL treatment for patients in the same trial with other epithelial cancers, includingliver cancerandcolorectal cancer. Dr. Rosenberg explained that results like this in patients with solid epithelial tumors are important because ACT has not been as successful with these kinds of cancers as with other types that have more mutations.

He said the "big picture" here is this kind of treatment is not cancer-type specific. "All cancers have mutations, and that's what we're attacking with this immunotherapy," he said. "It is ironic that the very mutations that cause the cancer may prove to be the best targets to treat the cancer."

The Land of the Free? You're joking?

From the Washington Examiner.

Civil asset forfeiture is just one example of laws designed to make it easy to get at criminals that are routinely used to violate the freedom of honest citizens.  That Sessions is ok with such laws shows that he is unfit for his office.

There is a tradeoff between making it easy to prosecute criminals and making it difficult to violate honest citizens' freedom.  Those concerned mostly with the former do not deserve the latter.
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His American dream was helping his family in Albania.

It ended when he walked through security at Cleveland Hopkins International Airport.

A U.S. citizen for more than a decade, Rustem Kazazi was flying back to Europe to help his Albanian family repair their home and maybe even to buy a little beach house somewhere along the Adriatic Sea. He placed $58,100 into three clearly marked envelopes, then packed the money away in his carry-on luggage.

It was 13 years of his life savings – and the federal government took every penny.

TSA employees discovered the cash, and agents with U.S. Customs and Border Protection seized it. But first they strip-searched Kazazi and interrogated the 64-year-old without a translator as he covered himself with a towel.

That was in October. Kazazi still hasn’t been convicted (or charged!) of any crime, and CBP didn’t offer any explanation for a month. But thanks to a law enforcement procedure called civil asset forfeiture, CBP also hasn’t given Kazazi his savings back. The federal government finally came up with an explanation: they suspectedhe was “involved in a smuggling/drug trafficking/money laundering operation.”

The large sum wasn’t for anything nefarious explained Kazazi, a former Albanian police office. “The crime in Albania is much worse than it is here,” he told the Washington Post. “Other people that have made large withdrawals [from Albanian banks] have had people intercept them and take their money.” Plus, hard U.S. currency is worth more.

And because traveling with that kind of cash isn’t a crime, the Kazazi family has filed suit against the federal government.

“You have the right to travel with cash in America, even when you’re flying internationally,” said Wesley Hottot, an attorney with the Institute for Justice, which represents the Kazazis in the lawsuit. “But again, we’re encountering a situation where law enforcement sees somebody with legal cash, assumes they must have done something criminal, and they just take the money. It is disturbing how little respect federal agents show for the civil rights of American citizens.”

Those federal agents aren’t an anomaly. It’s not just a bad apple here and a rotten one there. Civil asset forfeiture is the preferred policy of the nation’s top cop.

"I love that program," Attorney General Jeff Sessions said at a law enforcement conference last September. "We had so much fun doing that, taking drug dealers' money and passing it out to people trying to put drug dealers in jail. What's wrong with that?"

Turns out, a lot is wrong with the 1980s-era policy. Police aren’t just nabbing drug money. Around the country, law enforcement are taking cash, cars, and real-estatewithout ever charging victims with a crime. To seize property, the police only need to suspect it is connected to criminal activity. Afterwards, even clearly innocent citizens like Kazazi have no recourse except a lawsuit.

“This family’s case, like so many others, shows why civil forfeiture must end,” explained IJ attorney Johanna Talcott. “The Kazazis did nothing wrong and were never charged with a crime, but the government still won’t return their money all these months later. This kind of abuse is far too common because civil forfeiture is an inherently abusive process that will always have disastrous effects on innocent people. Enough is enough.”