Medical Student Perspectives on the Ethics of Pelvic Exams Under Anesthesia: A Multi-Institutional Study✰.

OBJECTIVE: Pelvic examinations under anesthesia (EUAs) are routine components of gynecologic surgery and often used to educate students about female pelvic anatomy. This multi-institutional survey study aims to describe students' experiences with conducting educational pelvic EUAs and their attitudes around the ethics of informed consent for these exams. DESIGN: An anonymous survey of Likert and open-text response questions about institutions' practices around educational pelvic EUAs was sent to medical students. SETTING: Medical schools included Vanderbilt University School of Medicine, Indiana University School of Medicine, Emory University School of Medicine, University of New Mexico School of Medicine, Meharry Medical College, and Warren Alpert Medical School of Brown University. PARTICIPANTS: A total 305 medical students who had completed their obstetrics and gynecology (OB/GYN) clerkship between June 2019 and March 2020 filled out the survey (33% response rate). RESULTS: Overall, 84% of students performed at least 1 pelvic EUA during their clerkship. Of the 42% (142) of students that observed patient informed consent processes most or every time, 67% reported they never or rarely witnessed an explicit explanation that a medical student may perform a pelvic EUA. Analysis of open-text responses found that students wanted to uphold patient autonomy but felt they did not have the personal autonomy to object to performing pelvic EUAs that they believed were unconsented. They faced significant emotional distress when consent processes were at odds with their personal ethos and professional ethical norms. Students favored more standardized and explicit patient consent processes for educational pelvic EUAs. CONCLUSIONS: While students regularly perform pelvic EUAs, their involvement is inconsistently disclosed to patients, causing significant distress to students and risking erosion of students' attitudes about upholding patient autonomy and informed consent. Medical institutions must develop consistent, ethical, and patient-centered processes for trainee disclosure around pelvic EUAs.

Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes.

OBJECTIVE: To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D). DESIGN: Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels. SETTING: University Medical Center. PATIENT(S)/ANIMAL(S): Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center. INTERVENTION(S): Nonobese diabetic mice were administered 200 µg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation. MAIN OUTCOME MEASURE(S): Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c. RESULT(S): Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values. CONCLUSION(S): The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.

Group B streptococcal infection of the genitourinary tract in pregnant and non-pregnant patients with diabetes mellitus: An immunocompromised host or something more?

Group B Streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive bacterium commonly encountered as part of the microbiota within the human gastrointestinal tract. A common cause of infections during pregnancy, GBS is responsible for invasive diseases ranging from urinary tract infections to chorioamnionitis and neonatal sepsis. Diabetes mellitus (DM) is a chronic disease resulting from impaired regulation of blood glucose levels. The incidence of DM has steadily increased worldwide to affecting over 450 million people. Poorly controlled DM is associated with multiple health comorbidities including an increased risk for infection. Epidemiologic studies have clearly demonstrated that DM correlates with an increased risk for invasive GBS infections, including skin and soft tissue infections and sepsis in non-pregnant adults. However, the impact of DM on risk for invasive GBS urogenital infections, particularly during the already vulnerable time of pregnancy, is less clear. We review the evolving epidemiology, immunology, and pathophysiology of GBS urogenital infections including rectovaginal colonization during pregnancy, neonatal infections of infants exposed to DM in utero, and urinary tract infections in pregnant and non-pregnant adults in the context of DM and highlight in vitro studies examining why DM might increase risk for GBS urogenital infection.

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction. A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.

Natural aversive learning in Tetramorium ants reveals ability to form a generalizable memory of predators' pit traps.

Many species of ants fall prey to pit-digging larval antlions (Myrmeleon spp.), extremely sedentary predators that wait, nearly motionless at the bottom of their pit traps, for prey to stumble inside. Previous research, both in the field and laboratory, has demonstrated a remarkable ability of these ants to rescue trapped nestmates, thus sabotaging antlions' attempts to capture them. Here we show that pavement ants, Tetramorium sp. E, an invasive species and a major threat to biodiversity, possess yet another, more effective, antipredator strategy, namely the ability to learn to avoid antlion traps following a single successful escape from a pit. More importantly, we show that this learned antipredator behavior, an example of natural aversive learning in insects, is more complicated than a single cue-to-consequence form of associative learning. That is, pavement ants were able to generalize, after one experience, from the learned characteristics of the pit and its specific location, to other pits and other contexts that differed in many features. Such generalization, often described as a lack of precise stimulus control, nonetheless would be especially adaptive in nature, enabling ants to negotiate antlions' pit fields, which contain a hundred or more pits within a few centimetres of one another. Indeed, the ability to generalize in exactly this way almost certainly is responsible for the sudden, and heretofore inexplicable, behavioural modifications of ants in response to an invasion of antlions in the vicinity of an ant colony.

MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling.

MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway-dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, codependencies of MEK, TAK1, and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacologic studies and cell-cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G1 accumulation, in a distinct subset of cell lines. Furthermore, TAK1 inhibition causes G2-M cell-cycle blockade and polyploidy in many of the cell lines. MEK plus TAK1 inhibition causes reduced G2-M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1-dependent cell lines as well as a subset of BRAF-mutant cells. Mechanistically, sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation, which promote expression of NF-κB-dependent proinflammatory cytokines, driving tumor cell survival and proliferation. MEK/TAK1 inhibition causes reduced mTOR, Wnt, and NF-κB signaling in TAK1/MEK-dependent cell lines concomitant with apoptosis. A Wnt/NF-κB transcriptional signature was derived that stratifies primary tumors into three major subtypes: Wnt-high/NF-κB-low, Wnt-low/NF-κB-high and Wnt-high/NF-κB-high, designated W, N, and WN, respectively. These subtypes have distinct characteristics, including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype. Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines. Therefore, N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics. IMPLICATIONS: This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to block with selective agents. Mol Cancer Res; 14(12); 1204-16. ©2016 AACR.