Davidson KW et al. Screening for prediabetes and type 2 diabetes: US Preventive Services Task Force recommendation statement. JAMA 2021 Aug 24; 326:736. (https://doi.org/10.1001/jama.2021.12531)  The Task Force found moderate-certainty evidence that screening is beneficial for nonpregnant adults (age range, 35–70) who are overweight (i.e., body-mass index [BMI], ≥25 kg/m2) or obese (BMI, ≥30 kg/m2) and have no symptoms of diabetes. Referring patients for, or directly providing, effective preventive interventions is recommended (B recommendation).  The main change from the 2015 recommendation is the lower age threshold for screening — 35 rather than 40. The decision was made because of the increasingly younger age of onset for diabetes and the known benefits of intervention at a wide range of ages. Notably, the USPSTF found little direct evidence that screening improves clinical outcomes;   Lifestyle modifications and metformin are considered appropriate interventions for preventing or delaying onset of diabetes; however, metformin is not approved for this specific use by the U.S. FDA. ---- NO NO NO NO NO NO NO you cant do that..    Aringer M et al. European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance. Ann Rheum Dis 2021 Feb 10; 80:775. (https://doi.org/10.1136/annrheumdis-2020-219373) Diagnosising SLE—its always lupus till its not lupus but new diagnosis criteria In 2019, the European League Against Rheumatism and the American College of Rheumatology published the following classification criteria for systemic lupus erythematosus (SLE; Ann Rheum Dis 2019; 78:1151):·                     Positive antinuclear antibody (ANA) test with titer ≥1:80 is a required “entry criterion.”·                     If the ANA criterion is met, points are assigned from seven clinical categories and three immunologic test categories; a criterion is not counted if another cause is more likely than SLE.  A score ≥10 is considered to be consistent with SLE. When these criteria were validated, sensitivity for SLE was 96%, and specificity was 93%. But ANA what about ANA Sensitivity and specificity of ANA were 99.5% and 19.4%, respectively. NEXT  Gómez-Outes A et al. Meta-analysis of reversal agents for severe bleeding associated with direct oral anticoagulants. J Am Coll Cardiol 2021 Jun 22; 77:2987. (https://doi.org/10.1016/j.jacc.2021.04.061)Use of direct oral anticoagulants (DOACs) is associated with about a 3% annual risk for major bleeding, though that varies by age, comorbidity profile, and concomitant therapies.  investigators examined clinical outcomes associated with the use of 4-factor prothrombin complex concentrate (4PCC), idarucizumab, or andexanet for severe DOAC-associated bleeding.These drugs are greatBut if you do bleed then about 20% of the time we cant get hemostasis with mortality around 18% DESPITE getting reversal agents.. This is good to talk to your patients about— The risk of bleeding in 1 and 33 per year..Out of every 3300 people treated about 20 people will have a bleed that isn’t controlled and 18 of those people will die.It sounds like a lot but remember without these drugs the risk of stroke is much much higher, of course depending on your comorbid conditions. NEXT  Cardiovascular risk prediction in type 2 diabetes before and after widespread screening: a derivation and validation study - ClinicalKeyLancet, The, 2021-06-12, Volume 397, Issue 10291, Pages 2264-2274, Copyright © 2021 Elsevier Ltd Formulas for cardiovascular (CV) risk calculations are based on population studies and generally include diabetes as a major risk factor. Do formulas that were derived when diabetes usually was diagnosed at later stages overestimate CV risk for people in whom diabetes is diagnosed early?? Basically long ago we diagnosed in DM at a1c of 12 not we diagnosis it at a1c of 6-6.5-7—even prediabetes at a1c of 5.5……Those are not the same population so now are we over diagnosing CV risk??? The answer for this new zeeland study was yes--In this modern diabetic population, the median 5-year risk for an adverse CV event, as estimated by the new formula, was 4.0% in women and 7.1% in men. The older formula overestimated median risk in women (14.7%) and in men (17.1%).This is has to do with new Zealand not the the more recent and commonly used American pooled cohort equation but even that I would love to see put through the ringer as many of the studies were done back in the 90s, over thirty years ago, when we were quite as sharp about diagnosing diabetes yet…either way you have to remember the ascvd risk score is for discussion it is not evidence based gold it is a conversation starter   Next DVT – I am always confused when people say airline travel is a risk factor. I have sat on my couch for 6 hours without moving and I never got a dvt so why would being on a plane for 3 hours. Well maybe it is something I don’t understand about air travel because as this paper Munger JA et al. Television viewing, physical activity and venous thromboembolism risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study. J Thromb Haemost 2021 Jun 2; [e-pub]. They looked to see if tv watching was associated with DVT and it was not – it didn’t matter if you just watched a little bit of tv per day or over 4 hours of tv per day, there was no association with increase DVT and TV hours per day once accounting for total activity.. yes those that are watching TV move less and are more obese but is it he TV watching or just all the risk factors…. This article says it is the risk factors. Last articleKelly CR et al. Prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol 2021 Jun; 116:1124. (https://doi.org/10.14309/ajg.0000000000001278)    Oral vancomycin or fidaxomicin generally is favored for treating patients with nonsevere CDI, but metronidazole is acceptable for low-risk patients — especially when cost is a factor. Patients with severe CDI should be treated with either oral vancomycin or fidaxomicin (but not metronidazole). Severe disease is defined as having a leukocytosis >15,000 white blood cells/mm3 or a creatinine level of >1.5 mg/dL. Fecal microbiota transplantation (FMT) should be considered for refractory or severe CDI. *******A first recurrence should be treated with tapering/pulsed-dose vancomycin or fidaxomicin if it was not the initial therapy. ********A patient experiencing a second or further recurrence of CDI should be treated with FMT, delivered via a colonoscope or capsules, with enemas used when colonoscopy or capsules are not available. Repeat FMT can be used to treat a recurrence within 8 weeks of initial FMT. *****Patients with recurrent CDI who are not FMT candidates or have relapsed after FMT can be given long-term oral vancomycin prophylaxis to prevent recurrences. Oral vancomycin prophylaxis also can be considered when patients with recurrent CDI are given systemic antibiotics. 

Questioning Medicine

Episode 185: 185. USPSTF, Lupus, Diabetes Risk Factor, C. Diff

I've found that I can often increase compliance with statins by having pt take them 3x/week or QOD.  I try this often especially in my secondary prevention group. I understand "any statin is better than none", but do data support this approach?   -- any is better than none! No rct with this but yes data supports every other day but that is observational..what about vascepa in reducing CAD risk both primary and secondary risk? Vascepa is now the first and only drug approved by the FDA as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular diseaseReduce it trial---The big trial which showed all the promise used mineral oil as a placeboAND then we have evaporate trial—which showed steady plaqueThe groups didn’t start off the same!When you do an RCT- everything is random and therefor EVERYTHING IS EQUAL—but that idnt happen. And yes the people were blinded but they don’t say that the people reading the CT was blindedThe placebo group had higher CRP and dramatically worse cholesterol panels after taking mineral oilThen most recently we have the strength it trial- which showed no difference and should have had high bioavailability! Like LDL that went up 50 points in the placebo group!! That shouldn’t happen!What about fibrates for triglycerides > 400 or 500 to prevent complications like pancreatitis? No – no- no- no evidence for fibrates, period, throw them away. DRUGECTOMY for everyoneGiven evidence is only for patient to age 79, what do you recommend for patients over 79 with high lipids or on who are on a statin if concern for risk of negative cognitive effects of statins in this group?   Remember 5 years or less to live. stop the statin. And the cognitive declinePlease comment on lipophilic vs hydrophilic statins and possible detrimental effects on cognition.If cognitive risk is so small, why is there a black-box warning? It makes it difficult to convince the patient to take a statin when they read this warning.ano M, Bell KL, Galasko D, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 2011;77(6):556-563.In this multicenter trial, the authors gave simvastatin or placebo to 406 patients with mild to moderate Alzheimer disease, aged at least 50 years, with a Mini-Mental State Examination score between 12 and 26, who otherwise would not have been taking a statin. Simvastatin was no better than placebo in slowing cognitive deterioration in patients with mild to moderate Alzheimer disease. (LOE = 1b)Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc 2013;61(9):1449-55.These researchers serially assessed approximately 3500 elderly patients for 3.4 years. The elders did not have dementia at baseline and approximately one third were using a statin. After 3.4 years of follow-up, the rate of cognitive decline among statin users was comparable with that of nonusers. https://www.ahajournals.org/doi/10.1161/circ.128.suppl_22.A10589Results: Significantly higher proportional reporting ratios (PRRs) were observed for lipophilic statins, which more readily cross the blood-brain barrier, (range: 1.48-3.50) compared to hydrophilic statins (range: 0.68-1.60). However, fluvastatin, lovastatin, and pitavastatin (lipophilic) had relatively few adverse reports in the AERS database. The signal of higher risk of cognitive dysfunction was observed for the lipophilic statin atorvastatin (PRR = 2.68, 95% confidence interval: 2.52-2.85) followed by simvastatin (PRR = 2.20, 95% confidence interval: 2.02-2.40).Conclusions: Inconsistent with the FDA class warning, highly lipophilic statins with specific pharmacokinetic properties (atorvastatin and simvastatin) appear to confer a significantly greater risk of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic solubility properties.“Keep in mind that cohort studies are unable to account for 2 important phenomena: the healthy-user effect and reverse causality. The healthy-user effect, the primary explanation for older theories of the "benefits" of hormone replacement, refers to the observation that healthy people are more likely to use preventive measures and that the outcomes are due to good health, not the intervention. In reverse causality, we find that patients in declining health stop using treatments because they no longer perceive a potential benefit. It takes a randomized trial to overcome these phenomena.”Last but not leastZhou Z et al. Effect of statin therapy on cognitive decline and incident dementia in older adults. J Am Coll Cardiol 2021 Jun 29; 77:3145. (https://doi.org/10.1016/j.jacc.2021.04.075)They followed 18,846 study participants for a median of 4.7 years. Participants' median age was 74 years, and 56% were women. With 85,557 person-years of follow-up, the investigators identified 566 incident cases of dementia. Statin use was associated with nonsignificant increases in all-cause dementia (hazard ratio, 1.16) and probable Alzheimer disease (HR, 1.33; 95% CI 1.00 to 1.77). Statin use was not associated with mild cognitive impairment, but there was a nonsignificant increase in association with Alzheimer disease (HR, 1.44).Any thoughts on coronary CTA (rather than calcium score) or carotid intimal medial thickness as a tool for risk assessment?          No—no prospective RCT—all retrospective. And the people are baseline high risk to begin with. if you would choose one single best statin for primary and secondary prevention, which one would you pick?  The one the pt will takeshould take a statin if it increases LFT??         YES remember we are decreasing heart attacks and strokes!! We have no evidence on was a smell increase in your LFT does long term but we have evidence that long term these drugs have a 30% RR reduction in heart attacks and strokes!Some patients like to take Co Q10 with their statin. What is your experience with this?  Taking it for muscle aches and remember there is no real difference in muscle aches compared to placebo. If you don't check cholesterol but every 10 years, how do you know that further risk reduction is needed for secondary prevention or additional medication to statin is needed  -- you do it based on their risk reduction! There are 3 criteria – 1. 1 event in last 12 months. 2. 2 eents in their life. 3. An event with 3 or more risk factors. what are the real risks of statins increasing risks of DM? depends where you read—cocochane has the HR at 1.18 but that is a 2 yr study. For our calculation of the risk of diabetes the answer likely lies between 0.4% and 4%, and we have chosen what we believe to be a conservative estimate of 2% as a midway point in this credible interval.The raw numbers of 270 and 216 new onset diabetes cases from 24 months of exposure to a statin and a placebo (respectively) can be extrapolated, assuming that increased diabetes risk is likely to continue linearly with exposure. This yields 675 and 540 cases at 5 years. How long do you do washout between statin? No hard science to this they have not randomized different months of wash out as far as I am aware of so 3-6 months and you will be fine. Anything to say about Nexletol?Is there any benefit in obtaining lipoprotein profiles? NO—not for the events we care about. There is evidence that you can get this panels and then you could add a drug or increase a dose and decrease a lab value but we treat patients not lab values and there is no evidence It improves patient orientated outcomes. WHATPCSK9 DO YOU USE? Whatever insurance will pay for and remember they are still really really really expensive and IV only so this should be dead last line and only in the highest of the highest of the highest risk. 

Episode 184: 184. Question and Answer From the Last Two Podcast

DYSh out information on DYSlipidemia: An Evidence-based Update on Cholesterol ManagementPlease contact me for more information:    Andrew Buelt, D.O.  andrewbuelt@gmail.com Questioning Medicine PodcastAthrosclerotic Cardiovascular Disease Risk Calculator (ASCVD) 10 yr ASCVD risk calculator developed in 2013 ASCVD event defined as nonfatal myocardial infarction, coronary heart disease (CHD) death, fatal or nonfatal stroke Development of ASCVD calculator used African-American and White men and women age 40 to 79 yrs old (not hispanic, watch for inclusion drift)  Risk assessment should occur every 5 yrs in moderate risk individuals and can occur more frequently if the patient is nearing a cutoff for treatment Serum Lipid Level Lipid levels are stable over long durations of time Serum lipid lab values have high intra-test variability Testing more frequently than every 10 years leads to overdiagnosis from lab error and not true changes in serum lipid levels.  Primary PreventionTreatment Statins are the only currently approved drug to reduce cardiovascular events in primary prevention patients  Primary prevention statins should be used for those with diabetes, LDL ≥ 190, ASCVD 10 yr risk of 11.25% No trial has EVER looked at treatment titration to a specific cholesterol number compared to standard treatment dose...EVER Coronary Calcium Scoring  No prospective RCT exist Largest observational study currently in existence had 5,185 patients, 58 patients were correctly reclassified, 292 patients incorrectly reclassified, 4,835 patients had no benefit or harm other than lost time, money, resources (0.3% benefit, 6.7% harm, 93% no benefit or harm) Secondary Prevention Define as individuals with previous angina, MI with or without intervention, ischemic stroke/TIA, peripheral arterial disease (claudication or abdominal aortic aneurysm) Treatment -First Line Treatment = Statin High dose statin reduces major adverse cardiovascular events by 1% more than moderate dose statin High dose statin cause adverse events WITH therapy discontinuation 1% more often moderate dose statin  ANY dose statin is better than no statin Statins cause myalgias at a rate that is not statistically different from placebo Second line treatmentIncrease statin dose to max tolerated then add Ezetimibe Third line treatmentPCSK9 inhibitor 

Episode 183: 183. PART 2 DYSH Out Information on DYSlipidemia, an Evidence Based Approach

part 1-- you dont get the CME but you get the information

Episode 182: 182. PART 1 DYSH Out Information on DYSlipidemia, an Evidence Based Approach

PodcastGregory J, Huynh B, Tayler B, et al. High-dose vs standard-dose amoxicillin plus clavulanate for adults with acute sinusitis. A randomized clinical trial. JAMA Network Open 2021;4(3):e212713Study design: Randomized controlled trial (double-blinded) primary care offices with sinus symptoms consistent with currently accepted clinical criteria for acute bacterial sinusitis. andomly received (concealed allocation assignment) either a standard-dose regimen of amoxicillin 875 mg plus clavulanate 125 mg plus placebo twice daily for 7 days or a high-dose regimen of amoxicillin 875 mg plus clavulanate 125 mg plus amoxicillin 875 mg twice daily for 7 days. They planned to have 240 patients enrolled in the trial but then COVID happened and the authors say “  At an unplanned interim analysis prompted by COVID-19 restrictions” made us look at the data and then stop the trial. They found that there was NO difference between the high dose and the standard dosea global rating of "a lot better" or "no symptoms" occurred in 44.3% of patients in the standard-dose group compared with 36.4% of patients in the high-dose group  79 randomized to the standard dose and 78 to the high dose; 9 and 12, respectively, withdrew or were lost to follow-up  Because of the high drop-out rate, the investigators assigned a negative outcome to everyone in the standard-dose group and a positive outcome to everyone in the high-dose group; the group difference in the primary outcome was still not significant.DONT DO SOEMTHING STAND THEREChina L, Freemantle N, Forrest E, et al, for the ATTIRE Trial Investigators. A randomized trial of albumin infusions in hospitalized patients with cirrhosis. N Engl J Med 2021;384(9):808-817.Study design: Randomized controlled trial (nonblinded)in hospitalized patients with decompensated cirrhosis dose Routine daily albumin infusions to target an albumin level of 30 g/L or more prevent infection, kidney dysfunction, or death?  The intervention group (n = 380) received a daily 20% albumin infusion at 100 mL per hour to target an albumin level of at least 30 g/L for a maximum of 14 days or until discharge. The control group (n = 397) received standard care. The primary outcome was a composite of new infection from any cause, kidney dysfunction, or in-hospital death between trial day 3 and trial day 15 or day of discharge (whichever occurred earlier). There was no significant difference detected in the composite endpoint with an approximately 30% event rate in both groups.And whats worseThe intervention group had more severe and life-threatening adverse events, including pulmonary edema or fluid overload (6.1% vs 2.0%) and lung infections (3.9% vs 2.0%). We all want to do something but do nothing, just stand thereOr dont just do something let your patients do somethingScarinci IC, Li Y, Tucker L, et al. Given a choice between self-sampling at home for HPV testing and standard of care screening at the clinic, what do African American women choose? Findings from a group randomized controlled trial. Prev Med 2021;142:106358. Clinical questionDoes giving women the option of doing home self-sampling for human papillomavirus increase the rates of cervical cancer screening? study identified 12 rural, underserved towns and randomized the towns to either  (1) a visit from a Black female community health worker with information about cervical cancer screening and encouragement to have a free Pap test at the local health department (standard care), or (2) a visit in which they were given the choice of a free Pap test at the health department or the option to do free home self-sampling for HPV (choice).  Among women in the standard care group, only 16 of 170 (9.4%) were ultimately screened, compared with 63 of 165 (38.2%) in the choice group.We all want to do something but do nothing, just stand thereClinical questionWhat is the effect of a delayed prescription approach for children with respiratory tract infection? Mas-Dalmau G, Villanueva López C, Gorrotxategi Gorrotxategi P, et al, for the DAP PEDIATRICS GROUP. Delayed antibiotic prescription for children with respiratory infections: a randomized trial. Pediatrics 2021;147(3):e20201323. Study design: Randomized controlled trial (nonblinded)

Episode 147: Weekly Medical Update 181

Delay of Pregnancy Among Physicians vs Nonphysicians JAMA Intern Med 2021 May 03;[EPub Ahead of Print], MC Cusimano, NN Baxter, R Sutradhar, E McArthur, JG Ray, AX Garg, S Vigod, AN Simpson It has been hypothesized based on just rumor and people repeating it that women physicians are more likely to delay childbearing than nonphysicians. This population-based retrospective cohort study looked to see if that was true. They compared childbirth rates among physician and compared it to nonphysicians Physicians were less likely to experience childbirth at younger ages (HR for childbirth at 15–28 years, 0.15; P < .001) and more likely to experience childbirth at an older age (HR for 29–36 years, 1.35; P < .001; HR for ≥37 years, 2.62; P < .001). BUT BUT BUT do they delay child birth all together?? Well in simple terms, NO. female physicians have children rates equal to that of nonphysician women over time, although the time Basically this says what lots of us know in the women try not to have children during med school or residency because the cutoff was age 28 and if you go through it as fast as possible you are 29-30 provided you take the fast route possible. I think this makes sense an I would have liked to see them separate it out by age even a little more but overall I think residency and med schools should change the mantra and how the handle women becoming pregnant during training. It seems odd to me that so much emphasis these days is on burn out and making sure you have family time but often women are punished for having children during training years…..you cant have your cake and eat it to, you cant say one thing but do another…..although to me that is exactly what it seems like. Gender, Race, Ethnicity, and Sexual Orientation of Editors at Leading Medical and Scientific Journals: A Cross-sectional Survey | Medical Journals and Publishing | JAMA Internal Medicine | JAMA Network You have to know who was in the room… If a bunch of old white men created the machine or law or toy then it will be bias towards then and on the counter to that if a bunch of black or asiain people made the same law, toy, machine then it will be bias towards them and their perception of reality. It is our own individual bias that exist no matter how hard we try to fight it. This paper looked to see what is the general break down of the editorial staff of major medical and science journals and while there was a nice almost 50/50 split of men and women the mean age was 51 yrs old and white made up 77% with Hispanic and black only making up 5% COMBINED!! I am not saying we need to hire all Hispanic or black editors for major medical journals but maybe a few more… I say it like this, if I was an editor for lets say Jama internal medicine and in my previous life I was a vascular surgeon, Don’t you think even if I fought it that my bias would be to publish more papers that have something to do with vascular surgery or could somehow be related to vascular surgery. Our perception of reality is what we choose to see and the publication of paper is no different Annals for Hospitalists Inpatient Notes - A Critical Look at Procalcitonin Testing in Pneumonia | Annals of Internal Medicine (acpjournals.org) We all want a test that will help us—we all would love for procal to work but does it?? In addition, the 2019 joint guideline on community-acquired pneumonia (CAP) from the American Thoracic Society and Infectious Diseases Society of America recommends against the use of PCT testing to guide initiation of empirical antibiotic therapy for radiologically confirmed pneumonia (strong recommendation, moderate evidence) This is largely based on a study of 1735 patients admitted with CAP who had bronchs or procedures to identify pathogens… viral and bacterial pathogens were identified in 24% and 14% of cases, respectively. the negative predictive value of a PCT value less than 0.1 ng/mL was 82.4% (95% CI, 71.2% to 86.9%). Said differently, approximately 1 in 5 patients with microbiologically confirmed bacterial CAP had a negative PCT test result (2). failing to initiate antibiotics in nearly 20% of patients with confirmed bacterial CAP is unacceptable and not a good test! Now you could say but andrew—24% plus 14% is only roughly 40% what about the other 60% of people that didn’t have a confirmed source you cant just throw them out.. sure you are correct and if you include everyone then the egative predictive value of PCT increased to 93.9% (CI, 91.9% to 95.5%). BUT that is still missing 1 in 10 which is a lot! We think NNT of 25 at 2-3 years of a trial are good. This is if we should start therapy for an infection that could kill you or at least put you in the ICU and it is missing 1 in 10! If you really don’t know the diagnosis then can a procal be helpful in the context of the rest of your History and physical, sure, it is not completely worthless it is another data point. However, I will say I almost never order it but if it is already ordered I wont not look at it. My fear is that in much of the country procal became this golden, it can never be wrong, lab test and that is just simply not true. Sure there is an idea to trend procal and maybe we will discontinue antibiotics early but a major of pna is community acquired pna and the recommendations are for only 5 days of antibiotics as is. So maybe you decrease it by a day—is there really that much resistance that occurs from day 4 to day 5?? I doubt it but I have no evidence for or against that statement so I will leave it to you. The Problem of Aducanumab for the Treatment of Alzheimer Disease | Annals of Internal Medicine (acpjournals.org) Fda0 nov 2020- FDA statistician recommended this drug not be approved But via the “accelerated approval” pathway It was approved Accelerated approval is intended for products expected to provide a meaningful advantage over available therapies for a serious disease but for which there is uncertainty about clinical benefit. Under accelerated approval, a drug is approved on the basis of its effect on a surrogate marker of a disease—in this instance, brain β-amyloid levels—rather than clinical outcomes, such as signs or symptoms of Alzheimer disease. I will grant you we have nothing good for alzheimers and I do seriously mean there is no good medication for it but to approve it based on no clinical outcomes is potentially harmful or just a really expensive placebo because it will have no effect just like every other drug we have tried Aducanumab's phase 1 study showed lower levels of β-amyloid levels for those on the drug BUT SADLY aducanumab's phase 3 trials shows an unclear relationship between β-amyloid reductions and cognitive improvements so we have a drug the improves a surrogate outcome of amyloid levels but decreasing amyloid levels have never consistently proven or shown to improve cognitive outcomes EVEN IN THEIR OWN PHASE THREE TRIALS the company says it will continue to do research while the drug is on the market and expect it done by 2030 BUT until that time they are going to be collecting a lot of money for the next 9 years The drug's annual price per patient—$56 000— 56k per patient per yar for the next 9 years on a drug that we don’t know if it works for anything that we care about! This is a sad day—or a sad approval by the FDA and I can only wonder who was paying who to make this happen as the last line of this paper almost perfectly states “The FDA has approved a first-in-class product for Alzheimer disease on the basis of reduction in β-amyloid plaques. We all must wait for evidence of whether this in fact benefits patients." And with that! 

Episode 146: Weekly Medical Update 180 (I'm Back)

1) nurses commit more suicide and average population (doctors don't)2) AK will turn in to SCC at a rate of about 2% per year3) STOP SMOKING (even if you gain weight)4) zofran is about equal to the rest for pregnant patients and the outcomes we care about5) Tubes in the ear for children with acute otitis media?? It works about the same as medical managementAssociation of US Nurse and Physician Occupation With Risk of Suicide | Nursing | JAMA Psychiatry | JAMA Network This retrospective cohort study used US data from 159 372 suicides reported in the National Violent Death Reporting System from 2007 to 2018. Researchers found that suicide was more common among nurses compared with the general population (sex-adjusted incidence, 23.8 per 100,000 vs 20.1 per 100,000; RR, 1.18). By sex, the physician suicide rate was not different from that of the general population Ten-Year Follow-up of Persons With Sun-Damaged Skin Associated With Subsequent Development of Cutaneous Squamous Cell Carcinoma | Dermatology | JAMA Dermatology | JAMA Network authors use Kaiser Permanente Northern California data to investigate a patient’s risk of SCC after an AK in more than 200,000 patients with AKs (they give a bunch of fancy results but I am just going to tell you exactly what you need to know or want to know and that is what is the risk of AK turning into SCC and the answer is about 2% per year. An absolute risk is straightforward to use when thinking about patients: these results suggest that, if you see 10 patients with AKs on a given clinic day, one of them will have an SCC in the next 5 years. People don’t want to quit smoking, usually because it is addictive but some of the things they tell themselves is they smoke to stay skinny Sahle BW et al. Weight gain after smoking cessation and risk of major chronic diseases and mortality. JAMA Netw Open 2021 Apr 1; 4:e217044. (https://doi.org/10.1001/jamanetworkopen.2021.7044) prospective cohort study, looked at weight gain and associated mortality in about 17,000 adults over 8 years,during the 8 years of follow up 47% never smoked, 22% continued to smoke, and 31% quit smoking. participants who quit smoking gained on average 3.1 kg or almost 7 pounds compared with those who continued to smoke those who quit and gained weight had a hazard ratio for all-cause mortality around 0.30 compared to those who continued to smoke. This means if your risk of dying is 1 if you continue to smoke then if you stop smoking your risk of dying goes down to 0.3!This is insanely large, we have no drugs that give this big of a benefit and certainly not for mortality. That is a 70% decrease in mortalityIt just goes to show that although treatment is good, prevention, and discontinuing cigarette smoking is better. Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort | Clinical Pharmacy and Pharmacology | JAMA Network Open | JAMA Network Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. Data from 456 963 pregnancies were included to evaluate exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs. Somethings we do in medicine we do because no one really questions it— Tympanostomy Tubes or Medical Management for Recurrent Acute Otitis Media | NEJM performance of tympanostomy-tube placement for recurrent acute otitis media has been the commonplace observation—OBSERVATION!! Previous trials of tympanostomy-tube placement for recurrent acute otitis media historically have many flaws For Examplemost were conducted before the introduction of pneumococcal vaccine (which is important later)they are of small sizeuncertain validity of diagnoses of acute otitis mediashort periods of follow-up so what if we could have a study that made acute otitis media diagnoses by a validated otoscopists, used a standardized protocol for treating episodeslooked at 250 childrenand used a follow up of at least 2 yrs what if we could have that study???? WE ARE IN LUCKTympanostomy Tubes or Medical Management for Recurrent Acute Otitis Media | NEJM this trial involves 250 children 6 to 35 months of age who had a history of recurrent acute otitis media to undergo tympanostomy-tube placement or receive nonsurgical medical management, with the option of tympanostomy-tube placement in the event of treatment failure The primary measure was the average number of episodes of acute otitis media per child-year (rate) during the 2-year follow-up period. episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P=0.66). episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P=0.66). – which mean NO DIFFERENCE to be fair the authors did a per protocol analysis which is inappropriate, you should do an intention to treat. Intention to treat is real life, it is what group is the person assigned to. If they are assigned to a drug or a treatment and don’t get the drug or treatment or in this case procedure, that is real life that is what really happens but when you want to find a positive outcome you do a per protocol analysis. A per protocol is just the people that finished the protocol, it will typically over exaggerate the effects of treatment. Well in this study 10% of the children in the tympanostomy-tube group did not undergo tympanostomy-tube placement and 16% of the children in the medical-management group underwent tympanostomy-tube placement at parental request, the per-protocol analysis, which gave corresponding episode rates of 1.47±0.08 and 1.72±0.11, respectively—which was significant. However that is not how you should ever look at data from an RCT and I find it interesting that the authors did in this paper. The true take home and conclusions of this paper are stated perfectly by the authors--- ‘Among children 6 to 35 months of age with recurrent acute otitis media, the rate of episodes of acute otitis media during a 2-year period was not significantly lower with tympanostomy-tube placement than with medical management. ‘ And although not powered for this they did show that among children who received pneumococcal vaccine tympanostomy-tube placement was not superior to medical management in reducing the rate of episodes of acute otitis media. So maybe this is not only a win for getting your kid vaccinated but a dagger for pediatric ENT physician everywhere. I can see it now, all the ENT physicians move to California where all the of the antivaxers live!

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Donanemab doesn't work for alzheimers if you actually read the study. Mammograms should be done every other year and starting at age 50. Blue-blockers don't prevent eye strain on the computerand sleep varies but at this time the evidence doesnt suggest it causes obesityhttps://www.nejm.org/doi/full/10.1056/NEJMoa2100708new drug donanemab vs placebo = 257-patient double-blind randomised TRAILBLAZER-ALZ trial. the authors say “In patients with early Alzheimer’s disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. “ but lets review individuals with a Mini-Mental State Examination (MMSE) score of 20-28 were included in the study The primary outcome was the change in the Integrated Alzheimer’s Disease Rating Scale at 76 weeks. (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) the change in the iADRS score at 76 weeks was -6.86 in the donanemab group and -10.06 in the placebo group (difference, 3.20; 95% confidence interval [CI], 0.12 to 6.27; P=0.04). SADLY--—both groups still got worse just not as worse with donanemab. There was no benefit of donanemab over placebo seen on the secondary outcomes, ((((((Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini–Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.)))))) So you have a 3 point change on a 144 point scale with no other positive findings and you say BAM look at this fantastic drug we have…Although there were no safety concerns I think my listeners will know I think this is a perfect study to question medicine and maybe save in a drawer to give students about the importance of stastical vs clinical significance and how small changes on big scales can give you a positive study but that doesn’t mean it was a positive study clinically speaking.. Recommendations From Breast Cancer Centers for Frequent Screening Mammography in Younger Women May Do More Harm Than Good | Breast Cancer | JAMA Internal Medicine | JAMA Network This is from the “less is more” series and it tackles one of my most favorite discussions—the benefits of mammograms- who should get them?? How often should they get them? What age should we begin? The CDC says-- “Women aged 40 to 44 years should have the choice to start breast cancer screening once a year with mammography if they wish to do so. The risks of screening as well as the potential benefits should be considered. Women aged 45 to 49 years should be screened with mammography annually.” “The most recent (2016) US Preventive Services Task Force (USPSTF) breast cancer screening recommendations for women with average risk advise biennial screening in women aged 50 to 74 years” What about 40-49? Well the USPSTF says they do not recommend it but think it should be dicussed in a shared decision making conversation The AAFP says exactly what the USPSTF says – which is usually a safe and great bet—(rant on what told brian about USPSTF) American cancer society says yearly at age 40, start yearly mammograms at 45, transition to every other year at age 55. ACOG says mammograms every 1-2 years from women 40-49 then annually after that. And when no one agrees that means the evidence is borderline at best OR it is borderline with heavy bias from big pharmat. Every society agrees on the big ticket items like treating blood pressure but when it starts to vary by society then you know that the actual evidence is terrible. So lets talk about risk and benefits and should you do it starting at age 40? first- lets start with how often—yearly or every other year??? EVERY other year Biennial mammography is preferred because it has benefits similar to those of annual screening but with fewer harms. The problem with mammograms is the false positive rate—obviously the more test you have the more likely you are to have a positive- debateable if that is true or false positive. Over 10 yrs if done annualy the false positive rate is 61% but if done every other year then you are doing less test and that rate of having a false positive result drops to 42% Now false positives are bad because of the stress they put on the families and the women but that is mental health and hard to quantify because we can never randomize people to get false positive results and true positive results… so lets talk numbers…. As in numbers of biopsies If you get annual mammograms for 10 yrs you have a 7% risk of undergoing biopsy but if you get mammograms every other year then your risk is 4.8% So we do less test, we have less false positives, we do less unnecessary biopsies AND there is not real difference in breast cancer mortality among younger women between annual and biennial screening. But now lets look at the age--- a paper titled Benefits and harms of breast cancer screening with mammography in women aged 40–49 years: A systematic review In the journal in international journal of cancer Was a systematic review looking at evidence from RCTs on the benefits and harms of breast cancer screening with mammography in women aged 40–49 years. They found “The results showed no significant effect on breast cancer mortality (Age trial: RR 0.93 (95% CI 0.80–1.09); CNBSS‐I: HR 1.10 (95% CI 0.86–1.40)) nor on all‐cause mortality (RR 0.98, 95% CI 0.93–1.03) in women aged 40–49 years offered screening.” Over‐diagnosis of invasive breast cancer evaluated 20 years after completion of the of screening was estimated to be 48%.They say—and I quote- “Based on the current evidence from randomised trials, extending mammography screening to younger age groups cannot be recommended. ‘ The recommendation for annual mammography in women younger than 50 years is, at best, confusing for patients – I think the evidence is clear for screening every other year and start at 50 with a conversation starting at 40. so just maybe the USPSTF got it right. Do blue-blocking lenses reduce eye strain from extended screen time? A double-masked, randomized controlled trial - American Journal of Ophthalmology (ajo.com) Measures of eye strain included critical flicker-fusion frequency, saccadic eye movements, near point of accommodation, near point of convergence, and blink rate. blue-blocking lenses during 2 hours of computer use did not alter subjective nor clinical measures of eye strain. - sad but I think the authors are spot on when they say “ "it is extremely unlikely that blue light is a contributory factor to eye strain associated with computer use." This next paper is a real sleeper, titled“Association of Sleep Duration and Variability With Body Mass IndexSleep Measurements in a Large US Population of Wearable Sensor Users” Which was a retrospective cohort study of sleep data from 200,000 De-identified individualsusing a commercially available wearable device such as FitbitThey were looking at the Association between sleep and the associated BMIAnd their major findings were“(1) individual sleep durations and patterns are highly variable, and (2) shorter sleep durationand greater sleep variability were both associated with higher BMI” Taking those one by one, it didn’t take any study to understand individuals vary in their durationand pattern of sleep. This is an obvious statement from maybe even your own household. SomePeople are early risers and some people are night owls. But I am most interested in the second major finding which was that shorter sleep duration andgreater sleep variability was associated with a higher BMI.How did they find this?Well they used a BMI cutoff of obesity, so a BMI of 30 and they looked to see if it wasassociated with a shorter sleep duration or a more variable sleep pattern and they found thatindeed it was associated with both.However, when you look at the numbers you will find that the sleep duration of those individuals who had a BMI greater than 30 had a sleep duration of 6.6 hours per night while those who had BMI under 30 longer sleep duration at 6.8 hours per night. This was a pvalue of 0.001. but when you break it down that is on 15 minutes!!!! this is pure association not causation. Use your brain, does and extra 15 minutes of sleep really prevent you from being obese? or does 15 minutes less of sleep make you obese???Sad this is the data that will be used in future studies and future meta analysis. other authors will look at this data or this abstract and say look at the positive Association with sleep and lower BMI.Using this logic then even 1 extra minute should have significant power. Or just maybe,just maybe this is another example of data mining, an example of large data which can findtrends that are likely not significant. Remember the more people you enroll or look at in a studythe more likely you find a small difference is a very real difference statistically speaking but themore people you enroll or look at the more you need to question if the statistical finding isplausible or clinically significant. I think my take home is that sleep is important but this data does not prove that extra time sleeping either prevents or causes you to have a BMI 

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CirculationBariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease: A Population-Based Retrospective Cohort StudyCirculation 2021 Apr 13;143(15)1468-1480, AG Doumouras, JA Wong, JM Paterson, Y Lee, B Sivapathasundaram, JE Tarride, L Thabane, D Hong, S Yusuf, M Anvari Patients with CVD who underwent bariatric surgery were matched 1:1 with similar CVD patients who did not undergo bariatric surgery. primary outcome was major adverse cardiovascular events (MACE) (first occurrence of all-cause mortality, myocardial infarction, coronary revascularization, cerebrovascular events, and heart failure hospitalization)n follow-up of 4.6 years, the primary outcome was lower in the surgery group compared with the control group occurred in 11.5% (151/1319) of the surgery group and 19.6% (259/1319) of the controls that is roughly a NNT of 12. But enough with the observational trials- do what we want to see or don’t do it. And while observation studies annoy me, sometimes they are necessary evil lead to practice or board changing answers, Girometti N et al. Clinical and serological outcomes in patients treated with oral doxycycline for early neurosyphilis. J Antimicrob Chemother 2021 Mar 30; [e-pub]. (https://doi.org/10.1093/jac/dkab100) The board question is someone comes in with neurosyphilis but is allergic to penicillin- the answer on every test is always who cares give it to them anyways. You go with penicillin desensitation, with is painfully slow and annoying. But in this study retrospectively evaluated 87 patients with early neurosyphilis who either received intramuscular (IM) penicillin with oral probenecid for 14 days (71%), 200 mg oral doxycycline twice daily for 28 days (18%), 2 g IM or intravenous ceftriaxone daily for 14 days (3%), a majority did get the penicillin but . All patients attained seroreversion to a negative rapid plasma regain [RPR] or a fourfold decline in RPR titer.AndAt 30 days after completion of therapy, 91% of patients receiving parenteral penicillin therapy and 100% of doxycycline recipients achieved symptomatic resolution. But enough of the observation data lets move onto a viewpoint in JAMA Industry-Sponsored Speaker Programs—End of the Line? | Law and Medicine | JAMA | JAMA Network November 16, 2020 for only the 6 times in 20 years the the Office of Inspector General (OIG) for the US Department of Health and Human Services (HHS) issued a Special Fraud Alert on “abuse risks associated with the offer, payment, solicitation, or receipt of remuneration” relating to industry-sponsored speaker programs Now when I was a resident I took a free dinner but I was never invited back because I would ask a bunch of hard questions about the methods of the study that the speaker wasn’t prepared to answer. It was entertainment, education, and a free meal. SINCE becoming an attending I have not been to one and I said that with pride. industry-sponsored speaker programs dates back to the 1950s and they have always been ‘dirty’ with physician kick backs and bias. And off these CME or speaker sponsored programs are “offered under circumstances that are not conducive to learning. ALSO lets be very clear often these drugs are not better than current standard of practice and they are more expensive which is a losing situation for our patients. But why this fraud alert issued?? Well July 1, 2020, During covid peak, Novartis quietly agreed to pay 678$ million dollar settlement for fraud charges of payment to physician and speak programs. And I quote- Novartis “violated the federal False Claims Act and Anti-Kickback Statute by providing doctors with cash payments, recreational outings, lavish meals, and expensive alcohol to induce them to prescribe Novartis cardiovascular and diabetes drugs reimbursed by federal healthcare programs.” From 2017 to 2019, drug and device companies reported paying health care professionals nearly $2 billion in compensation for services other than consulting but I suspect this will be going down significantly in the near future as it is hard to continue to issue kickbacks when you have the attention of the office of the inspector general. SOO if you are a big pharma industry sponsored event attendee that like a free industry sponsored meal, enjoy it while you can because this for the betterment of medicine and the well being of our patients is likely going away. And while we are talking about government lets talk politicians and something they did positive which is usually few and far between but on December 27, 2020, congress passed the Surprises Act — which banned “surprise billing” and in order to talk about how this is a good thing lets quickly make sure we are all on the same page. Lets say a patient gets sick and goes to the ER and then gets admitted to the hospital. Once in the hospital that patient has no control over what doctors they see. IF they see a doctor or two that are out of their network. Since insurance plans aren’t required to pay out-of-network providers their full charges, clinicians may bill the patient for the difference between the insurance payment and their charges. This ends of up being a surprise bill and usually a surprise that is a lot of money. This is terrible. You get sick, you just want to get better, you are at a hospital and you have no control if the pulmonologist or cardiologist is in your insurance plan but yet SURPRISE you get stuck with the bill. BUT BUT BUT Effective January 1, 2022, patients receiving out-of-network emergency services, air-ambulance transportation, or out-of-network nonemergency services at in-network facilities may be billed only the amount they would owe for an in-network provider. Finally lets end with a little game from JAMA internal med. Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication | Atrial Fibrillation | JAMA Internal Medicine | JAMA Network ASA and anticoagulation is done wrong all the time so lets play a game The combination of ASA with oral anticoagulation can be indicated for patients with?? The answer iscertain devices (eg, left ventricular assist devices) , patients with nonvalvular atrial fibrillation and have acute coronary syndrome (ACS) and undergo percutaneous coronary intervention (PCI). And finally those with venous thromboembolism (VTE) and have acute coronary syndrome (ACS) and undergo percutaneous coronary intervention (PCI). Boom that is it! If you use combination therapy outside this setting then likely more harm than good and in this registry-based cohort study researchers looked at the medical records of almost 3300 patients and matched up Roughly 1000 patients who received a DOAC plus aspirin were matched to 1000 who received a DOAC alone. During a 12month follow-up, patients on combination therapy were more likely to experience a bleeding event and Hospitalization for bleeding. BUT Thrombotic events, did not differ between the groups.So you bleed more but you have the same risk of thrombotic events which sounds like a major losing strategy and something we should all keep in our minds for times when we can do a drugectomy and remove either the ASA or the anticoagulant, which ever is not needed.So I ask you againThe combination of ASA with oral anticoagulation can be indicated for patients with?? The answer iscertain devices (eg, left ventricular assist devices) patients with nonvalvular atrial fibrillation and have acute coronary syndrome (ACS) and undergo percutaneous coronary intervention (PCI).And finally those with venous thromboembolism (VTE) and have acute coronary syndrome (ACS) and undergo percutaneous coronary intervention (PCI). 

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Compression stocking to prevent cellulitis? NOT SO FAST! Vitamin D still doesn't work even for depression. Hip fractures are on teh decline and it is not because of drugs. A scribe cost money, but how much? What about doing an LP with anticoagulants, it is probably safer than you think. What do you do with kidney stones? Finally, there is a lot of medical waste, so stop ordering MRIs for low back pain! https://pubmed.ncbi.nlm.nih.gov/33058700/https://pubmed.ncbi.nlm.nih.gov/32989711/https://www.auajournals.org/doi/10.1097/JU.0000000000001318https://jamanetwork.com/journals/jama/fullarticle/2771609https://www.acpjournals.org/doi/10.7326/M20-0428https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2768887https://jamanetwork.com/journals/jama/fullarticle/2768978https://www.nejm.org/doi/10.1056/NEJMoa1917197

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1- make sure pts follow up on positive FIT test2. symptom severity — driven particularly by catching/locking and clicking/popping — correlated significantly with the burden of cartilage damage. CARTILAGE DAMAGE!!3. U.S. Food and Drug Administration announced it is allowing the use of the Binx Health Assay for point-of-care testing for Chlamydia trachomatis and Neisseria gonorrhoeae4. In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin5. ADHD- “results favored using methylphenidate in children and adolescents, and amphetamines in adults as first-line, short-term (12 weeks or under) treatment.”6. when it comes to PAD it is true what they say! no pain no gain- but maybe they should say no walking pain less loss and more walking pain much bigger gains in 6minute walking distanceThe Push for Timely Follow-up After Abnormal At-home Colon Cancer Screening Results | Cancer Screening, Prevention, Control | JAMA | JAMA Network The pandemic has brough on way more things done at home which Is good and badMore stay at home school- badMore stay at home colon cancer screening- goodArticle talked about a need to make sure pts if positive then get the colonoscopy. Poit out one study where only 44% completed a colonoscopy within 6 months of a positive FIT result even though 89% received a referral,Reasons for the low rates are complex. Patients who are reluctant to get a colonoscopy. and physicians don’t always convey the importance of follow-up. Other factors such as inadequate insurance, lack of transportation, or a facility backlog may be out of a patient’s control.I think in the end we just have to make sure we do our part and while I wouldn’t say scare them make sure they know the importance of this test and how likely it is that they have colon cancer based on it being positive And as a reminderZorzi M, Hassan C, Capodaglio G, et al. Long-term performance of colorectal cancer screening programmes based on the faecal immunochemical test. Gut 2018;67(12):2124-2130.Over a 10-year period, the rates of detection of colorectal cancer (CRC) and advanced adenomas using fecal immunochemical testing (FIT) are similar to those seen in studies of screening colonoscopy. But how good is it you ask? Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget Stool DNA Testing for Colorectal-Cancer Screening. N Engl J Med 2014;370(14):1287-1297.FIT was 74% sensitive and 95% specific.Which in pt terms means for every 11 positive FIT there was 1 cancer detected on colonoscopy A positive fit has you down to a 1 in 10 chance of cancer—get the follow up! And speaking of follow upPatient-reported catching or locking of the knee and other “mechanical symptoms” (i.e., popping, clicking, or pain on pivoting) Usually gets a follow up with an ortho surgeon That patient usually goes to get an arthroscopic knee surgery for symptoms attributed to meniscal tears.BUT BUT BUT what if the text book and board question of pain or instabilitiy with (i.e., popping, clicking, or pain on pivoting) Isn’t a meniscus problem at all?? Meniscal and Mechanical Symptoms Are Associated with Cartila... : JBJS (lww.com)Farina EM et al. Meniscal and mechanical symptoms are associated with cartilage damage, not meniscal pathology. J Bone Joint Surg Am 2021 Mar 3; 103:381. (https://doi.org/10.2106/JBJS.20.01193) Researchers prospectively evaluated 565 patients (mean age, 48) who had arthroscopic knee surgery for symptoms connected to meniscus pathology. Pts were asked about the presence and severity of symptoms prior to surgery and then while in surgery, the surgeon recorded characteristics of meniscal tears and the severity of cartilage damage. In the end “We did not observe an association between meniscal pathology and preoperative patient-reported knee symptoms." Instead they found overall symptom severity — driven particularly by catching/locking and clicking/popping — correlated significantly with the burden of cartilage damage. CARTILAGE DAMAGE!! And if you had tricompartmental cartilage damage (i.e., medial, lateral, and patellofemoral). Then there was even greater symptoms severity…almost a dose response of cartilage damage to symptoms severity Perhaps the observations in this study help to explain why arthroscopic meniscal surgery has not consistently proven to be better than conservative management in randomized trials FDA Allows for First Point-of-Care Chlamydia and Gonorrhea Test to be Used in More Near-Patient Care Settings | FDA the U.S. Food and Drug Administration announced it is allowing the use of the Binx Health Assay for point-of-care testing for Chlamydia trachomatis and Neisseria gonorrhoeae, The test, which uses female vaginal swabs and male urine specimens, takes about 30 minutes and can be done right there in the office This is the first point of care test approved for Chlamydia trachomatis and Neisseria gonorrhoeae testing And I have no idea how much it will cost but my guess is a pretty penny Next article Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve | NEJM The primary outcome was a composite of death, major cardiovascular events (stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding at 12 months.In this open-label design Randomized trial of 1005 patients who were randomized to either20 mg once daily rivaroxaban vs dose-adjusted warfarin in patients with atrial fibrillation and a bioprosthetic mitral valve In the end In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin When it came to the composite primary outcome of death, major cardiovascular events, or major bleeding at 12 months. I have a couple problemsIndustry funded and open-label design – immediate bias into event rates. People doing the trial get paid ot do the trial and enroll people. They want this to work, they will try to show benefit as much as possible whenever possible. Nothing wrong with them, just human nature.This is for bioprosthetic mitral valves NOT mechanical valves HOWEVERThis does seem to be consistent with observational and subgroup analysis from other studies and likely will change practice going forward. ADHD is real and what do you write for- well what if we could just get a large meta-analysis of almost 24K people Well we are in luck Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis - The Lancet Psychiatry Researchers examined efficacy and tolerability of data of the drugs used to treat attention-deficit/hyperactivity disorder from published and unpublished double-blind, randomized, controlled trials. In total they had 133 trials and included close to 14,000 children and 10,000 adults. They analysis was able to do indirect comparison which is when you take one study active arm and compare it to another study active arm and in the bit of statistical magic you get what appears to be results between the two active arms. So aspirin vs placebo and then Plavix vs placebo and then you can do an indirection comparison and BOOM stat magic and you have results for aspirin vs Plavix. Is it perfect? NO but is it better than nothing, usually.Some interesting resultsFor children based on teachers' ratings only methylphenidate and modafinil were more effective compared to placeboBUTIn adults modafinil didn’t beat placeboThe best drug for adults was amphetaminesI think one of the authors who commented on this said it best“results favored using methylphenidate in children and adolescents, and amphetamines in adults as first-line, short-term (12 weeks or under) treatment.”The authors did look for data at 26 and 52 weeks but found insufficient evidence. Which is to be expected as most mental health drugs only show improvement in the short instead of long duration but it also speaks to the importance of drug holidays when possible. These drugs have evidence for 12 weeks we have no idea what the good or bad long term effects are when taken for 12, 22, 32, or 42 years. Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial | Cardiology | JAMA | JAMA Network How long or fast do you need to walk if you have PAD Does a low-intensity work just as good at high intensity?305 participants with PAD Randomized to either low-intensity exercise, high-intensity exercise, and a nonexercise control group Participants in the walk groups were asked to walk 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. There were weekly phone calls with their ‘coach’ to help with adherence. Adherence was pretty good at around 85%!!! THAT ALONE IS IMPRESSIVE All participants did a 6 minute walk test at the beginning of the study and then again at the end of the study The primary outcome was mean change in 6-minute walk distance at 12 months In the end if you did Nothing then you decreased in for walk test distance by −15m,high intensity group GAIN 35m on their 6 minute walk test,but what about the low intensity- that is what we all care about is just a little bit of exercise beneficial. Is it ok to walk at a pace that is slow and doesn’t produce any pain andTHOSE randomized to the load intensity group showed a DECREASE in their 6minute walk distance! They went down by -6.4M! No pain no gain! If you have PAD you can just lolly gag your walk around the block you have to push it. Sure a lolly gag pace wont lose you as much as doing nothing but if you push it you will see gains! I guess when it comes to PAD it is true what they say!no pain no gainbut maybe they should say no walking pain less loss and more walking pain much bigger gains in 6minute walking distance

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DOAC are just as safe if not safer for warfarin for valvular afib (NOT valve replacement but moderate to severe mitral stenosis). Please, just give normal lovenox for covid patients. Stop DM drugs in the elderly cause no-glycemia is more dangerous than hyperglycemia. semaglutide works as along as you keep taking it. gestational diabetes screening should be a two stop process. Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 0, No 0 (acpjournals.org) researchers did a New-user retrospective propensity score–matched cohort study matching roughly 28,000 new users of DOACs with new users of warfarin. During a median follow-up of roughly 130 days,primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding. the rate of stroke or systemic embolism was significantly lower among DOAC users than warfarin users (3.9 vs. 6.0 events per 100 person-years). NNT of 50The rate of major bleeding events was also lower among DOAC users (7.1 vs. 10.6 events per 100 person-years). And a NNH 28 to prescribe warfarin This would be great because no longer need an echo prior to writing for a doac—a reminder part of this exclusion was bioprosthetic or mechanical heart valve replacement Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial | Critical Care Medicine | JAMA | JAMA Network What are the effects of intermediate-dose compared with standard-dose prophylactic anticoagulation in patients with COVID-19 admitted to the intensive care unit (ICU)? Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. results Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. Do the trial and don’t just blindly do it based on what you believe to be true or voodoo magic But interia takes over and we keep doing the same thing Lega IC et al. Glycemic control and use of high-risk antihyperglycemic agents among nursing home residents with diabetes in Ontario, Canada. JAMA Intern Med 2021 Mar 1; [e-pub]. We all know no glycemia is a lot worse then hyperglycemia- I also think we all know that The ADA recommends relaxed glycemic targets for older patients with diabetes and comorbidities population-based retrospective study, glycemic control among 15,000 Ontario nursing home residents with type 2 diabetes who were receiving at least one glucose-lowering drug. Mean glycosylated hemoglobin (HbA1c) level was 7.3%. On average, patients were receiving two glucose-lowering agents; about half of patients had HbA1c levels ≤7.0%. How intertia might be a good thing especially if it comes to semaglutide Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial | Clinical Pharmacy and Pharmacology | JAMA | JAMA Network randomized clinical trial of adults with overweight or obesity, 803 participants completed a 20-week run-in of weekly treatment with subcutaneous semaglutide, 2.4 mg, with a mean weight loss of 10.6%, and were randomized to continued treatment with subcutaneous semaglutide vs placebo for an additional 48 weeks. Lets make no false predictions. 10% weight loss is a ton especially over 20 weeks BUTwhat happens when you stop this weight loss drug?? The primary end point was percent change in body weight from week 20 to week 68; With continued semaglutide, from week 20 to week 68 was −7.9% continued decrease in weight but you gained +6.9% with the switch to placebo (difference, −14.8 [95% CI, −16.0 to −13.5] percentage points; P  Semaglutide works while you take it but then it goes away. This would be great for weight loss if you can use it as a bridge to get people jump started into healthier lifestyles and more activity and if it were free or pennies on the dollar but it is not and likely will be cash pay as not FDA approved for weight loss yet and in my opinion still requires a serious shared decision making conversation. A Pragmatic, Randomized Clinical Trial of Gestational Diabetes Screening | NEJM pragmatic, randomized trial comparing 24,000 pregnant women, researchers compared a one-step, 75-g glucose load with a two-step, 50-g (followed by 100-g if positive) glucose load for gestational diabetes screening. The primary outcomes were a diagnosis of gestational diabetes, large-for-gestational-age infants, a perinatal composite outcome (stillbirth, neonatal death, shoulder dystocia, bone fracture, or any arm or hand nerve palsy related to birth injury), gestational hypertension or preeclampsia, and primary cesarean section. Researchers found higher rates of gestational diabetes diagnosis with the one-step screen!! maternal and neonatal outcomes (including hypertensive disorders of pregnancy, primary cesarean section, large-for-gestational age infants, shoulder dystocia, stillbirth) were not different between the two groups. if you’re identifying more cases of gestational diabetes without changing related disease outcomes, this is bad. identifying more disease, the burden of disease diagnosis is significant with multiple daily glucose checks for the remainder of pregnancy as well as the mental and emotional toll diagnosis can have on a pregnant woman. Besides who cares if you find more of a number- that is just a LOOs if you are not finding more POOs.

174. Gestational Diabetes Screening, DOAC for Valvular Afib, COVID19, Semaglutide

Uterine Fibroid and heavy bleeding might have a new drug if your normal drug was giving placebo. HPV Vaccine is still awesome and very very safe. Copper IUD has a new kid in town when it comes to emergency contraception and Colchicine should not be used for secondary prevention (at least not when I read the trial)HTTPS://WWW.NEJM.ORG/DOI/FULL/10.1056/NEJMOA2008283 Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding.Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss About 70% of the individuals in either relugolix group reached the primary endpoint compared with about 20 in the placebo group This is great!! We stop bleeding—but this is a straw man argument that tells us nothing!!They compared it to placebo.That is not real life- to get into the trial you had have a diagnosis of fibroids with heavy menstrual bleeding--- you needed to be losing 160ml in one cycle or 80ml in two consectutive cycles… who is going to get that history and do nothingPARTICIPANTSPremenopausal women 18 to 50 years of age who had a diagnosis of fibroids as confirmed on ultrasonography and who had heavy menstrual bleeding, 9 Heavy menstrual bleeding was defined as a volume of menstrual blood loss of 80 ml or more per cycle for two cycles or a volume of 160 ml or more during one cycle. ... [Message clipped] View entire message Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study (bmj.com) A large linked database linked to Korea Immunization Registry Information System This study is so cool because they did a cohort analysis and self-controlled risk interval analysis382 020 girls aged 11-14 years who had been vaccinated against HPV and compared them to 59 379 had not been vaccinated against HPV. This is what we all know as a cohort analaysis. You look at a bunch of data at one point in time, preferable with the outcome you are looking at specified before looking at the data and you see if the data confirms your hypothesis. It is observational, its not the best form of data but it could be worse and sometimes it is the only way to find what you are looking for, such as serious adverse events from a vaccine. BUT they also did a self-controlled risk interval analysis. Let me propose to you what if there is a difference between those who get vaccines and those who don’t?! What if a kid get a tetnus vaccine then 6months later develop migraines or narcolepsy. Do you blame it on the tetnus vaccine or the hpv vaccine?? So a self-controlled risk interval analysis – use each individual self as a controlled risk analysis. All girls who received the HPV vaccine had to also have received the Japanese encephalitis vaccine and tetanus, diphtheria, pertussis vaccine. This combination of other vaccines in the same girl served as a comparator for safety profiles compared to the hpv vaccine. So the hpv vaccine is compared to girls who have never got a vaccine and then also compared to other vaccines in the same individual! The ultimate safety test to measure it against yourself and against others! They wanted to be extra extra safe!They looked at 33 OUTCOMES!!! Remember p 0.05! Graves’ disease, Hashimoto’s thyroiditis, hyperthyroidism, hypothyroidism, type 1 diabetes, Crohn’s disease, ulcerative colitis, peptic ulcer, pancreatitis, Raynaud’s disease, venous thromboembolism, vasculitis, hypotension, ankylosing spondylitis, Behcet’s syndrome, juvenile arthritis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, Henoch-Schönlein’s purpura, erythema nodosum psoriasis, Bell’s palsy, epilepsy, narcolepsy, paralysis, migraine, Guillain-Barré syndrome, optical neuritis, neuralgia and neuritis, intracerebral haemorrhage, extrapyramidal and movement disorders, and last but not least tuberculosis. results“In this nationwide cohort study, with more than 500000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events” Association Between Indoor Tanning Frequency and Other Potentially Addictive Behaviors | PracticeUpdate Type a person or a type b person—but the key to life might be how to be an AB person and I am not talking about my initials Association between indoor tanning frequency during early life and other potentially addictive behaviors among US women- ClinicalKey In this cross-sectional analysis of the nurses health study II –as a reminder a Cross-sectional analysis looks at data collected at a single point in time, the authors investigated the relationship between the frequency of indoor tanning and other addictive behaviors,including smoking,alcohol intake,and caffeine consumption. Individuals who used an indoor tanner (>12 times/year) were2.5 times more likely to be current smokers, to consume >14 alcoholic drinks/week, and to drink >6 cups of coffee daily. AND THERE WAS A –response relationship with increasing tanning frequency. Many of you will know that a dose response relationshop is one of the keys for causation in observational studies. So could it be the tanning causes the smoking, drinking, and coffee drinking.. not directly. But could it be that the personality traits that cause you do go above and beyond are active in all actions of your life?? YES When you go above and beyong you go above and beyond for everything—its almost never something like well I am crazy about working out but I eat like garbage and vice versa if you eat terrible rarely are you crazy about working out. You burn it at both ends of the stick or you don’t the problem is controlling it in a healthy way which is maybe the key to life. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2775955?guestAccessKey=d35250c2-a79e-486c-80e9-67a886cb9ef1&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamainternalmedicine&utm_content=olf&utm_term=021521 #FDA tells the companies but the companies don't tell the public! (thread) #MedTwitter This should be a #publichealth issue.@MedTweetorials If there is question related to a drug products quality, safety, and efficacy then the FDA will issue a "refuse-to-file" to the COMPANY not to the public. However, shouldn't their be transparency? Over a decade ago the #FDA even had a task force for more transparency! https://fdanews.com/ext/resources/files/archives/f/FDA-2009-N-0247-0107.1.pdfhttps://www.fdanews.com/ext/resources/files/archives/f/FDA-2009-N-0247-0107.1.pdf I will say a "refuse-to-file" is a rare event (thank goodness). Between 2008-2017 only 4% or 103 out of 2475 applications received a refuse to file. BUT guess how many times the public was informed of these "refuse-to-file"? 15.5% of the time! Only 16/103! This is TERRIBLE! It may come as no surprise that NONE of these "refuse-to-file" letters were were published in their entirety but rather as a press release or abbreviated form. Just like there was a large push as one time for authors to post or register their #clinicaltrials I think there should be equal push for companies to register and publish their "refuse-to-file" letters. I didn’t know only copper IUD!!The New England Journal of MedicineLevonorgestrel vs. Copper Intrauterine Devices for Emergency ContraceptionN. Engl. J. Med 2021 Jan 28;384(4)335-344, DK Turok, A Gero, RG Simmons, JE Kaiser, GJ Stoddard, CD Sexsmith, LM Gawron, JN SandersIn this trial, the researchers randomized women to a copper IUD or levonorgestrel IUD for emergency contraception and found the levonorgestrel IUD to be noninferior to the copper for this purpose.In the US, the copper IUD is currently the only approved IUD for emergency contraception. This trial provides compelling evidence for the use of levonorgestrel for emergency contraception, providing more options for women in the 5 days following unprotected intercourse. Greenberg JC et al. Life saving therapy inhibition by phones containing magnets. Heart Rhythm 2021 Jan 4; [e-pub]. (https://doi.org/10.1016/j.hrthm.2020.12.032) he magnet in the iPhone 12 is strong enough to turn off therapies from implantable cardioverter–defibrillators.Implantable cardioverter-defibrillators (ICDs) are designed so that an application of a reasonably strong (10-gauss) magnet can inactivate the therapy. This safety feature enables the device's therapies to be suspended for surgeries with cauterization and inappropriate shocks caused by rapid atrial fibrillation (AF) and lead fractures, among other issues. Theoretical concerns have been raised about interference of ICDs by cell phones; however, this interaction in real-life patients has rarely, perhaps never, been reported.Apple's new iPhone 12 contains a powerful magnet, which enables it to correctly align with external accessories (e.g., for wireless battery charging). In an experiment with a single person with an implanted Medtronic transvenous ICD, investigators studied whether the magnet in an iPhone 12 could disable ICD therapies. And indeed, whenever the iPhone was brought near the ICD, the device's ventricular therapies were suspended.Inhibition of ICD therapies by an iPhone is a major concern. Cell phones are frequently carried in chest pockets, some of which are close to an implanted ICD. Even a turned-off iPhone might cause this interaction. Patients and physicians must be aware of this possibly harmful, potential inhibition of ventricular therapies by the iPhone 12, and patients must avoid carrying it in a left chest pocket. And speaking of, many people thought that 2020 would be the year that colchicine would find its way back into our hearts What many people call one of the top articles of 2020 was in the NEJM titled Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383:1838-47. https://pubmed.ncbi.nlm.nih.gov/32865380 Which was a study that looked at the use of low-dose colchicine to reduce the risk of cardiovascular (CV) events?5522 patients who had evidence of coronary disease and had been clinically stable for ≥6 months were randomized after a 1 month run in phase. During the run in phase pateitns got colchicine, 0.5 mg/d. 15% of the patients were not randomized after randomization. 15%! Keep that in mind Basically 1 out of 6.5 people who were attempted to enter the trial were not able to tolerate the trial Remember a run in phase false elevates the results of the treatment arm. Because instead of having 100% of people taking place and only 85% taking the active drug since 15% could tolerate side effects. You only randomize people that could take the drug so then you have 100% taking the placebo and 100% taking the active arm. This makes it difficult because we don’t get run in phases in clinical practice.And the results were AMAZING! Or at least if you just read the conclusion“””In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo.” Not so fast-the risk of cardiovascular events—what is that?? It is the primary end point but what does it mean??? primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. If you add enough outcomes you will always always find something…so you need to look at the individual outcomesMI = NNT- 81ischemia-driven coronary revascularization= NNT 65 (which makes sense, cheating way to add more numbers to your outcome)cardiovascular death- no differenceischemic stroke, no difference now if you are actually reducing the number of heart attacks you would expect to see a decrease in the cardiovascular deaths but remember there was no difference in cardiovascular death. So if you are seeing a decrease in heart attacks and more patients are under going revascularization then these are suppose to be good things so why no change in cardiovascular deahts???And people say yes but there was a trend towards decrease in cardiovascular dath with 20 in the colchicine arm and 25 in the placebo arm. BUT what no one is talking about is there was was more non cardiovascular deaths in the colchicine arm 53 vs 35 in the placebo arm. HR 1.51 (95% CI 0.99–2.31) which would cross one and suggest not significant but remember it is all a continuum that we make up it is not that at this rate it works and at this rate absolutely no benefit.So when you have 5 few cardiovascular deaths in the colchicine arm but 18 more noncardiovascular deaths in the colchicine arm it works out to a net increase of 13 more deaths from any cause in the colchicine arm. THIS IS BADWe don’t want more death! So was this just magic skills on the part of the trials where you move a few deaths this way and you slide a few more that way so you can say “there was a trend toward decrease cardiovascular death” or was this that maybe colchicine causes increase in nonCV death. OR Is it that MI and revascularization are really not that important?? Or is it that MI and revascularization are soft endpoints…. You ask 10 difference cardiologist if a patient needs to go for a cardiac cath and you might get 10 different answers.I don’t have the answer but I will tell you many people think this was a big practice changer in 2020 and everyone should get colchicine and I think well I think Based on a study that had 1 out of every 6 patients drop out during the run in phase and was only able to show a change in two very soft end points with no change in all cause death and almost a stastically significant negative change in the nonCVD death, I will not be prescribing this medication for my patients for secondary CV prevention anytime soon. 

173. Uterine Fibroid Symptoms, HPV Vaccine, Copper IUD, Colchicine

Part 2 of the top articles of 20201) statins and the nocebo effect2) VA DOD Lipid guidelines- Don't check more than every 10 years!3) blood in the urine and what to do about it per the newest guidelines. 4) SGLT2i, FLOZINS!!! The data and how to use it in practice with really really sick patients

172. Top Articles of 2020 PART 2

A two part podcast on the top published articles of 2020

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Questioning Medicine

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