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.

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.

Attachment representations and autonomic regulation in maltreating and nonmaltreating mothers.

This study assessed attachment representation and attachment-related autonomic regulation in a sample of 38 maltreating and 35 nonmaltreating mothers. Mothers' state of mind regarding attachment was measured using the Adult Attachment Interview. They further watched an attachment-based comfort paradigm, during which we measured skin conductance and vagal tone. More maltreating mothers (42%) than nonmaltreating mothers (17%) had an unresolved/disoriented attachment classification. Attachment representation was related to physiology during the comfort paradigm: an unresolved state of mind and a nonautonomous classification were associated with a decrease in skin conductance during the comfort paradigm, specifically during the responsive caregiver scenario. However, physiology did not differ between maltreating and nonmaltreating mothers. The decrease in skin conductance of unresolved mothers during the comfort paradigm might be indicative of a deactivating response, which is congruent with the dissociative nature of the unresolved state of mind. The results point to the potential utility of interventions focused on attachment representations for maltreating mothers.

Photoreceptor degeneration by intravitreal injection of N-methyl-N-nitrosourea (MNU) in rabbits: a pilot study.

BACKGROUND: Pilot study on the attempt to induce selective photoreceptor degeneration in the rabbit eye by intravitreal injection of MNU, facing the difficulties of the evaluation of retinal degeneration by different in-vivo and in-vitro methods in such a large eye animal model. METHODS: Eight pigmented Chinchilla Bastard rabbits were injected intravitreally with MNU (1 × 1mg/kg body weight (BW), 1 × 2mg/kg BW, 3 × 3mg/kg BW, 1 × 4mg/kg BW, 1 × 6mg/kg BW, and 1 × DMSO + PBS as control). One, 2, and 3 weeks after injection, the effects on the rabbit retina were examined in vivo using clinical observation (macroscopic images, funduscopy, weighing of the animals), measurement of intraocular pressure (IOP), full-field Electroretinography (ffERG), and spectral-domain Optical Coherence Tomography (sd-OCT). After 3 weeks follow-up, blood samples were taken to evaluate the general health status of the animals, and immunohistochemistry (IH) was performed on sections obtained from six different regions throughout the whole retina to evaluate MNU effects in more detail. RESULTS: It was difficult to observe the effects of MNU on retinal structure by OCT in vivo. Only the temporal quadrant of the retina could be visualized. Therefore, it was indispensible to evaluate the effects of MNU on the retina in vitro by examining six areas of the retina using immunohistochemistry. Furthermore, immunohistochemistry plays a decisive role to evaluate the effects on retinal cells other than photoreceptors while in H&E staining, namely the cell count of the ONL can be observed. The results obtained in vivo and in vitro in this study mainly follow the results of a previous study in mice. The low doses of MNU (1, 2 mg/kg BW) had no effects on retinal function and morphology, while high doses (4, 6 mg/kg BW) led to retinal changes in combination with significant side-effects (e.g., cataractous changes). Injection of 3 mg/kg BW MNU induced selective photoreceptor degeneration. However, the degree of degeneration varied between different parts of the same retina and between retinae of different animals. In two of three animals, a complete loss of ERG potentials was observed. Negative effects on the contralateral eye or on general welfare of the animal were never observed. CONCLUSIONS: In rabbits, the intravitreal injection of 3 mg/kg BW MNU leads to selective but inhomogeneous photoreceptor degeneration.

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.

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.

Do Intervention Programs in Child Care Promote the Quality of Caregiver-Child Interactions? A Meta-Analysis of Randomized Controlled Trials.

This meta-analysis reports on the effectiveness of targeted interventions focusing on child care professionals to improve child care quality, caregiver interaction skills, and child social-emotional development. Within randomized controlled trials, interventions are moderately effective in improving overall caregiver-child interactions (k = 19, Hedges' g = 0.35) and in improving child care quality on the classroom level (k = 11; Hedges' g = 0.39), the caregiver level (k = 10; Hedges' g = 0.44), and the child level (k = 6; Hedges' g = 0.26). Based on these findings, the implementation of evidence-based targeted interventions on a larger scale than currently exists may lead to better social-emotional development for children under the age of 5 years. There remains, however, an urgent need for more and larger randomized controlled trials with a solid design and high quality measures in order to shed more light on which child care components for which children are most critical in supporting children's socio-emotional development.

Salivary α-Amylase Reactivity to Infant Crying in Maltreating Mothers.

Deviant physiological reactivity to infant stimuli has been suggested to underlie maladaptive parenting behavior. Our study involved 44 maltreating and 42 non-maltreating mothers. During a standardized cry paradigm, mothers listened to nine cry sounds of varying pitches. Saliva was collected at baseline, after each cry sound, and after a recovery episode. Salivary α-amylase (sAA) as a marker of autonomic nervous system (ANS) activity was assayed from saliva samples. Maltreating mothers showed lower overall sAA levels and an attenuated reactivity pattern to infant crying as compared to non-maltreating mothers. No effect of type of maltreatment (neglect only vs. neglect and abuse) was found. Furthermore, positive correlations between sAA and heart rate (HR) for non-maltreating mothers differed significantly from non-significant correlations between sAA and HR for maltreating mothers. This suggests anomalous asynchrony between different aspects of the ANS in maltreating mothers. Results indicate a lack of functional autonomic (re)activity as a contributing risk factor to child maltreatment.

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.

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.

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.

cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock.

BACKGROUND: In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock. RESULTS: We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals. CONCLUSIONS: cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.

Effective preventive interventions to support parents of young children: Illustrations from the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD).

Secure attachment relationships are essential for children's current and later development. From attachment theory and research, it can be derived that sensitive parenting is the key to positive parent-child relationships. Is it possible to design effective interventions to enhance sensitive parenting? In this article, we review elements that are crucial for effective attachment-based interventions, and we proceed with illustrations from the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD). We describe how this intervention program was developed, how it has been implemented in practice in different types of families and in daycare settings, and how effective the program is. We conclude that intervention programs like the VIPP-SD could play an important role in the community by serving families in need of parenting support.

cGMP-dependent protein kinase I mediates the negative inotropic effect of cGMP in the murine myocardium.

To study the role of cGMP-dependent protein kinase I (cGKI) for cardiac contractility, force of contraction (F(c)) was studied in electrically driven heart muscle from wild-type (WT) mice and from conventional and conditional cGKI knockout mice. Both 8-Br-cGMP and 8-pCPT-cGMP reduced Fc in cardiac muscle from juvenile WT but not from juvenile cGKI-null mutants. Similarly, the cGMP analogues reduced F(c) in forskolin-stimulated ventricular muscle from WT mice but not from cGKI-null mutants. In contrast, carbachol reduced F(c) in both groups of animals. 8-Br-cGMP reduced F(c) also in heart muscle from adult WT mice but not from adult cardiomyocyte-specific cGKI-knockout mice. These results demonstrate that cGKI mediates the negative inotropic effect of cGMP in the myocardium of juvenile and adult mice.

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.