New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation.

Transplant vasculopathy (TV) causes thickening of donor blood vessels in transplanted organs, and is a significant cause of graft loss and mortality in allograft recipients. It is known that patients with repeated acute rejection and/or donor specific antibodies are predisposed to TV. Nevertheless, the exact molecular mechanisms by which alloimmune injury culminates in this disease have not been fully delineated. As a result of this incomplete knowledge, there is currently a lack of effective therapies for this disease. The immediate intracellular signaling and the acute effects elicited by anti-donor HLA antibodies are well-described and continuing to be revealed in deeper detail. Further, advances in rejection diagnostics, including intragraft gene expression, provide clues to the inflammatory changes within allografts. However, mechanisms linking these events with long-term outcomes, particularly the maladaptive vascular remodeling seen in transplant vasculopathy, are still being delineated. New evidence demonstrates alterations in non-coding RNA profiles and the occurrence of endothelial to mesenchymal transition (EndMT) during acute antibody-mediated graft injury. EndMT is also readily apparent in numerous settings of non-transplant intimal hyperplasia, and lessons can be learned from advances in those fields. This review will provide an update on these recent developments and remaining questions in our understanding of HLA antibody-induced vascular damage, framed within a broader consideration of manifestations and implications across transplanted organ types.

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.

Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.

Intent to participate in future cervical cancer screenings is lower when satisfaction with the decision to be vaccinated is neutral.

BACKGROUND: HPV vaccination programs have adversely affected participation in future cervical cancer screening. The purpose of this study is to determine the influence of decision satisfaction with accepting/rejecting the HPV vaccine, as well as traditional clinical factors, on the intent to participate in future screening. METHODS AND FINDINGS: From January 2011 through August 2012 women 18-26 years old presenting for health care in an urban college student health and wellness clinic in the US Midwest were asked to complete a descriptive and medical history survey including a six element decisional satisfaction survey scored on 5-point Likert scales, where the intent to participate in future cervical cancer screening was measured. Of the 568 women who completed the decisional satisfaction survey, 17% of those <21 years and 7% ≥ 21 years indicated no intent to participate in future cervical cancer screenings. Among women of current screening age, the univariate risk factors of race/ethnicity, contraceptive use, number of lifetime sexual partners, and receipt of HPV vaccine were not predictors of intent for future cervical cancer screening. Instead, only a history of a prior Pap test was a significant positive predictor and only a decisional satisfaction of 'neutral' (Likert score = 3) for any of the four decisional satisfaction elements was a significant negative predictor. For the decisional satisfaction element "best for me personally", there was a 78% decreased likelihood of intending to participate in future screening if the satisfaction was neutral rather than firm (aOR = 0.22, 95% CI: 0.05-0.91) and a 26 fold increased likelihood if she had had a prior Pap test (aOR = 26, 95% CI: 5-133). CONCLUSIONS: HPV vaccination implementation programs must help women be the owner of their decision around HPV vaccination and understand the importance of future participation in cervical cancer screening.

Women have a preference for their male partner to be HPV vaccinated.

BACKGROUND: Peer influence and social networking can change female adolescent and young adult behavior. Peer influence on preferences for male human papillomavirus (HPV) vaccination has not been documented. The primary aim of this study was to determine if women had preferences about male sexual partner HPV vaccination receipt. METHODS AND FINDINGS: A prospective survey of women 18-26 years of age was conducted at an urban university student health clinic. Education about the two HPV vaccines, cervical cancer and genital warts was provided. Women self-reported their demographic and medical history data, as well as their own preferences for HPV vaccine and their preferences for their male partner HPV vaccine using a 5 point Likert scale. 601 women, mean age of 21.5 years (SD 2.4), participated between 2011 and 2012. Nearly 95% of respondents were heterosexual; condoms and contraceptives were used in over half of the population. Regardless of the woman's vaccination status, women had significantly higher (strongly agree/agree) preferences for the male partner being vaccinated with HPV4 than not caring if he was vaccinated (63.6% vs. 13.1%, p<0.001). This preference was repeated for sexual risk factors and past reproductive medical history. Women who received HPV4 compared to those choosing HPV2 had a significantly lower proportion of preferences for not caring if the male partner was vaccinated (13% vs. 22%, p = 0.015). CONCLUSIONS: Women preferred a HPV vaccinated male partner. Peer messaging might change the male HPV vaccination uptake.

Quantifying the decisional satisfaction to accept or reject the Human Papillomavirus (HPV) vaccine: a preference for cervical cancer prevention.

OBJECTIVE: Only a portion of the US population is willing to consider HPV vaccination to date. The primary aim of this study is to determine the decisional satisfaction associated with HPV vaccination. STUDY DESIGN: This is a prospective survey conducted at an urban college where women 18-26 years old completed a decisional satisfaction survey about their HPV vaccine experience. RESULTS: Regardless of the decision to accept or reject HPV vaccination, the decisional satisfaction was very high (mean 5-item score = 21.2 (SD 3.8)). Women without HPV vaccination were decisionally neutral significantly more often than those already vaccinated; 22% were decisionally neutral for the option to accept HPV vaccination at that visit. Cervical cancer prevention was preferred significantly more often than genital wart prevention in all analyses. CONCLUSIONS: Targeting those who are decisionally neutral about HPV vaccination may result in a higher uptake of HPV vaccination.