Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects infants and young children. In this report, we describe culture conditions that ...enabled the sustained growth of tumor cells obtained from the cerebrospinal fluid (CSF) of an infant with AT/RT. These cells retained the morphological and biomarker characteristics of the original tumor. A screening of receptor tyrosine kinases identified the presence of phosphorylated ErbB4, Insulin-R, PDGFR and IGF-IR, which appear to depend on Hsp90 to maintain their active form. IGF-IR activity is consistent with data from other established AT/RT cell lines. Inhibition of IGF-IR by the small molecular weight inhibitor AEW541 led to growth suppression of cultured AT/RT cells. In addition, neutralizing antibodies to IGF-II also inhibited the growth of these cells suggesting a potential autocrine function for this cytokine. We also compared cultured AT/RT cells to established cell lines to identify consistent drug sensitivity patterns among these cells. In addition to previously described cell lines and xenograft models, continuous culture of CSF derived cells may also provide an effective way to study the biology of AT/RT and to identify potential targets for future therapeutics for this tumor.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: Patients with septic shock may benefit from the initiation of corticosteroids. However, the comparative effectiveness of the 2 most studied corticosteroid regimens (hydrocortisone with ...fludrocortisone vs hydrocortisone alone) is unclear. OBJECTIVE: To compare the effectiveness of adding fludrocortisone to hydrocortisone vs hydrocortisone alone among patients with septic shock using target trial emulation. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study from 2016 to 2020 used the enhanced claims-based Premier Healthcare Database, which included approximately 25% of US hospitalizations. Participants were adult patients hospitalized with septic shock and receiving norepinephrine who began hydrocortisone treatment. Data analysis was performed from May 2022 to December 2022. EXPOSURE: Addition of fludrocortisone on the same calendar day that hydrocortisone treatment was initiated vs use of hydrocortisone alone. MAIN OUTCOME AND MEASURES: Composite of hospital death or discharge to hospice. Adjusted risk differences were calculated using doubly robust targeted maximum likelihood estimation. RESULTS: Analyses included 88 275 patients, 2280 who began treatment with hydrocortisone-fludrocortisone (median IQR age, 64 54-73 years; 1041 female; 1239 male) and 85 995 (median IQR age, 67 57-76 years; 42 136 female; 43 859 male) who began treatment with hydrocortisone alone. The primary composite outcome of death in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone (adjusted absolute risk difference, −3.7%; 95% CI, −4.2% to −3.1%; P < .001). CONCLUSIONS AND RELEVANCE: In this comparative effectiveness cohort study among adult patients with septic shock who began hydrocortisone treatment, the addition of fludrocortisone was superior to hydrocortisone alone.
•This study compares pars plana vitrectomy (PPV), scleral buckle (SB), and pneumatic retinopexy (PnR) as procedures for repair of primary noncomplex rhegmatogenous retinal detachment (RRD).•In an ...economic evaluation of simulated data for 100,000 adult patients, all 3 procedures were deemed to be cost-effective for repair of primary RRD. PPV was found to be the most cost-effective when compared to SB and PnR over a lifetime horizon at a $50,000/QALY threshold.•These results suggest that despite the higher associated cost compared to PnR, PPV and SB may be cost-effective treatment options for management of primary noncomplex RRD in adults.
To assess the cost-effectiveness of primary noncomplex rhegmatogenous retinal detachment (RRD) repair, comparing 3 different strategies, pars plana vitrectomy (PPV), scleral buckle (SB), and pneumatic retinopexy (PnR) from the health care payer perspective over a lifetime.
Model-based cost-utility analysis.
A simulated cohort of 100,000 adult patients (≥18 years old) requiring primary noncomplex RRD repair in theoretical surgical centers in the United States. Quality-adjusted life years (QALYs), lifetime costs (2022 United States dollars), and the incremental cost-effectiveness ratio (ICER) of the 3 interventions were projected over a lifetime horizon, with a cost-effectiveness threshold of ≤$50,000 per gained QALY.
Based on inputted parameters, the primary anatomical success was highest for PPV (95.00%) compared to SB (91.76%) and PnR (63.41%). The QALYs associated with PPV, SB, and PnR were (11.87, SD 1.62), (11.84, SD 1.63), and (11.59, SD 1.72), respectively. The incurred lifetime costs of RRD repair and associated postoperative surgeries for PPV, SB, and PnR were $4445.72 (SD 655.75), $4518.04 (662.92), and $3978.45 (728.50), respectively. Parameter-level simulations suggested that PPV was most likely to be the most cost-effective therapy compared to SB and PnR beyond a threshold of $3000/QALY. The incremental cost-effectiveness ratio for PPV compared to PnR was $1693.54. SB was dominant in all scenarios. Threshold analyses indicated that the success rate of PnR would have to be 100% and/or the cost would have to be $2000 or less over lifetime for it to be more cost-effective than PPV.
This study found PPV to be the most cost-effective primary procedure for RRD repair at a threshold of $50,000/QALY gained over a lifetime horizon from the health care payer perspective.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The use of hydrocortisone in adult patients with septic shock is controversial, and the effectiveness of adding fludrocortisone to hydrocortisone remains uncertain.
To assess the comparative ...effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone, and placebo or usual care in adults with septic shock.
A systematic review and a Bayesian network meta-analysis of peer-reviewed randomized trials were conducted. The primary outcome was all-cause mortality at last follow-up. Treatment effects are presented as relative risks (RRs) with 95% credible intervals (CrIs). Placebo or usual care was the reference treatment.
Among 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR, 0.85; 95% CrI, 0.72-0.99; 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR, 0.97; 95% CrI, 0.87-1.07; 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was based primarily on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared with hydrocortisone alone (RR, 0.88; 95% CrI, 0.74-1.03; 94.2% probability of superiority, moderate-certainty evidence).
In adult patients with septic shock, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Although we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.
Unlike total health care spending in Canada, which has increased steadily over the past 20 years, capital investment (that supports infrastructure and technology) has both varied more and declined in ...recent years, suggesting underinvestment and inequity in health care capital. Canada's health system is particularly vulnerable to fluctuations in capital spending because the cycles for capital investment are longer than our political cycles. For the most part, use of capital instruments in Canada has not been innovative, and there are fewer studies on financing models in Canadian health care than in other countries. Canada needs greater expertise in capital investment and further research to increase regular use of innovative financial tools.
The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium. The hypothesis was that ...intraoperative administration of phenylephrine, compared to ephedrine, is associated with higher odds of postoperative delirium.
A total of 103,094 hospitalized adults undergoing general anesthesia for noncardiac, non-neurosurgical procedures between 2008 and 2020 at two tertiary academic healthcare networks in Massachusetts were included in this multicenter hospital registry study. The primary exposure was the administration of phenylephrine versus ephedrine during surgery, and the primary outcome was postoperative delirium within 7 days. Multivariable logistic regression analyses adjusted for a priori defined confounding variables including patient demographics, comorbidities, and procedural factors including magnitude of intraoperative hypotension were applied.
Between the two healthcare networks, 78,982 (76.6%) patients received phenylephrine, and 24,112 (23.4%) patients received ephedrine during surgery; 770 patients (0.8%) developed delirium within 7 days. The median (interquartile range) total intraoperative dose of phenylephrine was 1.0 (0.2 to 3.3) mg and 10.0 (10.0 to 20.0) mg for ephedrine. In adjusted analyses, the administration of phenylephrine, compared to ephedrine, was associated with higher odds of developing postoperative delirium within 7 days (adjusted odds ratio, 1.35; 95% CI, 1.06 to 1.71; and adjusted absolute risk difference, 0.2%; 95% CI, 0.1 to 0.3%; P = 0.015). A keyword and manual chart review-based approach in a subset of 45,465 patients further validated these findings (delirium incidence, 3.2%; adjusted odds ratio, 1.88; 95% CI, 1.49 to 2.37; P < 0.001). Fractional polynomial regression analysis further indicated a dose-dependent effect of phenylephrine (adjusted coefficient, 0.08; 95% CI, 0.02 to 0.14; P = 0.013, per each μg/kg increase in the cumulative phenylephrine dose).
The administration of phenylephrine compared to ephedrine during general anesthesia was associated with higher odds of developing postoperative delirium. Based on these data, clinical trials are warranted to determine whether favoring ephedrine over phenylephrine for treatment of intraoperative hypotension can reduce delirium after surgery.
To evaluate whether different gamma-aminobutyric acidergic (GABAergic) sedatives such as propofol and benzodiazepines carry differential risks of post-extubation delirium in the ICU.
Retrospective ...cohort study.
Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA).
Ten thousand five hundred and one adult patients mechanically ventilated for over 24 hours.
None.
We tested the hypothesis that benzodiazepine versus propofol-based sedation is associated with fewer delirium-free days within 14 days after extubation. Further, we hypothesized that the measured sedation level evoked by GABAergic drugs is a better predictor of delirium than the drug dose administered. The proportion of GABAergic drug-induced deep sedation was defined as the ratio of days with a mean Richmond Agitation-Sedation Scale of less than or equal to -3 during mechanical ventilation. Multivariable regression and effect modification analyses were used. Delirium-free days were lower in patients who received a high proportion of deep sedation using benzodiazepine compared with propofol-based sedation (adjusted absolute difference, -1.17 d; 95% CI, -0.64 to -1.69; p < 0.001). This differential effect was magnified in elderly patients (age > 65) and in patients with liver or kidney failure (p-for-interaction < 0.001) but not observed in patients who received a low proportion of deep sedation (p = 0.95). GABAergic-induced deep sedation days during mechanical ventilation was a better predictor of post-extubation delirium than the GABAergic daily average effective dose (area under the curve 0.76 vs 0.69; p < 0.001).
Deep sedation during mechanical ventilation with benzodiazepines compared with propofol is associated with increased risk of post-extubation delirium. Our data do not support the view that benzodiazepine-based compared with propofol-based sedation in the ICU is an independent risk factor of delirium, as long as deep sedation can be avoided in these patients.
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