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BACKGROUND Trials and study-level meta-analyses have failed to resolve the role of corticosteroids in the management of patients with septic shock. Patient-level meta-analyses may provide more precise estimates of treatment effects, particularly subgroup effects. METHODS We pooled individual patient data from septic shock trials investigating the adjunctive use of intravenous hydrocortisone. The primary outcome was 90-day all-cause mortality, and it was also analyzed across predefined subgroups. Secondary outcomes included mortality at intensive care unit and hospital discharge, at 28 and 180 days, and vasopressor-, ventilator-, and organ failure–free days. Adverse events included superinfection, muscle weakness, hyperglycemia, hypernatremia, and gastroduodenal bleeding. RESULTS Of 24 eligible trials (n=8528), 17 (n=7882) provided individual patient data, and 7 (n=5929) provided 90-day mortality. The marginal relative risk (RR) for 90-day mortality of hydrocortisone versus placebo was 0.93 (95% confidence interval [CI], 0.82 to 1.04; P=0.22; moderate certainty). It was 0.86 (9% CI, 0.79 to 0.92) for hydrocortisone with fludrocortisone and 0.96 (95% CI, 0.82 to 1.12) without fludrocortisone. There was no significant differential treatment effect across subgroups. Hydrocortisone was associated with little to no difference in any of the secondary outcomes except vasopressor-free days (mean difference, 1.24 days; 95% CI, 0.74 to 1.73; high certainty). Hydrocortisone may not be associated with an increase in the risk of superinfection (RR, 1.04; 95% CI, 0.95 to 1.15; low certainty), hyperglycemia (RR, 1.05; 95% CI, 0.98 to 1.12; low certainty), or gastroduodenal bleeding (RR, 1.11; 95% CI, 0.83 to 1.48; low certainty). Hydrocortisone may be associated with an increase in the risk of hypernatremia (RR, 2.01; 95% CI, 1.56 to 2.60; low certainty) and muscle weakness (n=2647; RR, 1.73; 95% CI, 1.49 to 1.99; low certainty). CONCLUSIONS In this patient-level meta-analysis, hydrocortisone compared with placebo was not associated with reduced mortality for patients with septic shock. (Funded by “Programme d’Investissements d’Avenir,” a research Professorship from the National Institute of Health and Care Research, Leadership Fellowships from the National Health and Medical Research Council of Australia, and Emerging Leaders Fellowship from the National Health and Medical Research Council of Australia; PROSPERO registration number, CRD42017062198.)

In Britain marital fertility declined in the latter decades of the 19th century. Couples who married during 1861-1869 had on average 6.16 children; those who married during 1890-99 4.13 children; and those who married during 1920-24 2.31 children. Later surveys indicated that only an insignificant percentage of couples who married before 1910 used mechanical contraceptives. Many early-20th-century birth control advocates in Britain and North America distanced themselves from traditional fertility control methods and utilized the widespread fear of a perceived abortion epidemic. Self-induced abortion as a form of fertility control was widely used by working-class women although by 1900 hospital operations could be performed with relative safety. The first British organization to defend contraception the Malthusian League had supported fertility control on economic grounds that would permit the emergence of the happy family by sparing the woman unwanted pregnancies. Marie Stopes popularized birth control ideology in England. Her favored methods of contraception were the cervical cap (also with a soluble quinine pessary) and the diaphragm. However working-class women were repelled by the male middle-class medical atmosphere of clinics she recommended for fitting contraceptives. the ratio of abortion deaths to the total number of pregnancy-related deaths is marked by the fact that the infant mortality rates fell from 130 deaths per 1000 live births in 1905 to 55 per 1000 by 1935 while the maternal mortality rates remained at about 5 per 1000 in the first decades of the century and began to rise in the 1930s. Abortion as a means of fertility control showed the high risks working-class women would take to control their fertility long before neo-Malthusian admonitions. Neo-Malthusians envisioned a model family in which the husband would use mechanical means of contraception to ensure the familys upward economic mobility. Birth controllers regarded abortion as wrong and dangerous posing both social and physiological threats.

Early intensification with MTX is a key component of most treatment regimens used for children, adolescents and young adults with ALL. We have previously shown that HDMTX is superior to C-MTX in B-ALL in COG Study AALL0232. Because there are differences in sensitivity to MTX and pegaspargase (PEG-ASNase) between B- and T-ALL that might affect outcome, we conducted a front-line, Phase III study for patients with T-ALL. COG AALL0434 was a 2 x 2 pseudo-factorial randomization comparing the COG augmented BFM (ABFM) regimen with C-MTX without leucovorin rescue to ABFM with HDMTX plus leucovorin rescue in T-ALL, and randomizing patients with T-ALL and T-lymphoblastic lymphoma to therapy with/without six, five-day courses of nelarabine. Study subjects with T-ALL received either block of MTX therapy during the 8-week Interim Maintenance (IM) phase; those with CNS3 status were non-randomly assigned to receive HDMTX. The T-ALL patients all received prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation (cXRT), except for the ~10% with low-risk T-ALL (NCI standard risk, CNS1 without extramedullary disease, and Day 29 minimal residual disease Figure 1. Figure 1. Disclosures Hunger: Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.