High-Dose Upadacitinib Therapy for Refractory Metastatic Crohn Disease.

This case report describes 2 patients with metastatic Crohn disease who were treated with upadacitinib.

Request and fulfillment of postpartum tubal ligation in patients after high-risk pregnancy.

OBJECTIVE: Female sterilization is one of the most prevalent methods of contraception in the United States. Prior studies have shown that nearly half of postpartum tubal ligation (PPTL) requests go unfulfilled. This study seeks to establish whether obstetric or medical risk status influences patients' request for or subsequent completion of PPTL. METHODS: This study was a retrospective cohort study of women delivering at a university hospital in 2009-2010 who received prenatal care in the faculty and resident clinics. High-risk status was defined by Society for Maternal-Fetal Medicine guidelines. Documentation of contraceptive plan and administration of contraceptive methods was abstracted from patient records. Subsequent pregnancies through March 1, 2013, were abstracted. RESULTS: Of 3063 participants (2048 low risk and 1015 high risk), 231 requested PPTL (7.5%). This was more likely among high-risk patients than low-risk patients (10.0% vs. 6.3%, p<.001), those with public insurance (13.8% vs. 3.2%, p<.001) and those with an unintended index pregnancy (13.8% vs. 4.1%, p<.001). Of the patients requesting PPTL, 118 (51.1%) underwent the procedure immediately postpartum. Completion was not associated with high-risk status (54.0%), or with race, insurance status or parity. Among 113 women with an unfulfilled PPTL request, there were 17 subsequent pregnancies (15.0%) during the 27 months of follow-up. CONCLUSIONS: Though women with high-risk pregnancies were more likely to request PPTL, they were not more likely to complete the procedure. Over one third of high-risk patients' requests were unfulfilled, indicating that significant barriers may remain. IMPLICATIONS: Though women with high-risk pregnancies were more likely to request PPTL, they were not more likely to complete the procedure. Providers should consider these procedures urgent, especially in high-risk women, and advocate for their patients' access to this procedure.

Postpartum contraceptive choice after high-risk pregnancy: a retrospective cohort analysis.

OBJECTIVE: To evaluate the effect of high-risk pregnancy status on antepartum contraceptive planning and postpartum use. METHODS: We performed a retrospective cohort study of women delivering at a university hospital during 2009-2010 who received prenatal care in the faculty or resident clinics. We defined high-risk status by Society for Maternal-Fetal Medicine guidelines. We abstracted contraceptive planning and postpartum administration from medical records and categorized these into World Health Organization tiers of contraceptive effectiveness. We identified subsequent pregnancies through March 2013. Chi-squared tests and binary logistic regression were used to assess correlations between risk status and contraceptive choice, actual postpartum use, and subsequent pregnancy. RESULTS: This study included 2048 low-risk and 1015 high-risk parturients. The index pregnancy was more likely to be unintended among low-risk than high-risk women (48.4% vs. 42.9%, p=.02). Low-risk and high-risk women showed interest in Tier 1 contraceptives while antepartum (54.4% low-risk vs. 58.0% high-risk, p=.2), with lower interest at discharge (42.3% vs. 50.7%, p<.001) and at the postpartum visit (33.8% vs. 40.1%, p=.002). Just 776 women (25.3%) actually received a Tier 1 method. 656 women (21.4%) had a subsequent pregnancy lasting more than 20weeks. Unintended pregnancy rates did not differ between low (36.6%) and high-risk (32.4%) women (p=.38). CONCLUSION: High-risk women had similar rates of planning for Tier 1 contraceptives but similar rates of subsequent unplanned pregnancy. Intention to use highly effective contraception did not translate into actual use. Further work is needed to identify barriers to uptake. IMPLICATIONS: Identification of barriers to uptake of highly effective contraceptive methods after high-risk pregnancy represents an important area for future research. Providers should continue to address postpartum contraception throughout pregnancy and be prepared to address barriers to such methods in the postpartum period.

Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma.

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.