Season 1
Part two of the dementia series, on management. It opens with the anti-amyloid antibodies, lecanemab and donanemab, working through CLARITY-AD and TRAILBLAZER-ALZ 2 in PICO form and spending real time on what the Clinical Dementia Rating Sum of Boxes measures, why a difference of about half a point becomes a "twenty-seven percent slowing," and how that compares with the smallest change patients and families notice. It covers ARIA and its ApoE4 gradient, the donanemab titration change, the anticoagulation and thrombolysis problem, and dosing burden; a JAGS study showing institutional websites present the benefit in relative terms three times as often as absolute; and real-world data showing only a third of early lecanemab users received the expected infusions, along with a VA implementation survey. Then the symptomatic drugs, cholinesterase inhibitors and memantine, with effect sizes, the side effects that drive prescribing cascades, and the evidence on stopping them. Then behavioral and psychological symptoms, using the Beers alternatives sequence and the DICE approach, antipsychotic mortality, and the WeCareAdvisor trial as a lesson in primary versus secondary outcomes. It closes with driving, including California's reporting requirement, decision-specific capacity, and care partners' use of the patient portal.
This week's sweep is organized around the comparator — what a treatment was actually tested against, and whether that's the comparison you face in clinic. It leads with VESALIUS-CV, the evolocumab trial in high-risk patients without a prior heart attack or stroke, covering what the twenty-five percent figure means in absolute terms, why "without prior MI or stroke" is not the same as primary prevention, the fact that only one in five patients was on ezetimibe and the 2026 guideline's decision to no longer require ezetimibe before a PCSK9 antibody, the diabetes subgroup published in JAMA, and the FDA label expansion that came before the trial. It pairs that with the VA/DoD lipid guideline synopsis in Annals, which lays out the stepwise path the trial skipped. Then a Core IM episode on triglycerides under the 2026 guideline — when to check non-HDL or apoB, a three-day carbohydrate trial, icosapent ethyl, fibrates for pancreatitis, and the new apoC-III drugs, with both open triglyceride thresholds now settled from the guideline text (apoB testing at one hundred fifty after a June correction; risk enhancer at one hundred seventy-five nonfasting or one hundred fifty fasting); the SUPER trial of supervised exercise after ACL reconstruction; the KDIGO 2026 anemia in CKD guideline in brief; and two Pediatrics in Review In Brief pieces, on diaper psoriasis and on retinoblastoma and the red reflex.
The weekly consolidation for the week of September twenty-eighth, covering four episodes — Monday's sweep, early-onset colorectal cancer, pediatric asthma and single maintenance and reliever therapy, and part one of the dementia series. It leads with six things worth keeping: the failure of pelacarsen and what it does to the lipoprotein(a) story, the short-acting beta agonist feedback loop and the four-to-five-course lifetime oral steroid budget, the distinction between the threshold for investigating a symptom and the age at which you screen, the way kidney disease pushes Alzheimer blood biomarkers above the diagnostic range while sarcopenia hides the kidney disease, the two strong tobacco recommendations most likely to change a prescription this week, and the one age band in which heavy drinking is rising. It also reports a correction made to the September seventeenth lipid episode. It closes on three appraisal threads: the gap between moving a number and changing an outcome, screening and diagnosis as genuinely different activities, and tests that behave differently in your patient than in the population where they were validated.
Part one of a two-part approach series on dementia, covering diagnosis. Built on Curbsiders episode 511 with Halima Amjad, the Alzheimer's Association's first clinical practice guideline on blood-based biomarkers, and a JAGS review on detecting Alzheimer neuropathology in chronic kidney disease. The organizing question is whether a primary care clinician should be ordering the new blood tests, and three credible sources disagree: the podcast says recent FDA clearances make primary care an appropriate setting, the Alzheimer's Association guideline explicitly declines to address primary care and restricts its recommendations to specialized settings, and the geriatrics literature says the tests should not be implemented anywhere without validation in kidney disease. It covers functional impairment as the line between mild cognitive impairment and dementia, cognitive testing and collateral history, alternative screeners for patients with little schooling or tested in a second language (education-adjusted MoCA cutoffs, MoCA-Basic, the RUDAS and its 2026 meta-analysis, the SLUMS and the limits of its education adjustment, the Mini-Cog as a first-step screen at Medicare Annual Wellness Visits and why a negative result is less reassuring than a negative PHQ-2, the AD8 informant questionnaire, and the Spanish-developed Fototest and Prueba Cognitiva de Leganés), what the MRI is for, the biomarkers themselves and the performance thresholds the guideline sets, why kidney disease produces false positives, the sarcopenia trap that hides kidney disease behind a normal creatinine, and why a positive amyloid result in an eighty-year-old means less than it sounds.
A pediatrics episode on asthma built around single maintenance and reliever therapy, from the April Pediatrics in Review In Brief by Jacobson and Jones, with the diagnostic half from the January issue's comprehensive asthma review. The organizing idea is that the albuterol inhaler we spent decades teaching families to reach for is itself part of the problem — regular short-acting beta agonist use, even for one to two weeks, increases airway hyperresponsiveness and blunts bronchodilator response, and SABA overuse tracks with more exacerbations and higher steroid exposure. SMART inverts the controller-versus-rescue distinction by using one ICS-formoterol inhaler for both. Two things have changed since the April article was written: GINA published a new strategy report in May 2026, and the CARE trial in the Lancet gave us the pediatric randomized evidence the field lacked, showing budesonide-formoterol as sole reliever cut asthma attacks roughly in half against salbutamol in children aged five to fifteen. It closes on the American implementation problem — the regimen is off-label here despite approval in over 120 countries, uptake in adults runs around fifteen percent, and the counseling requires un-teaching what we spent twenty years teaching.
An approach episode on early-onset colorectal cancer, built on part one of the Core IM five pearls series with gastroenterologists Rachel Issaka, Xavier Llor, Samir Gupta and Joseph Feuerstein, and on the 2026 American Cancer Society statistics report and screening guideline update. Its organizing idea is a distinction worth holding onto: rising incidence in young adults changes the threshold at which you investigate a symptom, and does not change the age at which you screen an asymptomatic person. Those are different activities and conflating them is how a thirty-eight-year-old with rectal bleeding gets told to come back at forty-five. It covers the incidence and mortality numbers, the birth cohort analysis showing men born in 1995 carry four to eightfold the risk of those born in 1960, what is and is not known about causes, the red flag symptoms and the specific language that elicits them, the rule that a benign diagnosis does not close the loop, why family history fails as a filter when only a quarter of early-onset cases have one, and the 2026 ACS screening update including where the blood-based test belongs.
This week's sweep is organized around one theme that turned up in almost every item — the gap between moving a number and changing an outcome. It opens with a correction to the lipoprotein(a) episode from the seventeenth: pelacarsen lowered Lp(a) substantially in a trial of more than eight thousand patients and did not reduce cardiovascular events, and ziltivekimab did the same thing with hsCRP. It then covers the new VA/DoD tobacco treatment guideline and its strong recommendations for varenicline over other monotherapy and combination over single-agent nicotine replacement, paired with a trial mailing varenicline directly to smokers; a national survey showing alcohol use falling overall while heavy drinking among adults fifty to sixty-four rose more than a third; coronary calcium added to PREVENT, where the reclassification arithmetic runs the wrong way; anticoagulation for intermediate-risk atrial fibrillation in a Korean trial; the oral PCSK9 inhibitor enlicitide; and the American Cancer Society's updated position on blood-based colorectal cancer screening.
The weekly consolidation for the week of September twenty-first, covering four episodes — Monday's sweep, Parkinson disease, pediatric headache, and the GLP-1 outcomes dive. It leads with six things worth keeping: the REM sleep behavior disorder question as the highest-yield prodromal screen in neurology, the reversal on when to start levodopa, the CHAMP placebo response and what it means for any pediatric preventive you start, the tirzepatide cardiovascular approval that rests on noninferiority rather than superiority, the finding that about half of patients on long-term opioids succeed with a well-supported taper and nothing added, and the rule that pediatric migraine criteria are not the adult criteria. It closes on three appraisal threads that ran through every episode this week: composite endpoints where one component carries the result, exposure definitions that manufacture benefit through immortal time, and implausible secondary findings functioning as failed negative controls.
An approach dive on what GLP-1 receptor agonists actually do beyond glucose and weight, built to answer the question Monday's sweep left open — that the evidence for anything harder than weight loss is thin. It starts with a new FPIN help desk answer in the August American Family Physician on GLP-1s and stroke prevention, and uses its second cited study as a worked example of immortal time bias and the healthy-user effect, since the study reports that urinary tract infections and candidiasis were less common in drug users, which no drug does. It then walks the outcome trials one at a time with PICO — SELECT for cardiovascular prevention without diabetes, FLOW for kidney disease, SOUL for oral semaglutide, STEP-HFpEF for heart failure with preserved ejection fraction, and STRIDE for peripheral artery disease — decomposing the composite endpoints to show which component is carrying each result. It closes on SURPASS-CVOT and the August 2026 FDA approval of tirzepatide for cardiovascular risk reduction, which is the first of these granted on noninferiority to an active comparator rather than superiority to placebo, and on the NAION labeling change European regulators made in June 2025.
A pediatrics episode on headache in children and adolescents, built on the Cribsiders episode with pediatric neurologist John Gaitanis and updated with two things that changed after it aired. The first is the August 2025 FDA approval of fremanezumab for episodic migraine down to age six, which makes a CGRP monoclonal antibody a pediatric option for the first time; the second is the March 2025 labeling change across the whole CGRP class for hypertension and Raynaud phenomenon. The episode covers how to take a headache history from a child who cannot give you one, the red flags that actually earn imaging and the far longer list that does not, why pediatric migraine looks different from adult migraine in the diagnostic criteria themselves, the CHAMP trial and its enormous placebo response, the acute and preventive drug options with doses, and the documented diagnostic disparity by race. It closes on the combined oral contraceptive and migraine-with-aura question, where the American and European guidance disagree.