Participation and adherence to mammography screening in the Capital Region of Denmark: The importance of age over time.

Mammography screening's effectiveness depends on high participation levels. Understanding adherence patterns over time is important for more accurately predicting future effectiveness. This study analyzed longitudinal adherence to the biennial invitations in the Capital Region of Denmark from 2008-2017. We analyzed participation rates for five-year age groups along with their percent changes in each invitation round using linear regressions. Participation in the mammography screening program increased from 73.1% to 83.1% from 2008-2017. The participation rate among all age groups increased from the first to the fifth round, with the oldest age group having the largest increase (average percent change = 3.66; p-value = 0.03).

Clinical excellence in child and adolescent psychiatry: examples from the published literature.

There has been growing interest in the past century in improving understanding of the development and treatment of psychopathology of children, with increasing government funding of research in the past two decades. However, child and adolescent psychiatry excellence in clinical care has not been well-documented in the existing literature. This article provides examples of clinical excellence in paediatric mental health to supplement existing guidelines for the clinical practice of paediatric psychiatry. A review of the literature identified 204 unique peer-reviewed articles that were then further evaluated for applicability and relevance to the definition of clinical excellence as outlined by the Miller-Coulson Academy of Clinical Excellence (MCACE). Cases were then identified and selected for each domain of clinical excellence as they apply to child and adolescent psychiatry and to provide a model for patient care. KeypointsClinical excellence in child and adolescent psychiatry has not previously been defined or extensively documented.The Miller-Coulson Academy of Clinical Excellence (MCACE) has developed a systematic method to measuring excellence in clinical care and created a definition of clinical excellence.The MCACE defined the domains of clinical excellence as communication and interpersonal skills, professionalism and humanism, diagnostic acumen, skilful negotiation of the healthcare system, knowledge, scholarly approach to clinical practice, exhibiting a passion for patient care and modelling clinical excellence, and collaborating with investigators to advance science and discovery.There are numerous case examples in the literature that represent mastery in paediatric psychiatry in these areas.Clinicians in paediatric mental health will likely benefit from future research on evidence-based approaches to training and education in these domains of clinical excellence.

Safety considerations in the psychopharmacology of pediatric bipolar disorder.

Introduction: The standard of treatment of pediatric bipolar disorder (BPD) often requires life-long psychopharmacological management. Several pharmacological agents are approved by the US FDA for the treatment of pediatric BPD. However, each medication may cause adverse events (AEs). Provider awareness of AE profiles of common pharmacologic agents would serve to better inform patients and families in evaluating and selecting between treatment options. Areas covered: This review focuses on medications that, in our clinical experience, are commonly prescribed for youth with BPD and were evaluated in prospective clinical trials for the treatment of pediatric BPD. This paper highlights acute and long-term AEs described in these studies. Expert opinion: Most medications increase risk of AEs in youth with BPD. Treatment with lithium may lead to thyrotropin elevations, but generally does not cause significant weight gain. Divalproex may lead to weight gain; however, this finding was not consistent in comparison studies with lithium. Olanzapine, risperidone, quetiapine, and asenapine are associated with metabolic abnormalities and weight gain. Studies of ziprasidone, aripiprazole and lurasidone do not suggest significant metabolic AEs. More studies are needed to assess efficacy and safety of medications in managing pediatric BPD. Special focus on long-term maintenance trials is required to further identify long-term AEs in this population.

The Benefits of Required Forensic Clinical Experiences in Residency.

OBJECTIVE: The growth of forensic psychiatry has spurred efforts to improve forensic psychiatry training in general psychiatry residency. The Accreditation Council for Graduate Medical Education requires that residencies provide an experience that "exposes" residents to forensic issues, but leaves the specifics to individual programs. However, there is growing need for psychiatrists to understand the unique circumstances of individuals with mental illness involved in the criminal justice system. METHODS: The authors developed a new mandatory forensic rotation for general psychiatry residents and conducted a pilot study to assess its impact on residents' interest and comfort working with criminal justice-involved patients, interest in forensic fellowship, and knowledge of available resources for consultation and supervision. RESULTS: Rotation completion was associated with a significantly increased interest in working with forensic populations and pursuing forensic fellowship, but no changes in residents' level of comfort or knowledge of supervisory and consultative resources. CONCLUSIONS: This study adds to the growing body of literature describing the benefits of expanding forensic education for residents.

Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila.

Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR's SNF2 domain, we identified an interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in a partially SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.

HEMERA Couples the Proteolysis and Transcriptional Activity of PHYTOCHROME INTERACTING FACTORs in Arabidopsis Photomorphogenesis.

Phytochromes (phys) are red and far-red photoreceptors that control plant development and growth by promoting the proteolysis of a family of antagonistically acting basic helix-loop-helix transcription factors, the PHYTOCHROME-INTERACTING FACTORs (PIFs). We have previously shown that the degradation of PIF1 and PIF3 requires HEMERA (HMR). However, the biochemical function of HMR and the mechanism by which it mediates PIF degradation remain unclear. Here, we provide genetic evidence that HMR acts upstream of PIFs in regulating hypocotyl growth. Surprisingly, genome-wide analysis of HMR- and PIF-dependent genes reveals that HMR is also required for the transactivation of a subset of PIF direct-target genes. We show that HMR interacts with all PIFs. The HMR-PIF interaction is mediated mainly by HMR's N-terminal half and PIFs' conserved active-phytochrome B binding motif. In addition, HMR possesses an acidic nine-amino-acid transcriptional activation domain (9aaTAD) and a loss-of-function mutation in this 9aaTAD impairs the expression of PIF target genes and the destruction of PIF1 and PIF3. Together, these in vivo results support a regulatory mechanism for PIFs in which HMR is a transcriptional coactivator binding directly to PIFs and the 9aaTAD of HMR couples the degradation of PIF1 and PIF3 with the transactivation of PIF target genes.

The importance of implementation strategy in scaling up Xpert MTB/RIF for diagnosis of tuberculosis in the Indian health-care system: a transmission model.

BACKGROUND: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited. METHODS AND FINDINGS: We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. CONCLUSIONS: The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

Modeling the impact of alternative strategies for rapid molecular diagnosis of tuberculosis in Southeast Asia.

Novel diagnostic tests hold promise for improving tuberculosis (TB) control, but their epidemiologic impact remains uncertain. Using data from the World Health Organization (2011-2012), we developed a transmission model to evaluate the deployment of 3 hypothetical TB diagnostic tests in Southeast Asia under idealized scenarios of implementation. We defined diagnostics by their sensitivity for smear-negative TB and proportion of patients testing positive who initiate therapy ("point-of-care amenability"), with tests of increasing point-of-care amenability having lower sensitivity. Implemented in the public sector (35% of care-seeking attempts), each novel test reduced TB incidence by 7%-9% (95% uncertainty range: 4%-13%) and mortality by 20%-22% (95% uncertainty range: 14%-27%) after 10 years. If also deployed in the private sector (65% of attempts), these tests reduced incidence by 13%-16%, whereas a perfect test (100% sensitivity and treatment initiation) reduced incidence by 20%. Annually detecting 20% of prevalent TB cases through targeted screening (70% smear-negative sensitivity, 85% treatment initiation) also reduced incidence by 19%. Sensitivity and point-of-care amenability are equally important considerations when developing novel diagnostic tests for TB. Novel diagnostics can substantially reduce TB incidence and mortality in Southeast Asia but are unlikely to transform TB control unless they are deployed actively and in the private sector.

Down regulation of CSL activity inhibits cell proliferation in prostate and breast cancer cells.

The Notch receptor pathway provides a paradigm for juxtacrine signaling pathways and controls stem cell function, developmental cell fate decisions, and cellular differentiation. The Notch pathway is constitutively activated in human cancers by chromosomal rearrangements, activating point mutations, or altered expression patterns. Therefore, the Notch pathway is the subject of chemotherapeutic intervention in a variety of human cancers. Notch receptor activation results in the gamma-secretase dependent proteolytic cleavage of the receptor to liberate the Notch intracellular domain that acts to mediate co-activator recruitment to the DNA binding transcription factor, CSL (CBF-1/RBP-Jκ, Su(H), Lag-1). Therapeutic targeting of the Notch pathway by gamma-secretase inhibitors prevents NICD production and regulates CSL-dependent transcriptional activity. To interrogate the loss of CSL activity in breast and prostate cancer cells, we used lentiviral-based shRNA knockdown of CSL. Knockdown of CSL expression was assessed by decreased DNA binding activity and resulted in decreased cell proliferation. In contrast, gamma-secretase inhibitor (GSI) treatment of these prostate and breast cancer cell lines resulted in minimal growth effects. PCR profiling of Notch pathway genes identified expression changes in few genes (Delta-like-1, Deltex-1, LMO2, and SH2D1A) after CSL knockdown. Consistent with differential effects of GSI on cell survival, GSI treatment failed to recapitulate the gene expression changes observed after CSL knockdown. Thus, CSL inhibition may provide a more effective mechanism to inhibit Notch-pathway dependent cancer cell proliferation as compared to GSI treatment.

Association of core-binding factor ß with the malignant phenotype of prostate and ovarian cancer cells.

Core binding factor (CBF) is a transcription factor complex that plays roles in development, stem-cell homeostasis, and human disease. CBF is a heterodimer composed of one of three DNA-binding RUNX proteins plus the non-DNA-binding protein, CBFß. Recent studies have showed that the RUNX factors exhibit complex expression patterns in prostate, breast, and ovarian cancers, and CBF has been implicated in the control of cancer-related genes. However, the biologic roles of CBF in solid tumors have not been fully elucidated. To test whether CBF is required for the malignant phenotype of various epithelial cancers, we used lentiviral delivery of CBFß-specific shRNA to significantly decrease CBFß expression in two prostate cancer cell lines (PPC1 and PC-3) and the SKOV-3 ovarian cancer cell line. We found that knockdown of CBFß significantly inhibited anchorage independent growth of each cell line. Further, CBFß knockdown in PPC1 cells suppressed xenograft tumor growth compared to controls. Mice injected with SKOV-3 ovarian cancer cells knocked-down for CBFß exhibited a survival time similar to control mice. However, human cells recovered from the ascites fluid of these mice showed CBFß expression levels similar to those from mice injected with control SKOV-3 cells, suggesting that CBFß knockdown is incompatible with tumor cell growth. Gene expression profiling of CBFß knockdown cells revealed significant changes in expression in genes involved in various developmental and cell signaling pathways. These data collectively suggest that CBFß is required for malignancy in some human cancers.

Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors.

Acquired imatinib resistance in chronic myelogenous leukemia (CML) can be the consequence of mutations in the kinase domain of BCR-ABL or increased protein levels. However, as in other malignancies, acquired resistance to cytostatic drugs is a common reason for treatment failure or disease progression. As a model for drug resistance, we developed a CML cell line resistant to cyclophosphamide (CP). Using oligonucleotide arrays, we examined changes in global gene expression. Selected genes were also examined by real-time PCR and flow cytometry. Neither the parent nor the resistant lines had mutations in their ATP binding domain. Filtering genes with a low-base line expression, a total of 239 genes showed significant changes (162 up- and 77 down-regulated) in the resistant clone. Most of the up-regulated genes were associated with metabolism, signal transduction, or encoded enzymes. The gene for aldehyde dehydrogenase 1 was over-expressed more than 2000-fold in the resistant clone. BCR-ABL was expressed in both cell lines to a comparable extent. When exposed to the tyrosine kinase inhibitors imatinib and nilotinib, both lines were sensitive. In conclusion, we found multiple genetic changes in a CML cell line resistant to CP related to metabolism, signal transduction or apoptosis. Despite these changes, the resistant cells retained sensitivity to tyrosine kinase inhibitors.

CpG oligodeoxynucleotides enhance FcgammaRI-mediated cross presentation by dendritic cells.

Dendritic cells (DC) can trigger naive CD8(+) T cell responses by their capacity to cross-present exogenous antigens via the major histocompatibility complex class I pathway. The myeloid class I IgG receptor, FcgammaRI (CD64), is expressed on DC, and in vivo targeting of antigens to FcgammaRI induces strong humoral and cellular immune responses. We studied the capacity of human FcgammaRI (hFcgammaRI) to facilitate DC-mediated cross presentation and T cell activation, and assessed the effect of CpG oligodeoxynucleotides on this process. We generated hFcgammaRI expressing immature DC from hFcgammaRI transgenic and immature DC from non-transgenic mice. Antigens were targeted to Fcgamma receptors as ovalbumin immune complexes, or selectively to hFcgammaRI via ovalbumin-CD64 mAb fusion proteins. Co-incubation of immature DC with CpG ODN led to markedly increased MHC class I presentation of FcgammaR-targeted antigens. When OVA was selectively targeted to hFcgammaRI, few differences were observed between Tg and NTg DC. However, upon co-incubation with CpG ODN, hFcgammaRI-triggered cross presentation was enhanced. These results document the capacity of hFcgammaRI on DC to trigger cross presentation via MHC class I upon co-culture with CpG ODN.

High-level expression of immunoreactive recombinant cat allergen (Fel d 1): Targeting to antigen-presenting cells.

BACKGROUND: Cat allergen Fel d 1 is a heterodimer encoded by 2 separate genes that has been difficult to produce as a fully immunoreactive molecule. OBJECTIVE: We sought to engineer recombinant (r) Fel d 1 with IgE and IgG antibody binding comparable with that of the natural allergen that could be targeted to antigen-presenting cells. METHODS: The rFel d 1 chains were coexpressed in baculovirus, either linked to the anti-CD64 antibody H22 (rFel d 1 H22(+)) or alone (rFel d 1 H22 (-)). Binding of expressed allergens to mouse and human antibodies was compared with that of natural (n) Fel d 1 by means of enzyme immunoassay and antigen-binding and inhibition RIAs. Binding of rFel d 1 H22 (+) to the CD64 receptor on leukocyte subpopulations and on the THP -1 cell line was analyzed by means of flow cytometry. RESULTS: The baculovirus-expressed allergens migrated with molecular weights of 49 kd (rFel d 1 H22(+)) and 22 kd (rFel d 1 H22 (-)). The rFel d 1 inhibited IgG antibody binding to nFel d 1 by greater than 95% and showed identical dose-dependent inhibition curves. There was an excellent quantitative correlation between IgE and IgG antibody binding to rFel d 1 and nFel d 1 in sera from patients with cat allergy (IgE: n = 258, r = > 0.72,P <.001). The rFel d 1 H22(+) bound to monocytes but not to lymphocytes or neutrophils, and binding of rFel d 1 H22(+) to THP-1 cells was inhibited by a soluble CD64 fusion protein. CONCLUSIONS: Recombinant Fel d 1 chains have been successfully coexpressed as mature proteins with comparable immunoreactivities to nFel d 1. The rFel d 1 can be targeted to antigen-presenting cells through CD64. These constructs will facilitate structural studies of Fel d 1 and the development of improved allergy diagnostics and therapeutics.