Background: The Food and Drug Administration has approved several pharmacotherapies for the treatment of obesity. This study assesses the cost-effectiveness of six pharmacotherapies and lifestyle intervention for people with mild obesity (body mass indices [BMIs] 30 to 35). Methods: A microsimulation model was constructed to compare seven weight loss strategies plus no treatment: intensive lifestyle intervention, orlistat, phentermine, phentermine/topiramate, lorcaserin, liraglutide, and semaglutide. Weight loss, quality-of-life scores, and costs were estimated using clinical trials and other published literature. Endpoints included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100 000/QALY. Results were analysed at 1-, 3-, and 5-year time horizons.Results: At each of the three follow-up periods, phentermine was the costeffective strategy, with ICERs of $46 258/QALY, $20 157/QALY, and $17 880/QALY after 1, 3, and 5 years, respectively. Semaglutide was the most effective strategy in the 3-and 5-year time horizons, with total QALYs of 2.224 and 3.711, respectively. However, the ICERs were prohibitively high at $1 437 340/QALY after 3 years and $576 931/QALY after 5 years. Deterministic and probabilistic sensitivity analyses indicated these results were robust. Conclusions:Phentermine is the cost-effective pharmacologic weight-loss strategy.Although semaglutide is the most effective, it is not cost-effective because of its high price.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem-what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a datadriven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that bloodlymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens. (Blood. 2012;120(7):1432-1438) IntroductionNaive T cells have the task of surveying both for foreign antigens and for weak interactions with self, which are required for optimal function. 1-3 Recognition of both takes place in lymph nodes, exquisitely constructed environments that facilitate the encounter of T and B lymphocytes with antigens. In mice, the naive CD4 and CD4 T-cell pools each comprise roughly 5 ϫ 10 7 cells, but the diversity of T-cell receptor (TCR) sequences is such that a remarkably small proportion are capable of recognizing a given antigen with sufficient affinity to reach an activation threshold. Estimates of the typical antigen-specific pool size in mice are in the range 10 to 1200 cells. [4][5][6][7][8][9] A high degree of polyclonality ensures both broad coverage and fine specificity of the TCR repertoire, but comes at the price of increasing the time required for the relevant cells in the total repertoire to locate a given peptide-MHC complex.In their search for TCR stimulation, naive T cells circulate continuously through the spleen, lymph nodes, lymphatic vessels, and blood. 10 At steady state, naive T cells enter lymph nodes from the blood at random through the high endothelial venules (HEVs), taking a few minutes to cross into the lymph node cortex. 11,12 There they encounter and survey DC presenting peptide-MHC ligands. While in the cortical region, T cells acquire competence to egress, at most 4 hours, 13 but possibly as little as 20 minutes 14 after crossing the HEV. T cells exit from the lymph node through lymphatic sinuses and return to the blood, first through lymphatics, and finally through the thoracic duct. Smith and Ford studied lymphocyte recirculation in rats and found that intravenously injected c...

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Objective Quantifying risk for cardiovascular disease (CVD) events among adolescents is difficult owing to the long latent period between risk factor development and disease outcomes. This study examined the 30‐year CVD event risk among adolescents with severe obesity treated with and without metabolic and bariatric surgery (MBS), compared with youths with moderate obesity, overweight, or normal weight. Methods Cross‐sectional and longitudinal comparisons of five frequency‐matched (age and diabetes status) groups were performed: normal weight (n = 247), overweight (n = 54), obesity (n = 131), severe obesity without MBS (n = 302), and severe obesity undergoing MBS (n = 215). A 30‐year CVD event score developed by the Framingham Heart Study was the primary outcome. Data are mean (SD) with differences between time points for MBS examined using linear mixed models. Results Preoperatively, the likelihood of CVD events was higher among adolescents undergoing MBS (7.9% [6.7%]) compared with adolescents with severe obesity not referred for MBS (5.5% [4.0%]), obesity (3.9% [3.0%]), overweight (3.1% [2.4%]), and normal weight (1.8% [0.8%]; all P < 0.001). At 1 year after MBS, event risk was significantly reduced (7.9% [6.7%] to 4.0% [3.4%], P < 0.0001) and was sustained for up to 5 years after MBS (P < 0.0001, all years vs. baseline). Conclusions Adolescents with severe obesity are at elevated risk for future CVD events. Following MBS, the predicted risk of CVD events was substantially and sustainably reduced.

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