Association Between Clinician Confidence and Making Guideline-Recommended Decisions in the Management of Abnormal Cervical Cancer Screening Results.

BACKGROUND: Guidelines for managing abnormal cervical cancer screening results are complex and adherence is challenging for clinicians. Previous studies have identified gaps in knowledge as a possible cause; few have explored the confidence clinicians have in their management decisions. Confidence in decision-making may influence management practices, particularly when guidelines are complex and evolving. OBJECTIVE: Assess whether confidence in decision-making is associated with making guideline-concordant recommendations for abnormal cervical cancer screening results. DESIGN: A clinician survey used vignettes to ask clinicians to make a management recommendation for different abnormal results and rate their level of confidence in their response. PARTICIPANTS: Physicians and advanced practice providers (APPs) at three diverse health systems in Washington, Texas, and Massachusetts. MAIN MEASURES: Correct response to each vignette based on either the 2012 or 2019 American Colposcopy and Cervical Pathology (ASCCP) management guidelines. KEY RESULTS: In total, 501 clinicians completed the survey between October and December 2020 (response rate 53.7%). Overall, most clinicians made guideline-recommended management decisions for two vignettes (73.2 and 73.7%), but fewer were confident in their selection (48.3% and 46.6%, respectively). Clinicians who reported high levels of confidence were more often correct than those who reported lower levels of confidence (85.8% vs. 62.2% and 87.5% vs. 60.7%, both p<0.001). After adjusting for clinician and practice characteristics, confidence remained significantly associated with selecting the correct answer. CONCLUSIONS: Clinician confidence in management decisions for abnormal cervical cancer screening results was significantly associated with knowing guideline-concordant recommendations. Given the complexity of cervical cancer management guidelines, solutions to improve clinician confidence in decision-making are needed.

Assessing Management of Abnormal Cervical Cancer Screening Results and Concordance with Guideline Recommendations in Three US Healthcare Settings.

BACKGROUND: Follow-up of abnormal results is essential to cervical cancer screening, but data on adherence to follow-up are limited. We describe patterns of follow-up after screening abnormalities and identify predictors of guideline-concordant follow-up. METHODS: We identified the index screening abnormality (positive human papillomavirus test or atypical squamous cells of undetermined significance or more severe cytology) among women of ages 25 to 65 years at three US healthcare systems during 2010 to 2019. We estimated the cumulative incidence of surveillance testing, colposcopy, or treatment after the index abnormality and initial colposcopy. Logistic regressions were fit to identify predictors of guideline-concordant follow-up according to contemporaneous guidelines. RESULTS: Among 43,007 patients with an index abnormality, the cumulative incidence of any follow-up was 49.6% by 4 years for those with atypical squamous cells of undetermined significance/human papillomavirus-negative and higher for abnormalities warranting immediate colposcopy. The 1-year cumulative incidence of any follow-up after colposcopy was 70% for patients with normal results or cervical intraepithelial neoplasia I and 90% for patients with cervical intraepithelial neoplasia II+. Rates of concordant follow-up after screening and colposcopy were 52% and 47%, respectively. Discordant follow-up was associated with factors including age, race/ethnicity, overweight/obese body mass index, and specific types of public payor coverage or being uninsured. CONCLUSIONS: Adherence to the recommended follow-up of cytologic and histopathologic abnormalities is inconsistent in clinical practice. Concordance was poor for mild abnormalities and improved, although suboptimal, for more severe abnormalities. IMPACT: There remain gaps in the cervical cancer screening process in clinical practice. Further study is needed to understand the barriers to the appropriate management of cervical abnormalities.

IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Timing of Colposcopy and Risk of Cervical Cancer.

OBJECTIVE: To quantify the association between time to colposcopy and risk of subsequent cervical cancer. METHODS: A longitudinal analysis of patients aged 21-79 years with an abnormal cervical cancer test result from health care systems in Texas, Massachusetts, and Washington was performed. The outcome was a cervical cancer diagnosis 12 months or more after the abnormal result. The primary analysis compared receipt of colposcopy within 3 months (91 days or less) with receipt of colposcopy at 3-12 months (92-365 days) and no colposcopy within 12 months of the abnormal test result; post hoc analyses compared colposcopy within 12 months (365 days or less) with no colposcopy within 12 months. Associations were assessed with multivariable Cox proportional hazards regression controlling for age, risk status, result severity, and health care system. RESULTS: Of 17,541 patients, 53.3% of patients received colposcopy within 3 months, 22.2% received colposcopy in 3-12 months, and 24.6% had no colposcopy within 12 months. One hundred forty-seven patients were diagnosed with cervical cancer within 12 months and removed from subsequent analyses. Sixty-five patients (0.4%) were diagnosed with cervical cancer more than 1 year (366 days or more) after the abnormal Pap or human papillomavirus test result. The risk of cervical cancer detection more than 1 year after the abnormal test result was not different in patients who received colposcopy within 3-12 months (hazard ratio [HR] 1.07, 95% CI 0.54-2.12) and higher among patients with no colposcopy within 12 months (HR 2.34, 95% CI 1.33-4.14) compared with patients who had colposcopy within 3 months. Post hoc analyses showed that the risk of cervical cancer diagnosis was 2.29-fold higher among those without colposcopy within 12 months compared with those who received colposcopy within 12 months (95% CI 1.37-3.83); among patients with high-grade cytology results, the risk of cervical cancer detection among those without colposcopy within 12 months was 3.12-fold higher compared with those who received colposcopy within 12 months (95% CI 1.47-6.70). CONCLUSION: There was no difference in cervical cancer risk at more than 1 year between patients who received colposcopy within 3 months compared with those who received colposcopy within 3-12 months of an abnormal result. Patients who did not receive colposcopy within 12 months of an abnormal result had a higher risk of subsequent cervical cancer compared with those who received a colposcopy within 12 months.

Factors associated with timely colposcopy following an abnormal cervical cancer test result.

Successful cervical cancer prevention requires screening and appropriate management of abnormal test results. Management includes diagnostic evaluation and treatment, if indicated, based on cervical cancer risk after most abnormal test results. There is little guidance on the optimal timing of diagnostic evaluation, and few data exist on factors associated with timely management. We quantified time-to-colposcopy within 12 months of an abnormal cervical cancer screening or surveillance test result from 2010 to 2018 across three diverse healthcare systems and described factors associated with timely colposcopy. Among 21-65 year-old patients with an abnormal test result for which colposcopy was indicated (n = 28,706), we calculated the proportion who received a colposcopy within 12 months of the abnormal test and used Kaplan-Meier methods to estimate the probability of colposcopy within 12 months. Across all systems, 75.3% of patients received a colposcopy within 12 months, with site-specific estimates ranging from 70.0 to 83.0%. We fit mixed-effects multivariable logistic regression models to identify factors associated with receipt of colposcopy within 12 months. The healthcare system and cytology result severity were the most important factors associated with of timely colposcopy. We observed that sites with more centralized processes had higher proportions of colposcopy completion, and patients with high-grade results were more consistently evaluated earlier than patients with low-grade results. Patient age also affected receipt of timely colposcopy, though this association differed by healthcare system and result severity. These data suggest opportunities for system-level interventions to improve management of abnormal cervical cancer test results.

The very large electrode array for retinal stimulation (VLARS)-A concept study.

OBJECTIVE: The restoration of vision in blind patients suffering from degenerative retinal diseases like retinitis pigmentosa may be obtained by local electrical stimulation with retinal implants. In this study, a very large electrode array for retinal stimulation (VLARS) was introduced and tested regarding its safety in implantation and biocompatibility. Further, the array's stimulation capabilities were tested in an acute setting. APPROACH: The polyimide-based implants have a diameter of 12 mm, cover approximately 110 mm2 of the retinal surface and carrying 250 iridium oxide coated gold electrodes. The implantation surgery was established in cadaveric porcine eyes. To analyze biocompatibility, ten rabbits were implanted with the VLARS device, and observed for 12 weeks using slit lamp examination, fundus photography, optical coherence tomography (OCT) as well as ultrasound imaging. After enucleation, histological examinations were performed. In acute stimulation experiments, electrodes recorded cortical field potentials upon retinal stimulation in the visual cortex in rabbits. MAIN RESULTS: Implantation studies in rabbits showed that the implantation surgery is safe but difficult. Retinal detachment induced by retinal tears was observed in five animals in varying severity. In five cases, corneal edema reduced the quality of the follow-up examinations. Findings in OCT-imaging and funduscopy suggested that peripheral fixation was insufficient in various animals. Results of the acute stimulation demonstrated the array's ability to elicit cortical responses. SIGNIFICANCE: Overall, it was possible to implant very large epiretinal arrays. On retinal stimulation with the VLARS responses in the visual cortex were recorded. The VLARS device offers the opportunity to restore a much larger field of visual perception when compared to current available retinal implants.

Cervical Cancer Burden and Opportunities for Prevention in a Safety-Net Healthcare System.

BACKGROUND: The high prevalence of cervical cancer at safety-net health systems requires careful analysis to best inform prevention and quality improvement efforts. We characterized cervical cancer burden and identified opportunities for prevention in a U.S. safety-net system. METHODS: We reviewed tumor registry and electronic health record (EHR) data of women with invasive cervical cancer with ages 18+, diagnosed between 2010 and 2015, in a large, integrated urban safety-net. We developed an algorithm to: (i) classify whether women had been engaged in care (≥1 clinical encounter between 6 months and 5 years before cancer diagnosis); and (ii) identify missed opportunities (no screening, no follow-up, failure of a test to detect cancer, and treatment failure) and associated factors among engaged patients. RESULTS: Of 419 women with cervical cancer, more than half (58%) were stage 2B or higher at diagnosis and 40% were uninsured. Most (69%) had no prior healthcare system contact; 47% were diagnosed elsewhere. Among 122 engaged in care prior to diagnosis, failure to screen was most common (63%), followed by lack of follow-up (21%), and failure of test to detect cancer (16%). Tumor stage, patient characteristics, and healthcare utilization differed across groups. CONCLUSIONS: Safety-net healthcare systems face a high cervical cancer burden, mainly from women with no prior contact with the system. To prevent or detect cancer early, community-based efforts should encourage uninsured women to use safety-nets for primary care and preventive services. IMPACT: Among engaged patients, strategies to increase screening and follow-up of abnormal screening tests could prevent over 80% of cervical cancer cases.

Cervical cancer screening among HIV-infected women in an urban, United States safety-net healthcare system.

OBJECTIVE: Little is known about cervical cancer screening and results patterns among HIV-infected (HIV+) women in real-world healthcare settings. We characterized two periods of screening opportunity. DESIGN: Retrospective cohort. SETTING: US safety-net healthcare system in Dallas County, Texas. PARTICIPANTS: We analyzed data from electronic medical records (EMR) of 1490 HIV+ women receiving care 2010-2014. MAIN OUTCOME MEASURES: At baseline, we categorized a woman's Pap status 15 months prior to index date as under-screened (vs. screened), and cytology result (normal vs. abnormal). Then, we examined screening completion and results, and colposcopy uptake and results after an abnormal screen, in the subsequent 15-month period. RESULTS: More than half of women (56%) had no evidence of a Pap test (i.e. under-screened) at baseline. Under-screened women were more likely to be older (50-64 years), have diabetes, and unknown viral load; they were less likely to be Black, Hispanic, have Medicaid, recently pregnant, have a HIV clinic visit, or a CD4 cell count at least 200 cells/µl. Nearly half of under-screened women (46%, n = 383) remained under-screened in the subsequent 15 months. Among women under-screened at baseline who later completed screening and follow-up during the study period, 21 high-grade dysplasia and three cancers were diagnosed. Overall, 40% of women did not receive colposcopy when needed, with most failures to follow-up occurring in women who were under-screened at baseline. CONCLUSION: Most HIV+ women receiving care in a safety-net system did not receive sufficient screening for cervical cancer and remained at exceptionally high risk of developing high-grade dysplasia.

Evidence-Based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States.

The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of colposcopy and directed biopsy for cervical cancer prevention in the United States (US). The recommendations were developed by an expert working group appointed by ASCCP's Board of Directors. An extensive literature review was conducted and supplemented by a systematic review and meta-analysis of unpublished data. In addition, a survey of practicing colposcopists was conducted to assess current colposcopy practice in the US. Recommendations were approved by the working group members, and the final revisions were made based on comments received from the public. The recommendations cover terminology, risk-based colposcopy, colposcopy procedures, and colposcopy adjuncts. The ASCCP Colposcopy Standards recommendations are an important step toward raising the standard of colposcopy services delivered to women in the US. Because cervical cancer screening programs are currently undergoing important changes that may affect colposcopy performance, updates to some of the current recommendations may be necessary in the future.

ASCCP Colposcopy Standards: Role of Colposcopy, Benefits, Potential Harms, and Terminology for Colposcopic Practice.

OBJECTIVES: The American Society for Colposcopy and Cervical Pathology Colposcopy Standards address the role of and approach to colposcopy and biopsy for cervical cancer prevention in the United States. Working Group 1 was tasked with defining the role of colposcopy, describing benefits and potential harms, and developing an official terminology. METHODS: A systematic literature review was performed. A national survey of American Society for Colposcopy and Cervical Pathology members provided input on current terminology use. The 2011 International Federation for Cervical Pathology and Colposcopy terminology was used as a template and modified to fit colposcopic practice in the United States. For areas without data, expert consensus guided the recommendation. Draft recommendations were posted online for public comment and presented at an open session of the 2017 International Federation for Cervical Pathology and Colposcopy World Congress for further comment. All comments were considered for the final version. RESULTS: Colposcopy is used in the evaluation of abnormal or inconclusive cervical cancer screening tests. Colposcopy aids the identification of cervical precancers that can be treated, and it allows for conservative management of abnormalities unlikely to progress. The potential harms of colposcopy include pain, psychological distress, and adverse effects of the procedure. A comprehensive colposcopy examination should include documentation of cervix visibility, squamocolumnar junction visibility, presence of acetowhitening, presence of a lesion(s), lesion(s) visibility, size and location of lesions, vascular changes, other features of lesion(s), and colposcopic impression. Minimum criteria for reporting include squamocolumnar junction visibility, presence of acetowhitening, presence of a lesion(s), and colposcopic impression. CONCLUSIONS: A recommended terminology for use in US colposcopic practice was developed, with comprehensive and minimal criteria for reporting.

Avaliação do estado nutricional e pressão arterial de adolescentes / Nutritional status assessment and blood pressure in adolescents

Introdução: O excesso de peso associa-se ao desenvolvimento de hipertensão arterial sistêmica independentemente da faixa etária. Portanto, objetivou-se verificar a associação entre estado nutricional e nível de pressão arterial em adolescentes. Método: Estudo transversal, realizado entre fevereiro e abril de 2013, com amostra constituída por 85 adolescentes, com idade entre 10 e 19 anos. A coleta de dados foi constituída pela aferição do peso, altura, índice de massa corporal, circunferência da cintura, pressão arterial e aplicação de um questionário estruturado, com questões sobre as condições socioeconômicas e o hábito alimentar. Resultados: A amostra foi composta por 52% (n=44) de adolescentes do gênero feminino e a média de idade foi de 14,05±1,48 anos. Na análise dos dados antropométricos, observou-se diferença estatisticamente significativa no grupo dos meninos nas variáveis de peso, altura e circunferência da cintura, quando comparados ao grupo das meninas. Na avaliação dos hábitos alimentares, verificou-se que o grupo dos meninos referiu consumir refrigerante diariamente e o grupo das meninas referiu nunca consumir (p=0,033). Não houve correlação significativamente estatística entre a classificação do índice de massa corporal e os níveis pressóricos (r=0,032; p=0,774). Verificou-se correlação entre índice de massa corporal e circunferência da cintura (r=0,581; p=<0,001). Conclusões: Foram encontradas diferenças estatisticamente significativas entre os grupos, houve diferença no grupo dos meninos nas variáveis de peso, altura, circunferência da cintura e consumo de refrigerantes, quando comparados ao grupo das meninas.(AU)

Introduction: Overweight is associated with the development of systemic arterial hypertension independently of the age group. Therefore, it was aimed to evaluate the association between nutritional status and blood pressure in adolescents. Methods: A cross-sectional study was conducted between February and April 2013, with a sample consisting of 85 adolescents aged between 10 and 19 years. Participants were assessed for weight and height to calculate body mass index, waist circumference and blood pressure. In addition, participants answered a structured questionnaire about socioeconomic conditions and feeding habits. Results: Fifty-two percent of the participants were females and the mean age was 14.05±1.48 years. Analysis of anthropometric data showed that weight, height and waist circumference were significantly higher in male participants than in females. In the evaluation of dietary habits, it was found that the male group reported consuming soft drinks daily, while the female group reported no consumption of this kind of beverage (p=0.033). No significant statistical correlation was observed between the classification of body mass index and blood pressure levels (r=0.032; p=0.774). There was a good correlation between body mass index and waist circumference (r=0.581; p=0.001). Conclusions: Statistically significant differences were observed between the groups, with higher levels in the variables weight, height, waist circumference and soft drink consumption in boys, when compared to the group of girls.(AU)

Investigation of changes in body composition, metabolic profile and skeletal muscle functional capacity in ischemic stroke patients: the rationale and design of the Body Size in Stroke Study (BoSSS).

BACKGROUND: Stroke is steadily increasing in prevalence. Muscle tissue wasting and functional changes are frequently observed in stroke, but this has not been studied in detail yet. There is a lack of data to support guideline recommendations on how to target muscle wasting in stroke patients. We hypothesise that pathophysiological metabolic profiles and muscle functional and structural impairment are developing in stroke patients, which are associated with stroke severity and outcome after stroke. METHODS: The Body Size in Stroke Study (BoSSS) is a prospective, longitudinal observation study that will explore associations between the metabolic profile, body tissue wasting and particular metabolic and functional changes in skeletal muscle tissue in stroke patients. Consecutive patients with acute stroke (n = 150) will be enrolled due to lacunar or territorial ischemic infarct in the area of the middle cerebral artery. Patients will be studied at annual intervals after 12 and 24 months. For comparison, healthy controls of similar age and patients with chronic heart failure will be used as control groups. The main objective is to study changes in body composition in stroke patients. Secondary, the study will focus on changes in insulin sensitivity of adipose tissue and skeletal muscle. Furthermore, measurements of endothelial function and peripheral blood flow will provide insight in the vascular regulation in stroke patients. CONCLUSION: This study will be the largest observational study providing insights into the metabolic and functional changes of muscle tissue in patients with acute ischemic stroke. The new data will increase our understanding of the pathophysiologic tissue wasting in stroke disease and help to develop new therapeutic strategies.

Off-label high-risk HPV DNA testing of vaginal ASC-US and LSIL cytologic abnormalities at Parkland hospital.

OBJECTIVE: To investigate the frequency and outcome of high-risk human papillomavirus (HPV) DNA testing of atypical squamous cell of unknown significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) vaginal ThinPrep Pap tests (TPPTs). METHODS: Atypical squamous cell of unknown significance and LSIL vaginal TPPTs (from women without a cervix) from 2005 to 2008 were identified retrospectively. The frequency of HPV testing in response to these cytologic abnormalities and results of testing were determined and compared with cervical TPPTs. The frequency and results of subsequent vaginal biopsies were reviewed. RESULTS: Of the ASC-US vaginal TPPTs, 76.5% (270/353) underwent HPV testing, with 31.9% (86/270) positive. Atypical squamous cell of unknown significance cervical TPPTs underwent HPV testing less often (69.5%, 7,155/10,297) but were more commonly HPV-positive (49.7%, 3,558/7,155). Similarly, the majority of LSIL vaginal TPPTs (59.2%, 202/341) underwent HPV testing, with 66% (133/202) testing positive. This compares with only 11.0% (1,092/9,947) of cervical LSIL TPPTs undergoing HPV testing, with 73.2% (799/1,092) positive. The increased rates of HPV test performance and lower rates of HPV positivity in vaginal ASC-US and LSIL TPPTs compared with similarly abnormal cervical TPPTs were statistically significant (p <.05) by χ analysis. Histologic evaluation was more common after HPV-positive ASC-US or LSIL vaginal TPPTs compared with HPV-negative results. Most high-grade vaginal neoplasias were diagnosed subsequent to a positive HPV result. CONCLUSIONS: Human papillomavirus testing of ASC-US and LSIL vaginal TPPTs is common; lower rates of HPV positivity were found in vaginal versus cervical ASC-US and LSIL TPPTs. The majority of high-grade vaginal neoplasias were diagnosed subsequent to positive HPV testing. Evidence-based guidelines for the use of HPV testing for the management of vaginal cytologic abnormalities are needed.

Loop electrosurgical excision procedure and risk of preterm birth.

OBJECTIVE: To examine whether preterm birth is related to the loop electrosurgical excision procedure (LEEP) itself or intrinsic to the women undergoing the procedure. METHODS: Rates of preterm birth, defined as births before 37 weeks of gestation, as well as causes were analyzed in women undergoing LEEP before or after an index pregnancy. These rates were compared with the general obstetric population. RESULTS: A total of 241,701 women were delivered of singletons at Parkland Hospital between January 1992 and May 2008; of these women, 511 previously had undergone LEEP and another 842 underwent LEEP after the index pregnancy. When compared with the general obstetric population, no increased risk of preterm birth was observed for either group. This was true regardless of the reason for preterm birth. Likewise, there was no increased risk of delivery before 34 weeks or between 34 and 36 weeks of gestation. CONCLUSION: No association was observed between LEEP and preterm birth in women undergoing the procedure before or after an index pregnancy.

Comparison of human papilloma virus testing and spectroscopy combined with cervical cytology for the detection of high-grade cervical neoplasia.

OBJECTIVE: This study compared the performance of cervical cytology plus human papilloma virus testing (Pap + HPV) or cervical spectroscopy (Pap + CS) for identifying high-grade cervical neoplasia in a high-risk population of women referred for colposcopy. MATERIALS AND METHODS: Each of 113 subjects underwent spectroscopy, thin-layer cytology, HPV testing, colposcopy, biopsy when indicated, and/or endocervical curettage. Evaluable data for analysis were collected for 102 of the subjects. Sensitivity and specificity were calculated for both strategies. RESULTS: Pap + HPV and Pap + CS achieved equivalent sensitivities (95%) for high-grade lesions, with both detecting 17 of 18 histology confirmed cervical intraepithelial neoplasia (CIN) 2+ lesions. Pap + HPV had a specificity of only 27.4% compared with 65.5% for Pap + CS (p < .0001). CONCLUSIONS: Spectroscopic interrogation of the cervix is equally sensitive and 2-fold more specific than HPV testing when combined with cervical cytology for identifying high-grade cervical neoplasia.

Abnormal neocortical development in mice lacking cGMP-dependent protein kinase I.

Cyclic GMP-dependent protein kinase type I (cGKI) is a key signaling intermediate important for synaptic potentiation in the hippocampus and cerebellum, but its expression and function in cortical development have not been elucidated. The expression of cGKI in the developing mouse neocortex was evaluated by immunofluorescence labeling, and effect of cGKI deletion on cortical development was studied in adult cGKI knockout mice. cGKI was expressed at highest levels at embryonic stages in young neurons and radial glial fibers, corresponding to the major period of radial migration and laminar development of pyramidal neurons (embryonic day E13.5-E14.5), declining upon maturation (E17.5-postnatal day P28). The cerebral cortex of homozygous null mutant mice lacking cGKI exhibited heterotopic collections of neurons in the upper cortical layers and abnormal invaginations of layer I, in accord with a neuronal migration or positioning defect. Some cGKI mutant mice displayed defects in midline development resulting in partial fusion of cerebral hemispheres with adjacent neuronal heterotopias. Apical dendrites of cortical pyramidal neurons were misoriented in the cerebral cortex of cGKI null mutants, as shown in reporter mice expressing yellow fluorescent protein in layer V pyramidal neurons and by Golgi impregnation. These results demonstrate a role for cGKI signaling in cortical development related to neuronal migration/positioning that is important for dendritic orientation and connectivity.

Neutrophil dysfunction in guanosine 3',5'-cyclic monophosphate-dependent protein kinase I-deficient mice.

The regulation of neutrophil functions by Type I cGMP-dependent protein kinase (cGKI) was investigated in wild-type (WT) and cGKI-deficient (cGKI-/-) mice. We demonstrate that murine neutrophils expressed cGKIalpha. Similar to the regulation of Ca2+ by cGKI in other cells, there was a cGMP-dependent decrease in Ca2+ transients in response to C5a in WT, but not cGKI-/- bone marrow neutrophils. In vitro chemotaxis of bone marrow neutrophils to C5a or IL-8 was significantly greater in cGKI-/- than in WT. Enhanced chemotaxis was also observed with cGKI-/- peritoneal exudate neutrophils (PE-N). In vivo chemotaxis with an arachidonic acid-induced inflammatory ear model revealed an increase in both ear weight and myeloperoxidase (MPO) activity in ear punches of cGKI-/- vs WT mice. These changes were attributable to enhanced vascular permeability and increased neutrophil infiltration. The total extractable content of MPO, but not lysozyme, was significantly greater in cGKI-/- than in WT PE-N. Furthermore, the percentage of MPO released in response to fMLP from cGKI-/- (69%) was greater than that from WT PE-N (36%). PMA failed to induce MPO release from PE-N of either genotype. In contrast, fMLP and PMA released equivalent amounts of lysozyme from PE-N. However, the percentage released was less in cGKI-/- (approximately 60%) than in WT (approximately 90%) PE-N. Superoxide release (maximum velocity) revealed no genotype differences in responses to PMA or fMLP stimulation. In summary, these results show that cGKIalpha down-regulates Ca2+ transients and chemotaxis in murine neutrophils. The regulatory influences of cGKIalpha on the secretagogue responses are complex, depending on the granule subtype.

Reflex human papillomavirus DNA testing on residual liquid-based (TPPT) cervical samples: focus on age-stratified clinical performance.

BACKGROUND: Liquid-based ThinPrep technology has made reflex human papillomavirus (HPV) DNA testing possible. In the current study, the clinical performance of reflex HPV testing as an adjunct to routine ThinPrep testing (TPPT) and the impact of age on various test parameters in a predominantly high-risk, minority population were evaluated retrospectively. METHODS: Reflex HPV testing was performed in 2114 women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology, using probes for low-risk (LR) and high-risk (HR) HPV types. Six hundred thirty women underwent subsequent biopsies with which HPV testing results were correlated. RESULTS: Approximately 86% of the patients were Hispanic and African-American and 12% were white. Of the younger women (ages 14-29 years), 81% were positive for HR types versus 50% in the older women (ages 30-77 years) (P < 0.0001). In women with ASCUS, 47% were found to be positive for HR types versus 78% of women with LSIL. The percentage of histologic high-grade lesions was 24% in younger patients versus 17% in older patients. Overall, 91% of high-grade lesions were positive for HPV DNA (HR-positive = 89% and LR-positive = 2%), and 9% were negative for both types. The sensitivities and specificities in "younger" versus "older" women were 92% (95% confidence interval [95% CI], 89-95%) and 22%% (95% CI, 17-26%), respectively, versus 84% (95% CI, 77-90%) and 59% (95% CI, 53-65%), respectively. CONCLUSIONS: The results of the current study demonstrate that reflex HPV testing performed in a routine clinical practice helps to identify the majority of women with high-grade disease. However, testing may be more beneficial in older women (age > or = 30 years) with ASCUS. Strategy using out-of-vial reflex testing is more cost-effective and sensitive than referring all women for colposcopies.