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To characterize the existence, accessibility, and content of parental leave policies, as well as barriers to program-level policy implementation among internal medicine (IM) program directors (PDs) and to assess the willingness of PDs to implement a national standardized policy.In 2019, the Association of Program Directors in Internal Medicine conducted a survey of 422 IM PDs. Along with other content, 38 questions addressed 4 primary outcomes: parental leave policy existence, accessibility, content, and barriers. The authors compared programs with and without a program-level policy and applied qualitative content analysis to open-ended questions about barriers to policy implementation and openness to a national standard.The response rate was 69.4% (293/422). Of responding programs, 86% (250/290) reported a written parental leave policy with 43% (97/225) of these originating at the program level. Program-level policies, compared with policies at other levels, were more likely to address scheduling during pregnancy (38%, 36/95 vs 22%, 27/124; P = .018); peer coverage (24%, 21/89 vs 15%, 16/109; P = .037), how the duration of extended training is determined (81%, 72/89 vs 44%, 48/109; P.001), and associated pay and benefits 61%, 54/89 vs 44%, 48/109; P = .009). PDs without program-level policy reported lacking guidance to develop policy, deferring upward to institutional policies, and wishing to retain flexibility. More than half of PDs (60%, 170/282) expressed agreement that a national standard for a residency program-level parental leave policy should exist. Those not in favor cited organization equity, lack of resources, implementation challenges, loss of flexibility, and potentially disadvantaging recruitment.While existing program-level policies included important content, most PDs reported not having them. A national standard to guide the development of program-level parental leave policies could be embraced if it provided flexibility for programs with limited resources.

Background Nonlinear career paths are increasingly common. Women in academia pursuing nonlinear career paths experience negative impacts on career trajectory. No published studies have examined how pursuit of nonlinear career paths might perpetuate gender inequities within academic hospital medicine. Objective (1) Compare the frequency of nonlinear career paths by gender among academic hospitalists; (2) assess the perceived impact of two types of nonlinear career paths—extended leave (EL) and non-traditional work arrangements (NTWA) on hospitalists’ personal lives and careers. Design, Setting, and Participants Cross-sectional descriptive survey study of adult hospitalist physicians in three academic centers within the USA. Intervention Electronic survey including closed- and open-ended items assessing respondent utilization of and experiences with nonlinear career paths. Main Outcomes and Measures (1) Associations between EL and demographic variables as well as gender differences in leave length and NTWA strategies using Fisher’s exact test; 2) grounded theory qualitative analysis of open-text responses. Key Results Compared with men, women reported taking EL more often (p = 0.035) and for longer periods (p = 0.002). Men and women reported taking NTWA at similar rates. Women reported negative impacts of EL within domains of personal life, career, well-being, and work-life integration whereas men only reported negative impacts to career. Men and women described positive impacts of NTWA across all domains. Conclusions Women academic hospitalists reported taking EL more often than men and experienced disproportionately more adverse impacts to personal lives and careers. Surprisingly, men reported taking NTWA to address burnout and childbirth at similar rates to women. Our findings lay the groundwork for additional exploration of cultural and policy interventions, particularly improved paid leave policies. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-022-07402-x.

PurposeSpeaking up and responding to others’ concerns promotes patient safety. We describe health professionals’ utilisation of these important skills.MethodWe developed an interactive e-learning module, Speak-PREP, to train healthcare professionals in speaking up and responding strategies. Participants completed interactive video-based exercises that engaged them with entering speaking up and responding statements, augmenting strategies from a list of prompting phrases and responding to a pushback. We report strategy utilisation.ResultsA total of 101 health professionals completed Speak-PREP training. Most frequently used speaking up strategies were: brainstorming to explore solutions (50%), showing consideration of others (45%) and encouraging others’ opinions through invitations (43%). Responding strategies included reflecting the concern expressed by colleagues, discussing next steps and expressing gratitude (70%, 67% and 50%, respectively). When prompted, participants augmented their statements with reframing concerns, asking questions to deepen understanding, using how or what to start questions and expressing curiosity (preflecting the concern and decreasing consideration, curiosity, empathy, expressing gratitude and encouraging others’ opinions (pConclusionsThe Speak-PREP module targeted deliberate practice in speaking up and responding skills. Future work should examine the application of these strategies in the clinical environment.

ObjectivesDespite training and the recognition that speaking up can mitigate harm to patients and save lives, healthcare professionals do not consistently speak up when they have patient safety concerns. The purpose of this study was to identify barriers to and facilitators of speaking up about patient safety concerns to inform the development of interventions that will increase this behaviour.DesignFrom October 2017 to February 2018, the study team conducted focus groups and interviews with nurses, advanced practice providers and physicians at three healthcare facilities. Participants were prompted to share their personal experiences with and perspectives on speaking up about patient safety concerns and to discuss strategies for communicating those concerns.SettingTertiary academic healthcare centre.Participants62 healthcare professionals participated in the study. Purposeful sampling was used to include participants of different health professions and experience levels.Main outcome measuresWe planned to answer questions about why more healthcare professionals do not consistently speak up when they have legitimate patient safety concerns and to identify ways to enhance current interventions on speaking up behaviours,ResultsTwelve focus group discussions and two interviews were conducted with 62 participants. We identified two recurring themes: (1) The predominantly hierarchical culture of medicine is a barrier to speaking up and (2) Institutional, interpersonal and individual factors can modulate the impact of medicine’s hierarchical culture on speaking up behaviours and inform the strategies employed.ConclusionsThe data highlighted the importance of moving beyond targeting front-line healthcare professionals for training in the skills of speaking up and engaging institutional leaders and systems to actively promote and reward speaking up behaviours.

PURPOSE To characterize how female residents make decisions about childbearing, factors associated with the decision to delay childbearing, and satisfaction with these decisions. METHOD In 2017, the authors sent a voluntary, anonymous survey to 1,537 female residents enrolled across 78 graduate medical education programs, consisting of 25 unique specialties, at 6 U.S. academic medical centers. Survey items included personal, partner, and institutional characteristics, whether the respondent was delaying childbearing during residency, and the respondent's satisfaction with this decision. RESULTS The survey response rate was 52% (n = 804). Among the 447 (56%) respondents who were married or partnered, 274 (61%) were delaying childbearing. Residents delaying childbearing were significantly more likely to be younger (P < .001), not currently a parent (P < .001), in a specialty with an uncontrollable lifestyle (P = .001), or in a large program (P = .004). Among self-reported reasons for delaying childbearing, which were not mutually exclusive, the majority cited a busy work schedule (n = 255; 93%) and desire not to extend residency training (n = 145; 53%). Many cited lack of access to childcare (n = 126; 46%), financial concerns (n = 116; 42%), fear of burdening colleagues (n = 96; 35%), and concern for pregnancy complications (n = 74; 27%). Only 38% (n = 103) of respondents delaying childbearing were satisfied with this decision, with satisfaction decreasing with increasing age. CONCLUSIONS Decisions to delay childbearing are more common in certain specialties, and many residents who delay childbearing are not satisfied with that decision. These findings suggest that greater attention is needed overall, and particularly in certain specialties, to promote policies and cultures that both anticipate and normalize parenthood in residency, thus minimizing the conflict between biological and professional choices for female residents.

OBJECTIVES The demands of residency training may impact trainees’ decision to have children. We examined characteristics of pediatric residents’ decisions regarding childbearing, determinants of resident parental leave, and associations with well-being. METHODS A survey of 845 pediatric residents at 13 programs was conducted between October 2019 and May 2020. Survey items included demographics, desire for future children, and logistics of parental leave. Outcomes included parental leave length, burnout and depression screening results, satisfaction with duration of breastfeeding, and satisfaction with parental leave and parenthood decisions. RESULTS Seventy-six percent (639 of 845) of residents responded to the survey. Fifty-two percent (330) of respondents reported delaying having children during residency, and 29% (97) of those were dissatisfied with their decision to do so. Busy work schedule (89.7%), finances (50.9%), and a desire not to extend residency (41.2%) were the most common reasons for delay. Of respondents, 16% were parents and 4% were pregnant or had pregnant partners. Sixty-one parental leaves were reported, and 67% of parents reported dissatisfaction with leave length. The most frequently self-reported determinant of leave duration was the desire not to extend residency training (74%). Program mean leave length was negatively associated with burnout, measured as a dichotomous outcome (odds ratio = 0.81 [95% confidence interval 0.68–0.98]; P = .02). CONCLUSIONS Many pediatric trainees delay parenthood during residency and are not satisfied with their decision to do so. Pediatric resident parental leave remains short and variable in duration, despite the positive association between longer leaves and overall well-being.

Purpose To conduct a scoping review of the literature on parenthood during graduate medical education (GME) and to develop a conceptual framework to inform policy and guide research. Method The authors searched PubMed and Embase for articles published from January 1993 through August 7, 2017, using a query framework that combined the concepts of "person" (e.g., "trainee") and "parenthood" (e.g., "breastfeeding"). They included studies describing parenthood or pregnancy of trainees in U.S. GME training programs. Two authors independently screened citations and abstracts and performed kappa coefficient tests to evaluate interreviewer reliability. Two authors performed a full-text review of and extracted data from each included article, and 4 authors coded data for all articles. The authors used descriptive statistics and qualitative synthesis to analyze data. Results Ninety articles met inclusion criteria, and nearly half (43/90; 48%) were published between 2010 and 2017. The authors developed 6 themes that surround resident parenthood: well-being, maternal health, others' perceptions, relationships, program preparation, and policy. They mapped these themes by relationship of stakeholders (e.g., infant and family, institutions) to the resident-parent to create a conceptual framework describing parenthood during GME. Conclusions The findings from this scoping review have implications for policy and research. Those authoring parental leave policies could collaborate with national board leaders to develop consistent standards and include nontraditional families. Gaps in the literature include the effect of resident parenthood on patient care, postpartum health, and policy execution. Research in these areas would advance the literature on parenthood during residency.

Expressing concerns that arise during patient care is essential to protecting patient safety. A speaking up episode occurs within a power hierarchy and carries high potential for personal and professional consequences. Existing curricula that promote speaking up, such as TeamSTEPPS ™ , extensively focus on verbal skills without recognizing the important emotional dimensions of speaking up. We developed the FIRST Speaking Up curriculum that covered the following: (a) inner barriers related to expectations of one's own identity, (b) cognitive distortions associated with speaking up, (c) the speaking up environment, (d) dialogue skills for the speaker and the listener, and (e) resilience strategies. The curriculum was delivered via 2 to 3 hours of interactive workshops to 109 participants, including 40 nursing staff and leaders, 24 plastic surgery residents, and 45 internal medicine residents. Evidence showed that training improved participants' motivations to speak up concerns. Our work expands on existing strategies for speaking up training by targeting both verbal and emotional skills. [ J Contin Educ Nurs. 2019;50(8):355–361.]

Background: The Council of Faculty and Academic Societies (CFAS) comprises representatives from medical schools and professional societies who guide the Association of American Medical Colleges (AA...

The ongoing novel Coronavirus disease 2019 (COVID-19) pandemic has created many threats as well as opportunities for the career development of physicians-in-training. Institutional responses to the demand for patient care reduced the time many residents have to pursue clinical electives, scholarship projects, and other experiences meant to clarify and advance their personal and professional goals. Moreover, many academic medical centers experienced profound fiscal losses that require thoughtful revisions to budgets and curricula. In this article, the authors recommend strategies for residency programs to mitigate these losses and capitalize on growth in virtual education, scholarship opportunities, and relationships arising from the pandemic. Drawing from career development guidelines from the National Career Development Association and existing literature about factors associated with positive career outcomes, the authors suggest leadership roles, curricula, and events that training programs can quickly and inexpensively implement to help residents grow as professionals, achieve personal training goals, produce scholarship, and attain future employment. To help trainees manage their careers, the authors recommend structured mentorship and education in career pathways and the preparation of job application materials. To foster attainment of specific knowledge and cultivate lifelong learning, the authors recommend leveraging existing resources to provide time, funding, academic coaching, and skills training for scholarship projects. To promote development of effective work relationships and community, the authors recommend appointment of a faculty champion for career advancement, scholarship showcases, attendance at virtual journal clubs, and networking through social media outlets. These recommendations for supporting career advancement may apply to early career faculty development as well as undergraduate and postgraduate medical education beyond the pandemic era. Outcomes studies will be needed to evaluate the impact of these recommendations.

Open communication between healthcare professionals about care concerns, also known as 'speaking up', is essential to patient safety.Compare interns' and residents' experiences, attitudes and factors associated with speaking up about traditional versus professionalism-related safety threats.Anonymous, cross-sectional survey.Six US academic medical centres, 2013-2014.1800 medical and surgical interns and residents (47% responded).Attitudes about, barriers and facilitators for, and self-reported experience with speaking up. Likelihood of speaking up and the potential for patient harm in two vignettes. Safety Attitude Questionnaire (SAQ) teamwork and safety scales; and Speaking Up Climate for Patient Safety (SUC-Safe) and Speaking Up Climate for Professionalism (SUC-Prof) scales.Respondents more commonly observed unprofessional behaviour (75%, 628/837) than traditional safety threats (49%, 410/837); p0.001, but reported speaking up about unprofessional behaviour less commonly (46%, 287/628 vs 71%, 291/410; p0.001). Respondents more commonly reported fear of conflict as a barrier to speaking up about unprofessional behaviour compared with traditional safety threats (58%, 482/837 vs 42%, 348/837; p0.001). Respondents were also less likely to speak up to an attending physician in the professionalism vignette than the traditional safety vignette, even when they perceived high potential patient harm (20%, 49/251 vs 71%, 179/251; p0.001). Positive perceptions of SAQ teamwork climate and SUC-Safe were independently associated with speaking up in the traditional safety vignette (OR 1.90, 99% CI 1.36 to 2.66 and 1.46, 1.02 to 2.09, respectively), while only a positive perception of SUC-Prof was associated with speaking up in the professionalism vignette (1.76, 1.23 to 2.50).Interns and residents commonly observed unprofessional behaviour yet were less likely to speak up about it compared with traditional safety threats even when they perceived high potential patient harm. Measuring SUC-Safe, and particularly SUC-Prof, may fill an existing gap in safety culture assessment.

To characterize determinants of resident maternity leave and the effect of length of leave on maternal well-being.In 2017, the authors sent a voluntary, anonymous survey to female residents at 78 programs, in 25 unique specialties, at 6 institutions. Survey items included personal, partner, and child demographics, and logistics of leave, including whether leave was paid or vacation or sick leave was used. Outcomes were maternity leave length; duration of breastfeeding; burnout and postpartum depression screens; perceptions of support; and satisfaction with length of leave, breastfeeding, and childbearing during residency.Fifty-two percent (804/1,537) of residents responded. Among 16% (126) of respondents who were mothers, 50% (63) had their first child during residency. Seventy-seven maternity leaves were reported (range, 2-40 weeks), with most taking 6 weeks (32% of leaves; 25) and including vacation (81%; 62) or sick leave (64%; 49). Length of leave was associated with institution, use of sick leave or vacation, and amount of paid leave. The most frequently self-reported determinant of leave was the desire not to extend residency training (27%; 59). Training was not extended for 53% (41) of mothers; 9% (7) were unsure. Longer breastfeeding duration and perceptions of logistical support from program administration were associated with longer maternity leaves. Burnout affected approximately 50% (38) of mothers regardless of leave length.This study illustrates variability in administration of resident maternity leaves. Targets for intervention include policy clarification, improving program support, and consideration of parent wellness upon return to work.

Purpose To characterise determinants of resident maternity leave and their effect on maternal and infant well-being. Among non-parents, to identify factors that influence the decision to delay childbearing Study design In 2016, a survey was sent to female residents at a large academic medical centre on their experiences with maternity leave, the impact of personal and programme factors on length of leave, reasons for delaying childbearing and measures of well-being. Results Forty-four percent (214/481) of residents responded. Fifty (23%) residents were parents, and 25 (12%) took maternity leave during training. The average maternity leave length was 8.4 weeks and did not differ across programme type, size or programme director gender but was longer for programmes with fewer women than men. The most common self-reported determinant of leave was financial. Residents with >8 weeks of leave were less likely to have postpartum depression or burnout and more likely to breastfeed longer, perceive support from colleagues and programme directors, and be satisfied with resident parenthood. Among 104 non-parents who were married or partnered, 84 (81%) were delaying childbearing, citing busy work schedules, concern for burdening colleagues and finances. Conclusions This study suggests that multiple aspects of resident wellbeing are associated with longer maternity leaves, yet finances and professional relationships hinder length of leave and lead to delayed childbearing. These issues could be addressed at a programme level with clear policies describing how work is redistributed during parental leave and at an institutional and state level through provision of paid family leave.

To develop and test the psychometric properties of two new survey scales aiming to measure the extent to which the clinical environment supports speaking up about (a) patient safety concerns and (b) unprofessional behaviour.Residents from six large US academic medical centres completed an anonymous, electronic survey containing questions regarding safety culture and speaking up about safety and professionalism concerns.Confirmatory factor analysis supported two separate, one-factor speaking up climates (SUCs) among residents; one focused on patient safety concerns (SUC-Safe scale) and the other focused on unprofessional behaviour (SUC-Prof scale). Both scales had good internal consistency (Cronbach's α0.70) and were unique from validated safety and teamwork climate measures (r0.85 for all correlations), a measure of discriminant validity. The SUC-Safe and SUC-Prof scales were associated with participants' self-reported speaking up behaviour about safety and professionalism concerns (r=0.21, p0.001 and r=0.22, p0.001, respectively), a measure of concurrent validity, while teamwork and safety climate scales were not.We created and provided evidence for the reliability and validity of two measures (SUC-Safe and SUC-Prof scales) associated with self-reported speaking up behaviour among residents. These two scales may fill an existing gap in residency and safety culture assessments by measuring the openness of communication about safety and professionalism concerns, two important aspects of safety culture that are under-represented in existing metrics.

In October 2010, the Accreditation Council on Graduate Medical Education (ACGME) published a long-awaited modification to its 2003 common duty hour standards following an international symposium and intensive task-force review of recent literature on safety, supervision, sleep and competence. Although this recent duty hour policy stopped short of adopting all recommendations of the 2008 Institute of Medicine (IOM) report (“Resident Duty Hours: Enhancing Sleep, Supervision, and Safety”), particularly the 5-h nap following 16 h of continuous duty, the new standards were strongly informed by the report, leaving many training programs scrambling to marshal resources and develop new systems to ensure compliance by the July 1, 2011 implementation deadline.

Major depressive disorder is associated with dysfunction in brain regions involved in language and emotion processing. Despite evidence of emotion processing biases in depression, neurophysiological evidence of language dysfunction for emotional words in depression has been inconsistent. This series of three studies evaluated whether depressed individuals exhibited abnormal semantic processing of emotionally-valenced words. During the passive viewing of sentences with mood congruent and incongruent sentence endings, the N400 component of the event-related brain potential was measured in patients with depression, dysthymia, or schizophrenia and in healthy controls. In each study, results revealed normal semantic processing in depression. That is, N400 was similar for both mood-incongruent (positive and neutral) endings and mood-congruent (negative) endings. In contrast, the small sample of individuals with schizophrenia exhibited a significantly exaggerated N400 for negative word endings compared to the depressed and healthy control groups. These data suggest anomalies in semantic network interactions with emotion processing in schizophrenia.

Homeless patients suffer disproportionately from medical disease and from barriers to healthcare, affecting their likelihood of presentation, severity of disease, long-term outcomes, and mortality. In the hospital, homeless patients are frequently cared for by hospitalists. Homeless patients' unstable social situation may challenge usual systems of inpatient care and discharge. To provide more effective care for this group, it is important to recognize the demographics of the hospitalized homeless patient. We suggest a structured approach to the inpatient care of the unstably housed patient, represented by a simple mnemonic checklist “A SAFE DC,” describing evidence-based adaptations of care, where available, and discussing systems-based approaches to discharge. Journal of Hospital Medicine 2009;4:375–381. © 2009 Society of Hospital Medicine.

Anticipation for future affective events and prediction uncertainty were examined in healthy controls and individuals with dysthymia (DYS) using behavioral responses and the contingent negative variation (CNV) and post-imperative negative variation (PINV) event-related potential (ERP) components. Warning stimuli forecasted the valence of subsequently presented adjectives ("+", positive; "=", neutral; "-", negative), and participants indicated whether each adjective would describe them over the next two weeks. Controls expected fewer negative, and individuals with DYS expected fewer positive, adjectives to apply to them. CNV amplitudes were enhanced in controls prior to positive versus other adjectives. Response times and PINV amplitudes were greater following neutral compared to other adjectives, and PINV was larger overall in dysthymics compared to controls. In sum, healthy controls and individuals with DYS exhibit different behavioral and neurophysiological biases in anticipation for future affective events. These results are discussed in the context of cognitive theories of depression.

This observational study aimed to establish prevalence of high-risk human papillomaviruses (hrHPV) in women attending three inner London community clinics for routine screening and to pilot hrHPV testing in the triage of either borderline or negative cytology after previous abnormalities. Hybrid Capture 2 was carried out on brush samples taken alongside conventional smears from 1434 women aged 20-49 years. hrHPV positivity prompted earlier referral of women with previous abnormalities and either low-grade or negative cytology. Outcome at colposcopy was compared with the records of 1871 women aged 20-49 years attending colposcopy during the same period of time (routine colposcopies).hrHPV was detected in 111/161 (68.9%) women with abnormal cytology, 76/460 (16.5%) with negative cytology after previous abnormalities and 105/813 (12.9%) with negative cytology and no previous abnormalities. Overall, hrHPV was detected in 292/1434 (20.4%) women in the study (95% CI 18.3-22.5). hrHPV prevalence increased with severity of cytological abnormality (p0.001) and decreased with age both with negative and low-grade cytology (p0.001). High-grade cervical intraepithelial neoplasia (CIN) biopsies were found more frequently in women in the study groups with low-grade (p0.001) or negative cytology than in routine colposcopies, but more women in the study groups attended colposcopy (8.2% compared with 4.1% routine colposcopies, p0.001).hrHPV positivity increased detection of high-grade CIN in the study groups at the expense of more colposcopies. hrHPV negativity could reduce the need for investigation of low-grade cytology in women aged over 35 years and for surveillance after previous abnormalities.

Rubella and congenital rubella syndrome (CRS) continue to be important health problems in many countries. In June 2004, the World Health Organization Steering Committee on Research Related to Measles and Rubella Vaccines and Vaccination met to evaluate data from research and operational activities and to identify critical scientific issues and gaps in knowledge that need to be addressed to improve the global control of rubella and CRS. Information about surveillance for rubella, natural and vaccine-induced immunity to rubella, laboratory diagnosis, the molecular epidemiological profile of rubella virus, and mathematical modeling to assess the burden of CRS and the impact of rubella vaccination was reviewed. This report summarizes the presentations and recommendations for future research.

The GC box binding transcription factor Sp3 both activates and represses transcription. We have found that Sp3 activity is regulated by SUMO-1 modification. Endogenous Sp3 is sumoylated and localized to the nuclear periphery and in nuclear dots. Removal of SUMO-1 from Sp3 by mutation of the SUMO acceptor lysines or expression of the SUMO-1 protease SuPr-1 converted Sp3 to a strong activator with a diffuse nuclear localization. Covalent attachment of SUMO-1 to Sp3 by gene fusion was sufficient to repress Sp3-dependent transcription and relocalize Sp3 to the nuclear periphery and nuclear dots. These studies reveal a direct effect of SUMO-1 modification on activity of a dual function transcription factor and provide a mechanism for functional specificity within the Sp transcription factor family.

This study investigated the relationship between human papillomavirus type 16 (HPV-16) antibodies detected in oral fluid from women with cervical neoplasia, their HPV-16 antibody seroprevalence, and their cervical HPV-16 DNA presence. Cervical HPV-16 DNA was detected by polymerase chain reaction in 43.2% (35/81) of these women. The prevalence of IgG and IgA antibodies to HPV-16 virus-like particles (VLP-16) in oral fluid and was investigated by enzyme-linked immunosorbent assay. Anti-VLP-16 IgA antibodies were detected in oral fluid from 54.3% (44/81) of women with cervical neoplasia, compared with 8% (3/36) in controls (P = 0.000002). Anti-VLP-16 IgG was detected in oral fluid from 43.2.9% (25/72) and 13.3% (4/30; P = 0.029), respectively. Women who were HPV-16 DNA positive at their cervical lesion, displayed an oral fluid anti-VLP-16 IgA prevalence of 60.7% (17/28) and HPV-16 DNA negative women an oral fluid anti-VLP-16 IgA prevalence of 50% (20/40; P = 0.38). Oral fluid anti-VLP-16 IgG prevalence in HPV-16 DNA positive women was 28.6% (8/28) compared with 40% (16/40) in oral fluid from HPV-16 DNA negative women (P = 0.3). Amongst HPV-16 DNA positive women, the anti-VLP-16 IgG seroprevalence was 75% (21/28) and IgA seroprevalence 35.7% (10/28) and for the HPV-16 DNA negative women these values were 60% (24/40) and 32.5% (13/40), respectively. Oral IgA antibody testing proved no more sensitive than serum antibody detection for the determination of HPV infection but could be useful as a non-invasive screening method for women with cervical neoplasia and for estimating the mucosal antibody response to HPV vaccines. J. Med. Virol. 65:149–154, 2001. © 2001 Wiley-Liss, Inc.

Infection with high-risk human papillomaviruses (HPV), is the most significant risk factor for cervical cancer and it may be possible to prevent this malignancy by immunisation. Before immunisation programmes can be designed, however, it is necessary to know the age of acquisition and all routes of infection for these viruses. Sexual transmission is well documented and vertical transmission has also been demonstrated, although the frequency of transmission remains controversial. We previously showed that vertical transmission frequently results in persistent infection, and now present data on the prevalence of HPV-16 DNA (the most prevalent high-risk HPV type) in healthy children. Buccal samples from 267 healthy children aged 3-11 years were tested for HPV DNA by generic PCR (MY09/MY11), and a HPV-16 specific nested PCR. Reverse transcriptase (RT)-PCR was used to determine the prevalence of transcriptionally active HPV-16 infection in a subset of children. HPV-16 DNA was detected by nested PCR in 138 of 267 (51.7%) samples, whereas HPV DNA was detected in only 45 (16.8%) specimens by generic PCR, that has a lower analytical sensitivity. There were no significant differences in prevalence according to age or sex. Early region mRNA was detected by RT-PCR in six (11.3%) of 53 HPV-16 E5 DNA positive samples. HPV-16 E5 DNA sequences from 10 children confirmed the identity of the sequences detected and identified 13 HPV-16 variants.

It is well recognised that high-risk human papillomaviruses (HPVs) are spread by sexual activity, but the possibility of non-sexual transmission remains controversial. We present evidence for vertical transmission from at least 30% HPV positive mothers to their infants, resulting in persistent infection in children. That the mother is the source of infant infection has been confirmed by DNA sequencing. We also discuss the evidence for oral HPV-16 infection in children. In our own studies, HPV-16 DNA was detected in buccal cells from 48% children, aged 3–11 and transcriptionally active infection was confirmed in some children. Other studies have reported prevalences of 19%-27% among children less than 11 years of age. Studies that have failed to detect high–risk HPVs in children have used techniques which were insufficiently sensitive to detect the low levels of virus present. Serological studies also suggest that ≤45% prepubertal children have acquired HPV-16. Thus, convincing evidence is now available for vertical transmission of high risk HPVs, which probably results in widespread infection among children. The consequences of such infections remain to be elucidated. Copyright © 1999 John Wiley & Sons, Ltd.

Proliferative responses to human papillomavirus type 16 (HPV-16) E5 peptides were determined for short-term cell lines derived from peripheral blood mononuclear cells of 75 women. Cell lines from 16 of the 75 women proliferated in response to stimulation with pooled E5 peptides; this was most common for patients with low-grade squamous cervical intraepithelial lesions (LSIL; 6 of 15 patients, 40%) and less frequent for asymptomatic women with no cervical lesions (4 of 20, 20%), those with high-grade squamous intraepithelial lesions(HSIL; 5 of 33, 15%) and others with cervical cancer (1 of 7, 14%, P = 0.027). Amongst these patients, proliferative responses were exclusive to those that were positive for HPV-16 DNA (12 of 41, 29%; c.f. none of 13 HPV-16 DNA-negative subjects exhibited a proliferative response; P= 0023) and were again most prevalent amongst HPV-16 DNA-positive LSIL (6 of 14, 43%), as compared with HPV-16 DNA-positive HSIL (5 of 23, 22%) or HPV-16 DNA-positive cervical cancer patients (1 of 4, 25%, P > 0.05). In contrast, for asymptomatic women, responsiveness was statistically independent of HPV-16 DNA status, i.e. responsiveness in HPV-16 DNA-positive and DNA-negative subjects was observed in 3 of 15 (20%) and 1 of 5 (20%) cases, respectively (P > 0.05). There were no associations between detection of HPV-16 mRNA and proliferative responses (P> 0.05). These data suggest that HPV-16 E5-specific T-helper activity is depressed amongst women with HSIL lesions.

Overexpression of p53 protein is common in cervical carcinoma. We investigated archival biopsies from 26 cervical cancer patients (24 with available lymph nodes) to determine the relationship between p53 overexpression and HPV infection at the cervix and lymph nodes. Twelve cervical carcinoma patients had p53 protein in cervical biopsies detectable by immunohistochemistry using monoclonal antibody DO-1, and 22 were positive for HPV DNA in polymerase chain reaction assays (16 contained HPV-16; 3, HPV-18; and, 3 HPV-X). Seven cervical cancer patients had one or more lymph nodes positive for p53 protein, and all but one of these were concordantly p53 positive at the cervix. However, detection of p53 protein in cervical biopsies was predictive neither of the expression of p53 at draining lymph nodes (P > 0.1) nor of the occurrence of metastases (P > 0.1). Fourteen patients were positive at one or more lymph nodes for HPV DNA. Cervical positivity for HPV DNA was associated significantly with concordant HPV positivity at the lymph nodes (P = 0.039) and was predictive of metastases (P = 0.019). There was no association between positivity for p53 and for HPV DNA at primary cervical carcinomas or at the lymph nodes (all P > 0.1). We conclude that, although detectable p53 protein is a common feature of cervical carcinomas, it is not predictive of metastases and is independent of HPV infection. J. Med. Virol. 53:111–117, 1997. © 1997 Wiley-Liss, Inc.

Individual types of human papillomaviruses (HPV) which infect mucosal surfaces have been implicated as the causative agents for carcinomas of the cervix, anus, penis, larynx and the buccal cavity, occasional periungal carcinomas, as well a:s benign anogenital warts. The identification of particular HPV types is thus important for: identifying patients with premalignant lesions who are at risk of progression to malignancy; epidemiological studies; studies of the natural history of these viruses; and even medico-legal cases of suspected sexual abuse of children. In this protocol we describe PCR assays for: the identification of DNA from the mucosal HPVs types -6, -11, -16, -18, -31 and -33; a consensus HPV PCR for detecting DNA from 20 characterised mucosal HPVs, as well as more than 25 novel HPVs; and, for a control PCR for β-globin.

Human papillomavirus type 16 (HPV-16) DNA is detected commonly in cervical carcinomas; in this study, we have determined the analytical sensitivities of Hybrid Capture, HPV-consensus PCR, and three HPV-16-specific polymerase chain reactions (PCRs) for the detection of HPV-16 DNA. Samples investigated included a cervical cancer cell line, cervical scrapes from 20 patients attending colposcopy clinics, and buccal swabs from eight immunosuppressed children. HPV-16 E7 and E5-nested PCRs [Cavuslu et al. (1996): Journal of Virological Methods, in press] produced positive signals from samples containing fewer than ten HPV-16 genomes per reaction. HPV-consensus PCR [Manos et al. (1989): Cancer Cells 7:209-214] and HPV-16 PCR using primers of van den Brule et al. [(1990): Journal of Clinical Microbiology 25:2739-2743] were of intermediate sensitivity (i.e., produced positive signals from samples containing 250 and 2,500 HPV-16 genoms/reaction, respectively) and Hybrid Capture could detect just 50,000 HPV-16 genomes/reaction. Highest rates of positivity for cervical samples were detected with HPV-16 E7 or E5-nested PCRs [50% (10 of 20 samples) and 60% (12 of 20 samples) positive, respectively], intermediate rates with HPV-consensus PCR and PCRs using the primers of van den Brule et al. [both 35% (7 of 20 samples)], and lowest rates of positivity [25% (5 of 20 samples)] with Hybrid Capture. None of eight buccal swab samples from immunosuppressed children were positive by Hybrid Capture, yet three (37.5%) were positive by HPV-16 E5-nested PCR. These data indicate that HPV-16 type-specific PCRs should be used for the investigation of specimens that may contain low amounts of HPV-16 DNA.

Background: E5-based nested polymerase chain reaction (PCR) assays and a PCR-enzyme immunoassay (EIA) to detect human papillomavirus type 16 (HPV-16) DNA have been developed. These assays were designed to detect small amounts of HPV-16 DNA for epidemiological studies of subclinical infection. Objectives: The E5 gene of HPV-16 may be lost in some cell lines derived from cervical carcinomas. The aim of this study was to determine if, and how frequently, E5 gene loss occurs in biopsy samples from patients with cervical lesions. Study design: Sixteen HPV-16 (E7) DNA positive and five HPV-16 DNA negative cervical lesions (nineteen cervical carcinomas, two cervical intraepithelial neoplasias) were investigated by E5 nested PCR and EIA. Results: Overall, 15 of the 16 (93.75%) HPV-16 E7 positive samples were positive for HPV-16 E5 DNA: 14 of 16 (87.5%) were positive by E5 PCR and 15 of 16 (93.75%) were positive by E5 PCR, nested PCR and by PCR-EIA. One of 14 HPV-16 (E7) DNA positive cervical carcinomas was negative for E5 DNA in all three assays. Conclusion: Loss of the HPV-16 E5 open reading frame (ORF) is a rare event in HPV-16 positive cervical carcinomas and was detected in just one of 14 (7.1%) cases.

Quality improvement (QI) and patient safety (PS) are essential competencies in residency training; however, the most effective means to engage physicians remains unclear. The authors surveyed all medicine and surgery physicians at their institution to describe QI/PS practices and concurrently implemented the Advocate for Clinical Education (ACE) program to determine if a physician-centered program in the context of educational structures and at the point of care improved performance. The ACE rounded with medicine and surgery teams and provided individual and team-level education and feedback targeting 4 domains: professionalism, infection control, interpreter use, and pain assessment. In a pilot, the ACE observed 2862 physician-patient interactions and 178 physicians. Self-reported compliance often was greater than the behaviors observed. Following ACE implementation, observed professionalism behaviors trended toward improvement; infection control also improved. Physicians were highly satisfied with the program. The ACE initiative is one coaching/feedback model for engaging residents in QI/PS that may warrant further study.

A new transgenic mouse model for global increases in the Sodium Dependent Vitamin C transporter 2 (SVCT2) has been generated. The SVCT2-Tg mouse shows increased SVCT2 mRNA levels in all organs tested and correspondingly increased ascorbic acid (ASC) levels in all organs except liver. The extent of the increase in transporter mRNA expression differed among mice and among organs. The increased ASC levels did not have any adverse effects on behavior in the SVCT2-Tg mice, which did not differ from wild-type mice on tests of locomotor activity, anxiety, sensorimotor or cognitive ability. High levels of SVCT2 and ASC were found in the kidneys of SVCT2-Tg mice and urinary albumin excretion was lower in these mice than in wild-types. No gross pathological changes were noted in kidneys from SVCT2-Tg mice. SVCT2 immunoreactivity was detected in both SVCT2 and wild-type mice, and a stronger signal was seen in tubules than in glomeruli. Six treatments with Paraquat (3x10 and 3x15 mg/kg i.p.) were used to induce oxidative stress in mice. SVCT2-Tg mice showed a clear attenuation of Paraquat-induced oxidative stress in lung, as measured by F(2)-isoprostanes. Paraquat also decreased SVCT2 mRNA signal in liver, lung and kidney in SVCT2-Tg mice.

Whilst genital papillomaviruses are commonly believed to be sexually transmitted, transmission of human papillomavirus type 16 (HPV-16) from mother to child at delivery has been described previously [Pakarian et al. (in press) British Journal of Obstetrics and Gynaecology]. In order to determine whether viral load in cervical/vaginal cells was an important determinant of transmission 15 pregnant women with HPV-16 infections were studied. Eight of these women had infants who were positive for HPV-16 DNA at genital and/or buccal sites. Viral load was estimated by laser densitometry of polymerase chain reaction (PCR) products. The eight mothers—four with a previous history of abnormal smears and two with previous genital warts— who transmitted infection to their infants had significantly higher viral loads (P < 0.05) than those who did not. It is concluded that viral load is an important, but not the sole, determinant for the transmission of HPV-16 from mother to infant. © 1994 Wiley-Liss, Inc.

Polyclonal antibodies were raised to partial and full-length synthetic peptides of human papillomavirus type 16 (HPV-16) E5. Antisera specificity for HPV-16 E5 was demonstrated by their ability to recognize not only their peptide immunogens but also full-length peptide and a glutathione S-transferase-E5 fusion protein. The most reactive antiserum, PE-6, raised to a full-length peptide, was used in Western blot analysis to identify HPV-16 E5 protein from exfoliated cervical cells. A strong, single band at approximately 20K was detected in two of six HPV-16-positive samples from women with a history of low-grade cervical intraepithelial neoplasia. The apparent M(r) by SDS-PAGE suggests that HPV-16 E5 forms homodimers in vivo, but not through cysteine linkage.

Background: Until rubella is eradicated there will be a continuing need for rubella antibody surveillance. Antigen production using recombinant DNA technology may be a viable alternative to traditional techniques of producing antigens for enzyme immunoassays (EIAs). Objectives: To investigate the potential of bacterial fusion proteins containing rubella E1 protein sequences for use in EIAs to detect rubella antibodies. Study design: Purified bacterial fusion proteins containing rubella E1 sequences to be used as antigens in EIAs and compared to ‘traditional' assays using virus derived antigens for rubella antibody screening. Results: cDNA clones coding for the complete rubella E1 protein sequence and subfragments of E1 were modified for expression as carboxy terminal fusions with either β-galactosidase or glutathione-S-transferase. β-galactosidase fusions with the complete E1 coding sequence or amino acids 201 to 307, which contain known epitopes, resulted in the production of predominantly insoluble fusion proteins unsuitable for use in EIA. Nine glutathione-S-transferase-E1 fusion proteins were produced with individual fusion proteins exhibiting varying properties with regard to the levels of protein produced, apparent stability, solubility and the potential for affinity purification using glutathione agarose. Reduction of the E1 component to only 44 amino acids containing three B-cell epitopes (Terry et al. , 1988) produced an abundant soluble GST-E1 fusion protein (3.5 μg/ml), which could be affinity purified using glutathione agarose. This fusion protein has been successfully used in EIA to detect rubella antibodies. Conclusions: We have shown that GST-E1 fusions have potential as antigens in tests for rubella antibodies.

Immunodominant, conserved and type-restricted external epitopes of bovine papillomavirus (BPV) major (L1) capsid protein have been identified using BPV particles and synthetic peptides. Antisera to disrupted BPV-1 recognized BPV-1 and BPV-2 particles in immune electron microscopy (IEM) studies and inhibited BPV-2-induced focus formation of NIH/3T3 cells. Thus BPV-1/BPV-2 cross-reactive epitopes occur on the surface of virions. The L1 protein appeared to be immunodominant as the antisera reacted with three dominant BPV-1/BPV-2 conserved B cell epitopes (amino acids 111 to 125, 131 to 145 and 191 to 205) in Pepscan assays of BPV-1 L1, whereas no common epitopes and less frequent antibody binding to peptides were detected in Pepscans of the L2 protein of BPV-1. Four discrete variable regions were identified in the sequences of L1 proteins of BPV-1 and BPV-2. Antisera against synthetic peptides corresponding to three of the four variable regions (amino acids 42 to 56, 435 to 449 and 485 to 499) of BPV-2 L1 caused clumping of BPV-2, but not of BPV-1, particles as examined by IEM, and antisera to one peptide (amino acids 485 to 499) inhibited BPV-2-induced focus formation of NIH/3T3 cells. These data suggest that these regions are type-specific BPV-2 L1 epitopes and that they occur on the virion surface. Although conformation-dependent epitopes remain to be identified on papillomaviruses, the linear epitopes identified in this study may be worthy of further study as constituents of experimental prophylactic vaccines.

Without appropriately timed specimens, serological confirmation of congenital rubella infection may be a problem. We have compared the persistence of specific IgM and low avidity specific IgG1 in 141 sera from 120 cases of serologically confirmed congenital rubella infection with the known time scales for postnatal primary rubella. The results demonstrate that the maturation of the immune response to the rubella virus is abnormally slow in congenital rubella cases both in terms of the isotype switch and especially the development of high avidity specific IgG1. Thus avidity studies may permit serological confirmation of congenital rubella for longer than is possible with tests currently in use. The pathological implications of prolonged low avidity antibody production are discussed.

Human papillomavirus type-16 (HPV-16) is strongly associated with cervical carcinoma and cervical intraepithelial neoplasia. It may soon be possible to develop prophylactic vaccines designed to induce neutralizing antibodies to HPV-16 virions in genital secretions and therapeutic vaccines to induce cytotoxic T-cell responses against HPV-16 early proteins in cervical intraepithelial neoplasia and cervical cancers. Although significant advances have been achieved, problems remain before such vaccines can be used routinely.

Persistence of specific IgM in sera following primary rubella infection was compared with the maturation of the specific IgG1 response. 206 sera, from 171 patients with primary rubella, taken 1 day to 2.5 years after onset of illness, were tested. Rubella-specific IgM was detected by M-antibody capture radioimmunoassay in 100% of sera taken 15–28 days after onset, but in only 9% taken 3–4 months after onset. However, using the diethylamine (DEA) shift value (DSV) method, low avidity specific IgG1 was detected in 91% sera taken at 3–4 months and at 5–7 months 21% of sera remained positive. Using an avidity index method, with urea in the wash buffer, none of the sera were positive for low avidity specific IgG1 beyond 3 months after onset. With DEA in the wash buffer, the number of sera positive rose to 38% at 3–4 months. Thus, the DSV method for detecting low avidity specific IgG1 is a useful additional test for confirming or refuting a diagnosis of primary rubella and is of particular value for assessing pregnant patients.

Antibodies to the major (L1) coat protein of human papillomavirus type 16 (HPV-16) in sera from patients with cervical intra-epithelial neoplasia (CIN) have been investigated by means of recombinant proteins and synthetic peptides. When L1-HPV-16 fusion proteins were used in immunoblot assays, no antibody reactivity was found in sera from 52 patients with CIN or from 21 unrelated children. Amino-acid sequence analyses indicated that L1-HPV-16 amino acids 473 to 492 may contain an HPV-16 type-restricted epitope since the greatest diversity occurs in this region. In the ELISA, seropositivity to peptides 473 to 492 was more common among CIN patients whose biopsies contained HPV-16 DNA (91%, 21 of 23) than among their children (24%, 5 of 21; p less than 0.001) or other CIN patients with HPV-16 DNA-negative biopsies (66%, 19 of 29; p less than 0.05), but was unrelated to the severity of the CIN lesion. Antibodies to L1-HPV-16 peptide 473 to 492 among seropositive CIN patients cross-reacted with the analogous L1-HPV-33, but not with the L1-HPV-6b peptide, and were predominantly IgM. In contrast, antibodies which recognized a less variable region of L1-HPV-16 (amino acids 279 to 293) showed no association with HPV-16 DNA status. Seropositivity to the L1-HPV-6b (amino acids 473-492) was less frequent (33%) among CIN patients and unassociated with HPV-16 DNA status (p greater than 0.1); however 51% (37 of 72) of patients with genital warts had antibodies to this peptide.