Exploring the feasibility of conducting a randomised controlled trial of group-based pregnancy care and education: a pilot randomised controlled trial in Melbourne, Australia.

BACKGROUND: In group-based pregnancy models, antenatal care and childbirth/parenting education are provided in groups of eight to 10 women, usually with two midwives, and six to eight sessions. Current evidence is inconclusive regarding potential benefit or harm. We aimed to explore the feasibility of implementing an adequately powered randomised controlled trial (RCT). METHODS: A two-arm pilot RCT was conducted in a tertiary maternity hospital in Melbourne, Australia. Women were randomly allocated to either the intervention to receive group-based antenatal care and education (group care) or to usual care, which included hospital-based midwife, caseload midwifery, team midwifery, or GP shared care. Participants were English-speaking, primiparous, low risk, and < 24 weeks gestation at booking. DATA COLLECTION: feasibility measures throughout pilot, baseline questionnaire at recruitment, clinical outcome data from the medical record, and a telephone-administered questionnaire 6 weeks postpartum. A focus group explored midwives' views. RESULTS: Seventy-four women were recruited from May to June 2017 (group care = 40, usual care = 34). Study uptake was 35%. Women allocated to group care rated their overall pregnancy care more highly (88% good/very good vs 77% in usual care). There was no evidence of harm related to group care. Overarching themes from the midwives were that group care helped 'build connections' and 'empower women'. All midwives would work in the model again and believed it should be expanded. CONCLUSION: Group care was acceptable to both women and midwives with no evidence of harm. The pilot demonstrated the feasibility of undertaking a large adequately powered RCT, important given the inconclusive evidence on clinical outcomes regarding the model, and its current relatively widespread implementation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000858695.

A rare case of multifocal craniospinal leptomeningeal melanocytoma: A case report and scoping review.

Introduction: Leptomeningeal melanocytomas are rare tumours originating from neural crest derived melanocytes. They are usually solitary and presentation with multifocal meningeal melanocytoma is very rare and indicative of potentially more aggressive behaviour. This case report and scoping review sought to evaluate the presentation, and key radiological features that can help differentiate multifocal meningeal melanocytoma from other differentials and provide a discussion of the key management and prognostic points once these tumours are diagnosed. Case presentation: A 26 year old male presented with neck pain radiating to both shoulders and subjective weakness in left shoulder movement. MRI demonstrated a large enhancing C2-C3 intradural-extramedullary lesion with further lesions at the T7/T8 level, left cerebellopontine angle and midline suprachiasmatic region. Whilst the imaging appearances were initially thought be indicative of a phacomatosis such as NF2-related schwannomatosis, surgical excision of the cervical tumour confirmed a melanocytic tumour of leptomeningeal origin, consistent with multifocal meningeal melanocytoma. Patient made a good post-operative recovery and remains under half yearly radiological surveillance, with repeat MRI 6 months after surgery demonstrating subtle growth of the untreated intracranial and spinal lesions. Literature review and conclusions: This is the first description, to our knowledge, of a multifocal meningeal melanocytoma associated with both cerebellopontine angle and suprasellar lesions. This case and included scoping review highlight the need to consider this rare diagnosis whenever multifocal craniospinal lesions are encountered, and the need to consider aggressive management through surgical resection and adjuvant craniospinal radiotherapy once these tumours are diagnosed.

Midwifery workforce challenges in Victoria, Australia. A cross-sectional study of maternity managers.

BACKGROUND: In Australia, there is a lack of accurate data on midwifery workforce staffing and skill mix, which in turn hinders workforce policy and planning. AIM: To describe the current staffing levels of the midwifery workforce in Victoria, Australia, explore workforce challenges and assess the impact of COVID-19 pandemic on staffing. DESIGN: Cross-sectional. METHODS: Midwifery managers in all public and private maternity services in Victoria, Australia were invited to complete a survey exploring midwifery staffing numbers and adequacy. Topics explored included midwifery turnover, recruitment, and skill mix. Descriptive statistics were used. FINDINGS: The survey was open March to October 2021, and 56 % (38/68) of managers responded. Of these, 76 % reported inadequate midwifery staff levels, with deficits ranging from one to 19 estimated Full-Time Equivalent (EFT) midwives, with a combined total deficit of 135 EFT. In the 12 months prior to the survey, 73 % of services had found it difficult to recruit midwives, with increased difficulty during the COVID-19 pandemic. Managers were concerned about retaining and recruiting 'experienced' midwives due to an ageing workforce and high turnover due to work/life imbalance and job dissatisfaction. These issues have led to a predominantly early career midwifery workforce and created concern about skill mix. CONCLUSION: Victorian maternity services have a midwifery workforce shortage and are experiencing significant skill mix issues. The pandemic has exacerbated these considerable gaps in the workforce. Urgent implementation of retention and recruitment schemes are needed, along with strategies to improve the working conditions for the current workforce.

Live Discharge of Hospice Patients with Alzheimer's Disease and Related Dementias: A Systematic Review.

Background: Hospice is intended to promote the comfort and quality of life of dying patients and their families. When patients are discharged from hospice prior to death (ie, experience a "live discharge"), care continuity is disrupted. This systematic review summarizes the growing body of evidence on live discharge among hospice patients with Alzheimer's Disease and related dementias (ADRD), a clinical subpopulation that disproportionately experiences this often burdensome care transition. Methods: Researchers conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reviewers searched AgeLine, APA PsycINFO (Ovid), CINAHL Plus with Full Text, ProQuest Dissertations & Theses Global, PubMed, Scopus, and Web of Science (Core Collection). Reviewers extracted data and synthesized findings from 9 records, which reported findings from 10 individual studies. Results: The reviewed studies, which were generally of high quality, consistently identified diagnosis of ADRD as a risk factor for live discharge from hospice. The relationship between race and live hospice discharge was less clear and likely dependent upon the type of discharge under investigation and other (eg, systemic-level) factors. Research on patient and family experiences underscored the extent to which live hospice discharge can be distressing, confusing, and associated with numerous losses. Conclusion: Research specific to live discharge among ADRD patients and their families is limited. Synthesis across included studies points to the importance for future research to differentiate between types of live discharge-revocation vsversus decertification-as these are vastly different experiences in choice and circumstances.

Supporting the midwifery workforce: An evaluation of an undergraduate midwifery student employment model at a large tertiary maternity service in Victoria, Australia.

BACKGROUND: In 2020, in response to major maternity workforce challenges exacerbated by the COVID-19 pandemic, the Victorian Department of Health implemented a number of workforce maximisation strategies, one of which was employment of undergraduate midwifery students called 'Registered Undergraduate Student Of Midwifery' (RUSOM). AIM: To evaluate the RUSOM model implemented in a tertiary maternity service in Melbourne, Australia. METHODS: A cross-sectional online survey was distributed to all RUSOMs and midwives at the study site in August 2021. FINDINGS: Twenty of 26 RUSOMs (77%) and 110 of 338 permanent midwives (33%) responded. Both groups considered the model to be a positive workforce strategy that contributed to work readiness of students, and increased confidence and competence to practise. RUSOMS and midwives reported positives for the organisation including improving workload for midwives on the postnatal ward, enhancing quality of care and outcomes for women and babies, and the value of RUSOMs as team members. RUSOMs felt well supported, supervised and clinically and theoretically prepared. Both groups considered RUSOMs were underutilised, and that they could undertake additional duties, and both thought that the RUSOM model should continue. CONCLUSION: The model was highly valued by both RUSOMs and midwives. There was strong agreement that the model should continue and that the list of duties could be expanded. Given these findings, further research should explore the expansion and sustainability of RUSOMs in the maternity workforce.

Translating evidence into practice: Implementing culturally safe continuity of midwifery care for First Nations women in three maternity services in Victoria, Australia.

Background: Strategies to improve outcomes for Australian First Nations mothers and babies are urgently needed. Caseload midwifery, where women have midwife-led continuity throughout pregnancy, labour, birth and the early postnatal period, is associated with substantially better perinatal health outcomes, but few First Nations women receive it. We assessed the capacity of four maternity services in Victoria, Australia, to implement, embed, and sustain a culturally responsive caseload midwifery service. Methods: A prospective, non-randomised research translational study design was used. Site specific culturally responsive caseload models were developed by site working groups in partnership with their First Nations health units and the Victorian Aboriginal Community Controlled Health Organisation. The primary outcome was to increase the proportion of women having a First Nations baby proactively offered and receiving caseload midwifery as measured before and after programme implementation. The study was conducted in Melbourne, Australia. Data collection commenced at the Royal Women's Hospital on 06/03/2017, Joan Kirner Women's and Children's Hospital 01/10/2017 and Mercy Hospital for Women 16/04/2018, with data collection completed at all sites on 31/12/2020. Findings: The model was successfully implemented in three major metropolitan maternity services between 2017 and 2020. Prior to this, over a similar timeframe, only 5.8% of First Nations women (n = 34) had ever received caseload midwifery at the three sites combined. Of 844 women offered the model, 90% (n = 758) accepted it, of whom 89% (n = 663) received it. Another 40 women received standard caseload. Factors including ongoing staffing crises, prevented the fourth site, in regional Victoria, implementing the model. Interpretation: Key enablers included co-design of the study and programme implementation with First Nations people, staff cultural competency training, identification of First Nations women (and babies), and regular engagement between caseload midwives and First Nations hospital and community teams. Further work should include a focus on addressing cultural and workforce barriers to implementation of culturally responsive caseload midwifery in regional areas. Funding: Partnership Grant (# 1110640), Australian National Health and Medical Research Council and La Trobe University.

Who is at risk of burnout? A cross-sectional survey of midwives in a tertiary maternity hospital in Melbourne, Australia.

BACKGROUND: Burnout is an occupational phenomenon with the potential to affect a person's physical and mental health, job satisfaction and quality of work. There is evidence of burnout occurring in the midwifery profession, but inadequate data on the prevalence of, and the factors associated with, burnout. AIM: Identify the prevalence of burnout in a population of midwives and explore what individual and workforce characteristics, and what occupational stressors, were associated with burnout. METHODS: A cross-sectional survey of permanently employed midwives was conducted in a tertiary maternity service in Melbourne, Australia in 2017. Data collected included individual and workforce-related characteristics and occupational stressors. Burnout was explored using the Copenhagen Burnout Inventory. Univariate and multivariate analyses were conducted to ascertain associations between respondents' characteristics, stressors, and burnout levels. FINDINGS: A total of 257/266 midwives (97%) responded. There were significant levels of exhaustion and fatigue among respondents; 68% of midwives were experiencing personal burnout, 51% work-related burnout, and 10% were experiencing client-related burnout. Being aged ≤ 35 years, and/or having inadequate support was associated with personal and work-related burnout. Having inadequate acknowledgement was associated with client-related burnout. CONCLUSION: Health services need to understand the risk factors for burnout among midwives, identify and support groups that are most vulnerable, and address areas that are amenable to intervention. In our context this means ensuring midwives receive adequate acknowledgement and support, particularly younger midwives. These findings need to be tested in other settings to help inform a broader understanding and ensure the sustainability of the midwifery profession.

Factors associated with midwives' job satisfaction and experience of work: a cross-sectional survey of midwives in a tertiary maternity hospital in Melbourne, Australia.

BACKGROUND: Significant factors affecting the Australian maternity care context include an ageing, predominantly part-time midwifery workforce, increasingly medicalised maternity care, and women with more complex health/social needs. This results in challenges for the maternity care system. There is a lack of understanding of midwives' experiences and job satisfaction in this context. AIM: To explore factors affecting Australian midwives' job satisfaction and experience of work. METHODS: In 2017 an online cross-sectional questionnaire was used to survey midwives employed in a tertiary hospital. Data collected included characteristics, work roles, hours, midwives' views and experiences of their job. The Midwifery Process Questionnaire was used to measure midwives' satisfaction in four domains: Professional Satisfaction, Professional Support, Client Interaction and Professional Development. Data were analysed as a whole, then univariate and multivariate logistic regression analyses conducted to explore any associations between each domain, participant characteristics and other relevant factors. FINDINGS: The overall survey response rate was 73% (302/411), with 96% (255/266) of permanently employed midwives responding. About half (53%) had a negative attitude about their Professional Support and Client Interaction (49%), and 21% felt negatively about Professional Development. The majority felt positively regarding Professional Satisfaction (85%). The main factors that impacted midwives' satisfaction was inadequate acknowledgment from the organisation and needing more support to fulfil their current role. CONCLUSION: Focus on leadership and mentorship around appropriate acknowledgement and support may impact positively on midwives' satisfaction and experiences of work. A larger study could explore how widespread these findings are in the Australian maternity care setting.

Prenatal Depression and Diet Quality During Pregnancy.

BACKGROUND: Maternal nutrition during pregnancy has a significant effect on the health of the offspring and mother, highlighting the need for identifying factors that may affect diet during pregnancy. Research in nonpregnant and pregnant populations suggest depression may play a role. OBJECTIVE: To investigate the relationship between prenatal depression and diet quality during pregnancy overall and by race/ethnicity and to explore the relationships between prenatal depression and the 12 Healthy Eating Index 2010 dietary components. DESIGN: A cross-sectional secondary analysis of a cohort study of Kaiser Permanente Northern California women entering prenatal care between October 2011 and April 2013. PARTICIPANTS/SETTING: Participants included 1,160 adult pregnant women. MAIN OUTCOME MEASURES: Poor diet quality was defined as a Healthy Eating Index 2010 score in the lowest quartile. STATISTICAL ANALYSES PERFORMED: Logistic regression was used to assess the relationship between prenatal depression (defined as a depression diagnosis, Patient Health Questionnaire score of 10 or greater or antidepressant medication dispensing between the last menstrual period and completion of the food frequency questionnaire) and poor diet quality overall and by race/ethnicity. Relationships between prenatal depression and each of the 12 Healthy Eating Index 2010 dietary components were assessed using t-tests and linear regression analyses. RESULTS: One hundred fifty-nine (14%) participants had prenatal depression. Women with prenatal depression had nearly two times the odds of poor diet quality (odds ratio 1.80, 95% CI 1.23 to 2.60) compared with women without prenatal depression, after adjusting for potential confounders. Differences emerged by race/ethnicity; after adjusting for potential confounders the adjusted odds of poor diet quality were significant only among Hispanic women. Hispanic women with prenatal depression had an increased odds of poor diet quality compared with Hispanic women without prenatal depression (odds ratio 2.66, 95% CI 1.15 to 6.06). Women with prenatal depression had a higher consumption of empty calories (from solid fats, alcohol, and added sugars; threshold for counting alcohol >13 g/1,000 kcal) (P=0.01) and lower consumption of greens and beans (P<0.05), total fruit (P<0.01), and whole fruit (P<0.01), compared with women without prenatal depression. Except for empty calories, these findings remained after adjusting for potential confounders. CONCLUSIONS: Study findings suggest that women with prenatal depression are at a higher risk of poor diet quality compared with women without prenatal depression, and the relationship is stronger among Hispanic women. Nutrition counseling interventions for women with depression should consider the use of culturally sensitive materials and target limiting empty calories from solid fats, alcohol, and added sugars and encourage eating more greens, beans, and fruit.

ClustR: A Space-Time Cluster Analysis R Package for Individual-level Data.

BACKGROUND: Until recently, large individual-level longitudinal data were unavailable to investigate clusters of disease, driving a need for suitable statistical tools. We introduce a robust, efficient, intuitive R package, ClustR, for space-time cluster analysis of individual-level data. METHODS: We developed ClustR and evaluated the tool using a simulated dataset mirroring the population of California with constructed clusters. We assessed Cluster's performance under various conditions and compared it with another space-time clustering algorithm: SaTScan. RESULTS: ClustR mostly exhibited high sensitivity for urban clusters and low sensitivity for rural clusters. Specificity was generally high. Compared with SaTScan, ClustR ran faster and demonstrated similar sensitivity, but had lower specificity. Select cluster types were detected better by ClustR than SaTScan and vice versa. CONCLUSION: ClustR is a user-friendly, publicly available tool designed to perform efficient cluster analysis on individual-level data, filling a gap among current tools. ClustR and SaTScan exhibited different strengths and may be useful in conjunction.

Spatial-Temporal Cluster Analysis of Childhood Cancer in California.

BACKGROUND: The observance of nonrandom space-time groupings of childhood cancer has been a concern of health professionals and the general public for decades. Many childhood cancers are suspected to have initiated in utero; therefore, we examined the spatial-temporal randomness of the birthplace of children who later developed cancer. METHODS: We performed a space-time cluster analysis using birth addresses of 5,896 cases and 23,369 population-based, age-, sex-, and race/ethnicity-matched controls in California from 1997 to 2007, evaluating 20 types of childhood cancer and three a priori designated subgroups of childhood acute lymphoblastic leukemia (ALL). We analyzed data using a newly designed semiparametric analysis program, ClustR, and a common algorithm, SaTScan. RESULTS: We observed evidence for nonrandom space-time clustering for ALL diagnosed at 2-6 years of age in the South San Francisco Bay Area (ClustR P = 0.04, SaTScan P = 0.07), and malignant gonadal germ cell tumors in a region of Los Angeles (ClustR P = 0.03, SaTScan P = 0.06). ClustR did not identify evidence of clustering for other childhood cancers, although SaTScan suggested some clustering for Hodgkin lymphoma (P = 0.09), astrocytoma (P = 0.06), and retinoblastoma (P = 0.06). CONCLUSIONS: Our study provides evidence that childhood ALL diagnosed at 2-6 years and malignant gonadal germ cell tumors sporadically occurs in nonrandom space-time clusters. Further research is warranted to identify epidemiologic features that may inform the underlying etiology.

Pre- and Early Pregnancy Onset Depression and Subsequent Rate of Gestational Weight Gain.

Background: Depression is associated with weight change outside of pregnancy. We assessed associations of prepregnancy or early pregnancy onset depression with gestational weight gain (GWG) rate overall and according to Institute of Medicine (IOM) recommendations. Materials and Methods: Depression from 6 months prepregnancy through 20 weeks gestation was identified in a health care system in northern California with perinatal depression screening (2011-2016; n = 87,600). GWG rate (lbs/week) was calculated using weight at delivery and at diagnosis or depression screening ≤20 weeks. Results: Compared to women without prepregnancy or early pregnancy depression, women with prepregnancy onset depression had 11% greater risk of GWG rate IOM recommendations (95% CI: 1.01-1.05), with a stronger association for >IOM in normal weight women. Early pregnancy onset depression was associated with 0.04 lbs/week greater GWG rate (95% CI: 0.02-0.07) and 4% greater risk of GWG rate >IOM recommendations (95% CI: 1.02-1.07) compared to no prepregnancy or early pregnancy depression, with stronger associations in obese women. Conclusions: Women with prepregnancy onset depression may be at higher risk for GWG both below and above recommendations. Women with early onset prenatal depression may be at slightly higher risk for GWG rate above recommendations. Our results suggest that the relationship between depression and GWG may vary based on timing of depression onset, prepregnancy body mass index category, and antidepressant use. Additional research should identify factors that predict how a woman's lifestyle behaviors and weight change after depression diagnosis.

Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis.

RATIONALE: The combination of the CFTR (cystic fibrosis transmembrane conductance regulator) corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes but did not evaluate CFTR function in patients. OBJECTIVES: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous patients with cystic fibrosis aged 12 years and older. METHODS: This prospective observational study assessed clinical outcomes including FEV1% predicted and body mass index, and CFTR biomarkers including sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of lumacaftor-ivacaftor. MEASUREMENTS AND MAIN RESULTS: A total of 53 patients were enrolled in the study, and 52 patients had baseline and follow-up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (interquartile range [IQR], -25.9 to -6.1; P < 0.001), nasal potential difference showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR, 0.0-26.1; P < 0.011), and intestinal current measurement showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR, 10.8-29.0; P < 0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes. CONCLUSIONS: Lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV1% predicted and body mass index. Clinical trial registered with www.clinicaltrials.gov (NCT02807415).

Long-term outcomes of infant behavioral dysregulation.

OBJECTIVES: To determine whether maternal report of infant behavioral dysregulation at 6 months is associated with a higher prevalence of behavioral concerns at 5, 14, and 21 years of age; and to assess the extent to which maternal and social factors may affect reported child behavior outcomes. METHODS: From the Mater-University of Queensland Study of Pregnancy cohort of 7223 live singleton babies, information on dysregulation was available for 6389 children at 6 months. Of those children, behavior data were available for 4836 at 5 years by using a modified Child Behavior Checklist, 4746 at 14 years by using a full Child Behavior Checklist and Youth Self-Report, and 3558 at 21 years by using a Young Adult Self-Report. Of the youth with dysregulation data at 6 months, 2308 completed the Composite International Diagnostic Interview at 21 years. Potential confounding and mediating factors were analyzed by using logistic regression. RESULTS: Maternal-reported behavioral dysregulation at 6 months was associated with a significantly higher prevalence of maternal-reported behavior problems at 5 and 14 years (P < .001), but not youth self-reported problems at 14 or 21 years, or Composite International Diagnostic Interview-Diagnostic and Statistical Manual diagnoses at 21 years. The strength of association between infant dysregulation and maternal-reported behaviors was greater at 5 years than at 14 years, and was substantially reduced by adjusting for maternal, social, and infant factors, especially potentially the mediating factors of maternal anxiety and depression. CONCLUSIONS: Infant behavioral dysregulation was a risk factor for maternal-reported behavior concerns at 5 and 14 years, although was unrelated to young adult mental health.

Immunochemical analysis of mutant CFTR in lung explants.

BACKGROUND/AIMS: Knowledge about the abundance and distribution of CFTR protein glycoforms in native lung tissue is scarce. For upcoming studies with correctors and potentiators for CFTR it is important to get more information about mutant CFTR protein biochemistry. Target for novel treatment is the most afflicted organ in cystic fibrosis (CF), the lung. METHODS: Lung tissue sampled from patients with CF and non-CF donors prior to lung transplantation was examined for CFTR-immunoreactive signals by immunoblot. Quantitation of the immunoreactive signals was carried out by densitometry. RESULTS: The complex-glycosylated and mannose-rich CFTR isoforms were present in all non-CF specimens, whereas no or only the immature CFTR isoform was visible in CF samples. Whereas some complex-glycosylated CFTR was often present in rectal biopsies of F508del homozygous subjects, no mature CFTR was detectable in CF lungs at the stage of terminal respiratory insufficiency. CONCLUSION: Immunoblot analysis of CFTR in lung tissue is feasible, but in context of the upcoming studies of CFTR correctors and potentiators rectal biopsies seem to be a more appropriate choice because of their safe and repeatable excision.

Intranodal interaction with dendritic cells dynamically regulates surface expression of the co-stimulatory receptor CD226 protein on murine T cells.

Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Depending on their maturation status, they prime T cells to induce adaptive immunity or tolerance. DCs express CD155, an immunoglobulin-like receptor binding CD226 present on T and natural killer (NK) cells. CD226 represents an important co-stimulator during T cell priming but also serves as an activating receptor on cytotoxic T and NK cells. Here, we report that cells of the T and NK cell lineage of CD155(-/-) mice express markedly elevated protein levels of CD226 compared with wild type (WT). On heterozygous CD155(+/-) T cells, CD226 up-regulation is half-maximal, implying an inverse gene-dosis effect. Moreover, CD226 up-regulation is independent of antigen-driven activation because it occurs already in thymocytes and naïve peripheral T cells. In vivo, neutralizing anti-CD155 antibody elicits up-regulation of CD226 on T cells demonstrating, that the observed modulation can be triggered by interrupting CD155-CD226 contacts. Adoptive transfers of WT or CD155(-/-) T cells into CD155(-/-) or WT recipients, respectively, revealed that CD226 modulation is accomplished in trans. Analysis of bone marrow chimeras showed that regulators in trans are of hematopoietic origin. We demonstrate that DCs are capable of manipulating CD226 levels on T cells in vivo but not in vitro, suggesting that the process of T cells actively scanning antigen-presenting DCs inside secondary lymphoid organs is required for CD226 modulation. Hence, a CD226 level divergent from WT may be exploited as a sensor to detect abnormal DC/T-cell cross-talk as illustrated for T cells in mice lacking CCR7.

CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions.

The chemokine receptor CCR7 represents an important determinant for circulating lymphocytes to enter lymph nodes (LN) via high endothelial venules. High endothelial venules also represent the major site of entry for plasmacytoid dendritic cells (pDC). In the steady-state, murine pDC have been suggested to home to LN engaging the chemokine receptors CXCR3, CXCR4, and CCR5, whereas responsiveness to CCR7 ligands is thought to be acquired only upon activation. In this study, we show that already resting pDC express minute amounts of CCR7 that suffice to trigger migration to CCL19/CCL21 in vitro. Upon activation with TLR ligands, CCR7 levels on pDC are strongly increased. Notably, CCR7-deficient mice display substantially reduced pDC counts in LN but not in bone marrow and spleen. Adoptive cell transfer experiments revealed that under both steady-state as well as inflammatory conditions, the homing of CCR7-deficient pDC is severely impaired, indicating that the reduced cell counts of naive pDC observed in CCR7(-/-) mice reflect an intrinsic homing defect of pDC. Together, these observations provide strong evidence that similar to naive lymphocytes, nonstimulated pDC exploit CCR7 to gain entry into LN. This adds to the repertoire of chemokine receptors permitting them to enter diverse tissues.

Orphan drug pricing and payer management in the United States: are we approaching the tipping point?

The Orphan Drug Act of 1983 paved the way for the development of drugs that treat rare diseases, defined in the United States as those affecting fewer than 200,000 patients. Orphan drugs can cost hundreds of thousands of dollars annually, but insurers have traditionally covered these therapies because the small populations involved did not typically lead to significant cost exposure. Payer sensitivity to the cost of orphan drugs is rising, however, with the accelerated rate of new launches of these agents amid intensified economic pressure. Payers are showing increasing levels of concern and scrutiny about coverage of orphan drugs. A new payer survey conducted between February 2008 and March 2009 provides insights on how payers are managing orphan drugs and the way it is likely to evolve in the future. Survey findings show that the patient share of orphan drug costs is rising and is expected to continue to rise, barring sweeping changes in public health policy. This shift in benefit design could affect patient access to orphan agents and, therefore, drug utilization. Manufacturers will have to invest in research to understand payer impact on the uptake of their orphan drugs in development. They will also benefit from being prepared to develop strategies to ensure patient access to and affordability of their orphan agents.