A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal-placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14(+)CD163(+)CD206(+)CD209(+) phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25(high)CD127(low)Foxp3(+) Tregs in parallel with increased IL-10 production, whereas production of IFN-gamma (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-beta, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance.

Funding Agencies|Medical Research Council [K2013-61X-22310-01-4]

Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.

Adoption and adherence to the MMA protocol increased substantially over the study period for patients undergoing thyroid and parathyroid surgery and was associated with a simultaneous significant decline in prescription of postoperative opioid analgesics. Use of nonopioid multimodal agents, incorporating NSAIDs, was safe and did not lead to increased incidence of bleeding. Availability of effective nonopioid MMA pathways may favorably influence physician prescribing practices and avoid unnecessary opioid prescriptions.

IMPORTANCE Perioperative analgesia strategies that rely solely on narcotics may contribute to adverse effects and concerns about opioid abuse or dependence. Multimodal analgesia protocols incorporating nonnarcotic agents may reduce the need for postoperative narcotic use.OBJECTIVE To evaluate the feasibility and safety of a multimodal analgesia protocol for outpatient head and neck surgical procedures and to identify the association of the multimodal analgesia protocol with postoperative pain perception scores and patient satisfaction. DESIGN, SETTING, AND PARTICIPANTSRetrospective evaluation of prospectively collected data on adults who underwent outpatient thyroid, parathyroid, and parotid surgery between July 2016 and February 2017 at the head and neck surgery service of a tertiary care hospital using a multimodal analgesia strategy with use of immediate preoperative acetaminophen and gabapentin, and intention to treat with a nonnarcotic postoperative outpatient analgesia strategy. MAIN OUTCOMES AND MEASURESOverall patient satisfaction scores, Overall Benefit of Analgesia Score (OBAS), and median resting and peak pain scores were recorded. Incidence of reliance on a narcotic-based postoperative outpatient analgesia strategy and adverse events related to altered analgesia strategy were identified.RESULTS Sixty-four patients (48 [75%] female; mean [SD] age, 54.6 [14.3] years) underwent outpatient thyroid, parathyroid, or parotid surgery with use of a multimodal analgesia protocol. On a 10-point rating scale, patients reported low resting pain perception scores (median, 2 [range, 0-8]) and peak pain scores (median, 4 [range, 0-9]). The OBAS assessment for composite effectiveness of analgesia indicated a favorable median score of 1 (range, 0-10; permissible range, 0-28, with lower scores better). Thirty-nine (61%) patients were able to avoid postoperative narcotic use on discharge. Fifty-six (88%) patients reported "high" or "very high" satisfaction with the multimodal analgesia strategy. No complications related to bleeding, hematoma, significant adverse events, or readmissions were observed. CONCLUSION AND RELEVANCEA multimodal analgesia strategy was feasible and safe in patients undergoing outpatient head and neck surgery and may reduce the need for narcotic use. It was associated with low pain perception scores, favorable OBAS, and overall satisfaction scores. The role of multimodal analgesia needs additional evaluation through comparative effectiveness assessment vs conventional pain management strategies.

An mFI score of 3 or higher is associated with increased risk for postoperative complications, longer hospitalization, and need for postdischarge skilled care following total laryngectomy. The mFI provides a personalized risk assessment to better inform patients, physicians, and payers when planning a total laryngectomy.

We demonstrate that care in a non-intensive care setting following vascularized free tissue transfer is safe, less costly, and decreases length of hospital stay compared to routine intensive care-based management.

IgG4-related sclerosing disease is a rare entity in the head and neck. There are documented reports of steroid therapy for this disease, but the patient presented here demonstrated clinical progression of disease with steroids alone. The use of combination therapy of surgery, dexamethasone, and rituximab provided clinical improvement and stable disease determined by radiographic means.

Medical and flap-related complications in patients 90 years and older are consistent with rates previously reported in elderly patients. Furthermore, patients 90 years and older can tolerate free flap reconstruction with favorable long-term outcomes.