Transitions to smokeless tobacco use among adult cigarette smokers in the Population Assessment of Tobacco and Health (PATH) Study, Waves 3-5 (2015-2019).

OBJECTIVE: Examine patterns of dual use of cigarettes and smokeless tobacco and complete switching over time among adult current cigarette smokers using data from the Population Assessment of Tobacco and Health Study Wave 3 (2015-2016), Wave 4 (2016-2018) and Wave 5 (2018-2019). METHODS: We examined four tobacco use states among 6834 exclusive smokers and 372 dual users at Wave 3 with two waves of follow-up data: exclusive cigarette use, exclusive smokeless tobacco use, dual use and use of neither product. RESULTS: Among exclusive smokers at Wave 3, only 1.6% (95% CI: 1.3% to 2.1%) transitioned to dual use at Wave 4, and 0.1% (95% CI: 0.07% to 0.2%) switched to exclusive smokeless tobacco use. Among exclusive smokers who switched to dual use, 53.1% (95% CI: 40.9% to 64.9%) returned to exclusive cigarette smoking, 34.3% (95% CI: 23.8% to 46.6%) maintained dual use and 12.6% (95% CI: 7.0% to 21.7%) did not smoke cigarettes after an additional wave of follow-up. Dual users at Wave 3 were likely to maintain their dual use status at Wave 4, 51.2% (95% CI: 46.1% to 56.3%) and Wave 5, 47.9% (95% CI: 40.1% to 55.8%). CONCLUSIONS: Very few cigarette smokers transition to smokeless tobacco use, and among those who do, dual use is more common than exclusive smokeless tobacco use. Further, the majority of exclusive cigarette smokers who transition to dual use at Wave 4 continue smoking cigarettes at Wave 5, either as dual users or as exclusive smokers.

Characteristics and Patterns of Cigarette Smoking and Vaping By Past-Year Smokers Who Reported Using Electronic Nicotine Delivery System to Help Quit Smoking in the Past Year: Findings From the 2018-2019 Tobacco Use Supplement to the Current Population Survey.

INTRODUCTION: Cigarette smoking has declined, while electronic nicotine delivery system (ENDS) use has increased in the United States. Understanding the role of ENDS in adult smoking quit attempts and cessation is important for estimating their population health impact. AIMS AND METHODS: We used data from 2018 to 2019 tobacco use supplement to the current population survey to examine demographic characteristics and ENDS use patterns among adult ENDS users who reported quitting smoking in the past year by trying to switch to ENDS ("switchers") and smokers who did or did not make a quit attempt in the past year. χ2 tests of proportions and t-tests were used to compare characteristics between groups. RESULTS: In 2018-2019, about three-quarters of switchers reported daily use of ENDS compared to only one-third of dual users with a recent quit attempt by trying to switch to ENDS. Compared to dual users who made a quit attempt by trying to switch to ENDS, switchers were more likely to use menthol/mint-flavored ENDS exclusively (5.6% vs. 13.1%; p = .004) but less likely to use tobacco-flavored ENDS exclusively (21.2% vs. 13.7%; p = .01). CONCLUSIONS: ENDS users who quit smoking in the past year and reported trying to quit by switching to ENDS were more likely to use menthol/mint flavors exclusively and use ENDS daily compared to dual users who made a quit attempt by trying to switch to ENDS. Longer-term prospective data may better clarify the role of ENDS in smoking quit attempts and cessation. IMPLICATIONS: This study provides information on patterns of ENDS use in former smokers and current smokers who tried to quit smoking by switching to ENDS in a national sample of U.S. adults. These results can inform policy actions concerning ENDS products.

Use of Comprehensive Participatory Planning and Evaluation in Rural Patient Engagement.

Comprehensive participatory planning and evaluation (CPPE), a model used in community engagement research, has not been applied to patient engagement in research. We describe our methodology and interim results using CPPE in a project focused on improving research engagement of rural and distant patients and stakeholders. Specifically, we describe our development of a causal map and the subsequent use of the map to guide patient and stakeholder-driven evaluation.

A randomized controlled trial of methylergonovine prophylaxis after dilation and evacuation abortion.

OBJECTIVE: To evaluate the efficacy of intramuscular methylergonovine maleate as prophylaxis against excessive bleeding when given after dilation and evacuation (D&E) at 20-24 weeks. STUDY DESIGN: We performed a randomized, double-blinded, placebo-controlled trial in patients without excessive bleeding requiring intervention after D&E completion. We administered study treatment within one minute of the end of the procedure. We primarily compared outcomes using a composite of indicators of excessive post-procedure blood loss (post-procedure measured blood loss exceeding 125 mL, uterine massage or compression for at least two minutes, administration of additional uterotonic medication, intrauterine balloon tamponade, uterine re-aspiration, blood transfusion, uterine artery embolization, hospital admission for bleeding, or major surgery). Secondary outcomes included individual indicator occurrences, satisfaction, and side effects. RESULTS: From March 3, 2015 to March 31, 2017, we randomized 284 participants (n = 140 methylergonovine, n = 144 placebo), five before we registered the trial with clinicaltrials.gov. Baseline characteristics were similar between groups. The composite outcome occurred in 78 (56%) methylergonovine and 75 (52%) placebo participants (p = 0.5). Methylergonovine recipients required more intrauterine balloon use (n = 20 [14%]) versus placebo (n = 10 [7%]), p = 0.04. We also observed a non-significant trend towards more uterotonic administration (n = 56 [40%] versus n = 43 [30%], p = 0.07) and hospital admissions for bleeding (n = 4 [3%] versus n = 0, p = 0.06) in the methylergonovine group compared to placebo. CONCLUSION: We observed no improvement in the composite outcome for excessive bleeding with prophylactic post-procedure methylergonovine. In addition, individual excessive bleeding outcomes occurred more frequently in the methylergonovine group, potentially indicating harm with its prophylactic use after D&E. IMPLICATIONS: When administered prophylactically immediately after dilation and evacuation abortion at 20-24 weeks, methylergonovine increases uterine bleeding. Given the lack of data for effectiveness as a prophylactic agent and our findings indicating harm, we do not recommend its use for post-operative prophylaxis.

ENDS Flavor Preference by Menthol Cigarette Smoking Status among US Adults, 2018-2019.

E-cigarette flavor preference may differ among smokers using e-cigarettes, but little information is available on preferences by menthol cigarette status. Using nationally representative data for US adults from the 2018-2019 Tobacco Use Supplement to the Current Population Survey, we analyzed e-cigarette flavor preference by menthol cigarette status and e-cigarette device type for dual-cigarette and e-cigarette users and e-cigarette users who had recently quit smoking by trying to switch to e-cigarettes ("switchers"). Approximately half (52.2%) of dual users of menthol cigarettes and e-cigarettes reported using menthol/mint-flavored e-cigarettes as did 41.4% of "switchers" who had smoked menthol cigarettes; exclusive menthol/mint flavor use was 13.1% for dual users and 21.3% for "switchers." A similar proportion (45.1%) of dual users who smoked nonmenthol cigarettes used tobacco-flavored e-cigarettes, but only 26.7% of "switchers" who had smoked nonmenthol cigarettes used tobacco-flavored e-cigarettes. Approximately 60% of dual users and "switchers" used fruit/other flavors, regardless of menthol cigarette use. By device type, 63.9% of dual users of cartridge-based e-cigarettes and menthol cigarettes used menthol/mint-flavored e-cigarettes. Approximately 75% of dual users and 85% of "switchers" who used tank or mod systems used fruit/other flavors. Menthol cigarette smokers may be particularly likely to use menthol/mint e-cigarettes, and a majority of dual users and "switchers" used fruit/other flavors. These results can inform policy measures concerning flavored electronic nicotine delivery system products.

The EMT spectrum and therapeutic opportunities.

Carcinomas are phenotypically arrayed along an epithelial-mesenchymal transition (EMT) spectrum, a developmental program currently exploited to understand the acquisition of drug resistance through a re-routing of growth factor signaling. This review collates the current approaches employed in developing therapeutics against cancer-associated EMT, and provides an assessment of their respective strengths and drawbacks. We reflect on the close relationship between EMT and chemoresistance against current targeted therapeutics, with a special focus on the epigenetic mechanisms that link these processes. This prompts the hypothesis that carcinoma-associated EMT shares a common epigenetic pathway to cellular plasticity as somatic cell reprogramming during tissue repair and regeneration. Indeed, their striking resemblance suggests that EMT in carcinoma is a pathological adaptation of an intrinsic program of cellular plasticity that is crucial to tissue homeostasis. We thus propose a revised approach that targets the epigenetic mechanisms underlying pathogenic EMT to arrest cellular plasticity regardless of upstream cancer-driving mutations.

Feasibility of Vaginal Hysterectomy for Female-to-Male Transgender Men.

OBJECTIVE: To describe the hysterectomy data among a cohort of transgender men and nontransgender (ie, cisgender) women with a particular goal to evaluate the feasibility of vaginal hysterectomy among transgender men. METHODS: This cohort study includes all hysterectomies performed for benign indications on transgender men and cisgender women at a single academic county hospital from 2000 to 2012. Hysterectomy cases and patient gender were identified by billing records and confirmed by review of medical records. Primary study outcome was the hysterectomy route among transgender men compared with cisgender women. We also examined risk factors and operative outcomes. Student two-sided t tests, χ analysis, and descriptive statistics are presented; sensitivity analyses using regression techniques were performed. RESULTS: Hysterectomies for benign gynecologic procedures were performed in 883 people: 33 on transgender men and 850 on cisgender women. Transgender men were younger, had fewer pregnancies and deliveries, and smaller uteri. The leading indication for hysterectomy differed significantly: pain (85%) was most common among transgender men (compared with 22% in cisgender women; P<.001), whereas leiomyomas (64%) was most common for cisgender women (compared with 21% in transgender men; P<.001). Vaginal hysterectomies were performed in 24% transgender men and 42% of cisgender women. Estimated blood loss was less among transgender men (P=.002), but when uterine size and route of hysterectomy were considered, the difference between gender groups was no longer significant. There was no difference in patients experiencing complications between the groups. CONCLUSION: Transgender men and cisgender women have different preoperative characteristics and surgical indications. Vaginal hysterectomies have been successfully completed among transgender men. Because vaginal hysterectomy is a viable procedure for this population, it should be considered in surgical planning for transgender men.

EMT: 2016.

The significant parallels between cell plasticity during embryonic development and carcinoma progression have helped us understand the importance of the epithelial-mesenchymal transition (EMT) in human disease. Our expanding knowledge of EMT has led to a clarification of the EMT program as a set of multiple and dynamic transitional states between the epithelial and mesenchymal phenotypes, as opposed to a process involving a single binary decision. EMT and its intermediate states have recently been identified as crucial drivers of organ fibrosis and tumor progression, although there is some need for caution when interpreting its contribution to metastatic colonization. Here, we discuss the current state-of-the-art and latest findings regarding the concept of cellular plasticity and heterogeneity in EMT. We raise some of the questions pending and identify the challenges faced in this fast-moving field.

Referrals for Services Prohibited In Catholic Health Care Facilities.

CONTEXT: Catholic hospitals control a growing share of health care in the United States and prohibit many common reproductive services, including ones related to sterilization, contraception, abortion and fertility. Professional ethics guidelines recommend that clinicians who deny patients reproductive services for moral or religious reasons provide a timely referral to prevent patient harm. Referral practices in Catholic hospitals, however, have not been explored. METHODS: Twenty-seven obstetrician-gynecologists who were currently working or had worked in Catholic facilities participated in semistructured interviews in 2011-2012. Interviews explored their experiences with and perspectives on referral practices at Catholic hospitals. The sample was religiously and geographically diverse. Referral-related themes were identified in interview transcripts using qualitative analysis. RESULTS: Obstetrician-gynecologists reported a range of practices and attitudes in regard to referrals for prohibited services. In some Catholic hospitals, physicians reported that administrators and ethicists encouraged or tolerated the provision of referrals. In others, hospital authorities actively discouraged referrals, or physicians kept referrals hidden. Patients in need of referrals for abortion were given less support than those seeking referrals for other prohibited services. Physicians received mixed messages when hospital leaders wished to retain services for financial reasons, rather than have staff refer patients elsewhere. Respondents felt referrals were not always sufficient to meet the needs of low-income patients or those with urgent medical conditions. CONCLUSIONS: Some Catholic hospitals make it difficult for obstetrician-gynecologists to provide referrals for comprehensive reproductive services.

Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility.

Single nucleotide polymorphisms (SNPs) are important biomolecular markers in health and disease. Down syndrome, or Trisomy 21, is the most frequently occurring chromosomal abnormality in live-born children. Here, we highlight associations between SNPs in several important enzymes involved in the one-carbon folate metabolic pathway and the elevated maternal risk of having a child with Down syndrome. Our survey highlights that the combination of SNPs may be a more reliable predictor of the Down syndrome phenotype than single SNPs alone. We also describe recent links between SNPs in p53 and its related pathway proteins and Down syndrome, as well as highlight several proteins that help to associate apoptosis and p53 signaling with the Down syndrome phenotype. In addition to a comprehensive review of the literature, we also demonstrate that several SNPs reside within the same regions as these Down syndrome-linked SNPs, and propose that these closely located nucleotide changes may provide new candidates for future exploration.

C1D family proteins in coordinating RNA processing, chromosome condensation and DNA damage response.

Research on the involvement of C1D and its yeast homologues Rrp47 (S. cerevisiae) and Cti1 (S. pombe) in DNA damage repair and RNA processing has remained mutually exclusive, with most studies predominantly concentrating on Rrp47. This review will look to reconcile the functions of these proteins in their involvement with the RNA exosome, in the regulation of chromatin architecture, and in the repair of DNA double-strand breaks, focusing on non-homologous end joining and homologous recombination. We propose that C1D is situated in a central position to maintain genomic stability at highly transcribed gene loci by coordinating these processes through the timely recruitment of relevant regulatory factors. In the event that the damage is beyond repair, C1D induces apoptosis in a p53-dependent manner.

Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.

Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.

Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs.

The recent advances in pharmacogenomics have made personalized medicine no longer a pipedream but a precise and powerful way to tailor individualized cancer treatment strategies. Cancer is a devastating disease, and contemporary chemotherapeutic strategies now integrate several agents in the treatment of some types of cancer, with the intent to block more than one target simultaneously. This constitutes the premise of synthetic lethality, an attractive therapeutic strategy already demonstrating clinical success in patients with breast and ovarian cancers. Synthetic lethal combinations offer the potential to also target the hitherto "undruggable" mutations that have challenged the cancer field for decades. However, synthetic lethality in clinical cancer therapy is very much still in its infancy, and selecting the most appropriate combinations-or synthetic lethal pairs-is not always an intuitive process. Here, we review some of the recent progress in identifying synthetic lethal combinations and their potential for therapy and highlight some of the tools through which synthetic lethal pairs are identified.

My Obstetrician Got Me Fired: How Work Notes Can Harm Pregnant Patients and What to Do About It.

Prenatal care providers are frequently asked to provide employment notes for their patients requesting medical leave or changes to work duties. Writing employment notes correctly can help patients negotiate for and obtain medically indicated workplace accommodations, allowing them to continue to work and earn an income. However, a poorly written or poorly timed note can jeopardize a patient's employment and salary. This commentary provides an overview of pregnancy-related employment laws and guidance in writing work accommodations letters that allow pregnant women to keep their jobs while maintaining a healthy pregnancy.

Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult.

Drug resistance is a challenge in chemotherapy, and, to date, there has been little resolution as to how it is induced. We previously isolated a host of doxorubicin resistance (DXR) genes in fission yeast and here we investigate the regulation of this resistance through two high mobility group (HMG) motif-containing DXR proteins, Nht1 and Hap2. The concurrent deletion of nht1 and hap2 did not confer cumulative sensitivity to doxorubicin, indicating that these factors cooperate closely in similar epistatic groups. We show that doxorubicin treatment resulted in the subcellular reorganization of Rhp54, a homologous recombination-dependent DNA damage repair protein. The disruption of either nht1 or hap2 attenuated Rhp54-foci formation, suggesting that these factors modulate the repair of doxorubicin-induced DNA lesions via the recruitment of homologous recombination machinery. Epistatic analyses further confirmed that Nht1 and Hap2 act in similar functional groups with complexes related to DSB repair but act synergistically with factors that regulate transcription and chromosome segregation. Overall, this work shows the molecular crosstalk coordinated by HMG proteins in conferring doxorubicin resistance in fission yeast.

Buccal misoprostol plus laminaria for cervical preparation before dilation and evacuation at 21-23 weeks of gestation: a randomized controlled trial.

OBJECTIVE: To describe the effectiveness of buccal misoprostol as an adjunct to laminaria for cervical ripening before later second-trimester abortion by dilation and evacuation (D&E). METHODS: A randomized, double-blinded, placebo-controlled trial of 196 women undergoing D&E between 21 and 23 weeks of gestation. Subjects had overnight laminaria and 400 mcg buccal misoprostol or placebo 3-4 h before the abortion. We used logarithmic transformation of the primary outcome--D&E procedure duration--to achieve a normal distribution. RESULTS: Mean D&E duration was 1.7 min shorter with misoprostol (p=.02). The median duration was 9.7 versus 10.4 min in the misoprostol and placebo groups, respectively (p=.09). Cervical dilation was slightly greater with misoprostol (median 75 mm vs. 73 mm, p=.04); however, physicians did not find the misoprostol D&Es easier to complete. Half of subjects reported severe pain after misoprostol vs. 11% with placebo (p<.001). CONCLUSION: Adjuvant buccal misoprostol results in slightly shorter D&Es at the cost of more side effects.

Contributions of hysterectomy and uterus-preserving surgery to health-related quality of life.

OBJECTIVE: To document the long-term effect of surgical interventions for noncancerous uterine conditions on health-related quality of life. METHODS: The Study of Pelvic Problems, Hysterectomy and Intervention Alternatives, conducted between 1998 and 2008, was a longitudinal study of 1,503 women with intact uteri experiencing abnormal uterine bleeding with or without leiomyomas, chronic pelvic pain, or pressure resulting from leiomyomas. Baseline and follow-up questionnaires included three condition-specific measures (Pelvic Problem Resolution, Pelvic Problem Impact Overall, and Pelvic Problem Impact on Sex) and five generic measures (Short Form-12 Mental and Physical Component Summaries, Current Health Utility, Feelings about Heath, and Satisfaction with Sex). We modeled changes over time in these patient-reported outcomes stratified by the most invasive treatment undergone (hysterectomy [13.7%], uterus-preserving surgery [9.0%], or nonsurgical therapy [77.3%]). RESULTS: Participants in all three groups reported significant improvement on all condition-specific measures and two of the five generic measures (Current Health Utility and Feelings about Health) from enrollment to final interview (all P values <.01). In general, greater improvements were experienced by women who had surgery. Trajectories modeled around the dates of surgery showed dramatic improvements after hysterectomy and, to a lesser degree, after uterus-preserving surgery. Although women who underwent uterus-preserving surgery tended to show immediate improvement, women who underwent hysterectomy experienced a 6-month delay in improvement in some outcomes with trajectories converging by 4 years postsurgery. CONCLUSION: Women seeking care for noncancerous uterine conditions can expect to experience improvement over time. Those who opt for surgery may experience most improvement. Understanding health-related quality-of-life trajectories may enhance counseling for women deciding between hysterectomy and alternative interventions. LEVEL OF EVIDENCE: II.

Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin.

Phosphotyrosine-binding domains, typified by the SH2 (Src homology 2) and PTB domains, are critical upstream components of signal transduction pathways. The E3 ubiquitin ligase Hakai targets tyrosine-phosphorylated E-cadherin via an uncharacterized domain. In this study, the crystal structure of Hakai (amino acids 106-206) revealed that it forms an atypical, zinc-coordinated homodimer by utilizing residues from the phosphotyrosine-binding domain of two Hakai monomers. Hakai dimerization allows the formation of a phosphotyrosine-binding pocket that recognizes specific phosphorylated tyrosines and flanking acidic amino acids of Src substrates, such as E-cadherin, cortactin and DOK1. NMR and mutational analysis identified the Hakai residues required for target binding within the binding pocket, now named the HYB domain. ZNF645 also possesses a HYB domain but demonstrates different target specificities. The HYB domain is structurally different from other phosphotyrosine-binding domains and is a potential drug target due to its novel structural features.

Great minds don't think alike: collaborative maternity care at San Francisco General Hospital.

For more than 30 years the collaboration between obstetrician-gynecologists and certified nurse-midwives at San Francisco General Hospital has led to the provision of high-quality care to women and families. This enduring partnership has been sustained by shared goals and values, most notably a commitment to excellence in both providing care to the underserved and training the next generation of physicians and nurse-midwives. Success has also depended on a mutual respect for differences that has enabled the collaborative to capitalize on the distinct expertise of each partner. The balance struck between independence and interdependence of the practice groups has led to innovation and successes that might otherwise not have come to being, while also enabling the collaborative to overcome the inevitable conflicts and challenges that arise within this type of long-standing partnership. This model holds promise for replication in other settings and informs broader considerations of health policy and regulation.

Improving diet and exercise in pregnancy with Video Doctor counseling: a randomized trial.

OBJECTIVE: To determine if an interactive, computerized Video Doctor counseling tool improves self-reported diet and exercise in pregnant women. METHODS: A randomized trial comparing a Video Doctor intervention to usual care in ethnically diverse, low-income, English-speaking pregnant women was conducted. Brief messages about diet, exercise, and weight gain were delivered by an actor-portrayed Video Doctor twice during pregnancy. RESULTS: In the Video Doctor group (n=158), there were statistically significant increases from baseline in exercise (+28 min), intake of fruits and vegetables, whole grains, fish, avocado and nuts, and significant decreases in intake of sugary foods, refined grains, high fat meats, fried foods, solid fats, and fast food. In contrast, there were no changes from baseline for any of these outcomes in the usual care group (n=163). Nutrition knowledge improved significantly over time in both groups but more so in the Video Doctor group. Clinician-patient discussions about these topics occurred significantly more frequently in the Video Doctor group. There was no difference in weight gain between groups. CONCLUSION: A brief Video Doctor intervention can improve exercise and dietary behaviors in pregnant women. PRACTICE IMPLICATIONS: The Video Doctor can be integrated into prenatal care to assist clinicians with effective diet and exercise counseling.