CELPI: trial protocol for a randomised controlled trial of a Carer End of Life Planning Intervention in people dying with dementia.

BACKGROUND: Dementia is a leading cause of death in developed nations. Despite an often distressing and symptom laden end of life, there are systematic barriers to accessing palliative care in older people dying of dementia. Evidence exists that 70% of people living with severe dementia attend an emergency department (ED) in their last year of life. The aim of this trial is to test whether a Carer End of Life Planning Intervention (CELPI), co-designed by consumers, clinicians and content specialists, improves access to end of life care for older people with severe dementia, using an ED visit as a catalyst for recognising unmet needs and specialist palliative care referral where indicated. METHODS: A randomised controlled trial (RCT) enrolling at six EDs across three states in Australia will be conducted, enrolling four hundred and forty dyads comprising a person with severe dementia aged ≥ 65 years, and their primary carer. Participants will be randomly allocated to CELPI or the control group. CELPI incorporates a structured carer needs assessment and referral to specialist palliative care services where indicated by patient symptom burden and needs assessment. The primary outcome measure is death of the person with dementia in the carer-nominated preferred location. Secondary outcomes include carer reported quality of life of the person dying of dementia, hospital bed day occupancy in the last 12 months of life, and carer stress. An economic evaluation from the perspective of a health funder will be conducted. DISCUSSION: CELPI seeks to support carers and provide optimal end of life care for the person dying of dementia. This trial will provide high level evidence as to the clinical and cost effectiveness of this intervention. TRIAL REGISTRATION: ACTRN12622000611729 registered 22/04/2022.

Downward Neighborhood Poverty Mobility during Childhood Is Associated with Child Asthma: Evidence from the Geographic Research on Wellbeing (GROW) Survey.

Causal evidence regarding neighborhood effects on health remains tenuous. Given that children have little agency in deciding where they live and spend proportionally more of their lives in neighborhoods than adults, their exposure to neighborhood conditions could make their health particularly sensitive to neighborhood effects. In this paper, we examine the relationship between exposure to poor neighborhoods from birth to ages 4-10 and childhood asthma. We used data from the 2003-2007 California Maternal Infant and Health Assessment (MIHA) and the 2012-2013 Geographic Research on Wellbeing (GROW) survey (N = 2619 mother/child dyads) to fit relative risks of asthma for children who experience different types of neighborhood poverty mobility using Poisson regression controlling for individual-level demographic and socioeconomic characteristics, and neighborhood satisfaction. Our results demonstrate that [1] living in a poor neighborhood at baseline and follow-up and [2] moving into a poor neighborhood were each associated with higher risk of asthma, compared with children not living in a poor neighborhood at either time. Exposure to impoverished neighborhoods and downward neighborhood poverty mobility matters for children's health, particularly for asthma. Public health practitioners and policymakers need to address downward neighborhood economic mobility, in addition to downward family economic mobility, in order to improve children's health.

Use of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients: a case series.

This case series reports on the safety and efficacy of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients. All patients used the device for contraception, with no documented cases of disseminated pelvic infection or unplanned pregnancy.

Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.

AIMS: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice. METHODS: DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs). RESULTS: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial. CONCLUSIONS: Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer.

AIMS: Small cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only ∼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice. METHODS: DNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations. RESULTS: A total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 1­10). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%). CONCLUSIONS: Greater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.

Management of dredge material in the Republic of Ireland - A review.

As an island nation the Republic of Ireland's ports and harbours are key to the economic wellbeing of the country as they are the primary transport link to the United Kingdom, mainland Europe and beyond. This paper examines the main aspects of the Irish dredging industry with comparison to international practice and standards, including the source of the dredge material and volumes generated annually, the dredging plant employed and the management processes currently practised. Relevant European and Irish legislation governing dredging, disposal at sea and waste licensing are presented. The potential impacts of disposal at sea are discussed with the implications for the Irish dredging industry of recently introduced European Directives assessed. Beneficial use rates for dredge material and the techniques implemented in Ireland are examined and compared with international practice. Recent notable beneficial use projects for dredge material and proposed innovative dredge material management techniques for specific dredging projects in Ireland are presented. Proposals to encourage greater beneficial use of dredge material and minimise disposal at sea for Ireland are presented including the introduction of environmental credits, tax breaks and a grant system for pilot schemes. An alternative disposal at sea charge fee structure is also recommended to encourage alternative dredge material management practices. Ireland's management of contaminated sediment is also presented with recent projects described highlighting the current practice of primarily exporting contaminated sediment to mainland Europe. Alternative methods of treatment of contaminated sediment are assessed in an Irish context. Future issues and challenges facing the Irish dredging industry are assessed and a critical analysis of the current approaches to dredge material management is presented.

An all-Ireland epidemiological study of MND, 2004-2005.

BACKGROUND AND METHODS: We conducted an all-Ireland population-based prospective epidemiological survey of motor neurone disease (MND) using the Northern Ireland and Republic of Ireland MND registers to examine the incidence and prevalence of the disease over the period 2004-2005. RESULTS AND CONCLUSIONS: Incidence of MND was 1.9 per 100 000 person-years and rates were comparable in both the north and south of Ireland. Prevalence of MND was 5.0 per 100 000 population. When compared with previous published surveys of MND performed in the Republic of Ireland over the last 10 years, rates of disease have remained relatively constant. When standardized to the 1990 US population, the incidence of MND in Ireland was found to be consistent with other European prospective surveys of MND.

Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004.

BACKGROUND: We conducted a prospective, population based study to examine trends in incidence and prevalence of amyotrophic lateral sclerosis (ALS) in Ireland from 1995 to 2004. METHODS: The Irish ALS Register was used to identify Irish residents diagnosed with ALS between the 3 year period from 1 January 1995 to 31 December 1997 and the 3 year period from 1 January 2002 to 31 December 2004. RESULTS: 465 Irish residents were diagnosed with ALS during the study periods. The annual incidence rate of ALS in Ireland remained stable over this time (2.0 cases per 100,000 person-years; 95% CI 1.9, 2.2). Median survival of Irish ALS patients was 16.4 months and did not change during the study period. Demographics and clinical features of the incident and prevalent Irish ALS cohorts were markedly different.

1,2-propanediol and the type of cryopreservation procedure adversely affect mouse oocyte physiology.

BACKGROUND: The aim of this work was to examine the effect of 1,2-propanediol (PrOH) and type of cryopreservation procedure (slow freezing and vitrification) on oocyte physiology. METHODS: Intracellular calcium of mouse metaphase II (MII) oocytes was quantified by fluorescence microscopy. The effect of PrOH on cell physiology was further assessed through analysis of zona pellucida hardening and cellular integrity. Protein profiles of cryopreserved oocytes were generated by time-of-flight mass spectrometry (TOF-MS). RESULTS: PrOH caused a protracted increase in calcium, which was sufficient to induce zona pellucida hardening and cellular degeneration. Using 'nominally calcium free' media during PrOH exposure significantly reduced the detrimental effects. Proteomic analysis identified numerous up- and down-regulated proteins after slow freezing when compared with control and vitrified oocytes. CONCLUSIONS: Using such approaches to assess effects on cellular physiology is fundamental to improving assisted reproduction techniques (ART). This study demonstrates that PrOH causes a significant rise in intracellular calcium. Using calcium-free media significantly reduced the increase in calcium and the associated detrimental physiological effects, suggesting that calcium-free media should be used with PrOH. In addition, analysis of the oocyte proteome following cryopreservation revealed that slow freezing has a significant effect on protein expression. In contrast, vitrification had a minimal impact, indicating that it has a fundamental advantage for the cryopreservation of oocytes.

Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma.

OBJECTIVE: To determine whether loss of melastatin (MLSN) is a universal phenomenon in American Joint Committee on Cancer (AJCC) stage I and II melanoma patients who experienced recurrence. MATERIAL AND METHODS: Paraffin blocks of primary melanomas (PMs) were retrieved from 30 patients who had a negative sentinel lymph node biopsy and developed recurrent melanoma (AJCC stage I and II). Chromogenic in situ hybridization (CISH) methods were utilized to evaluate the expression of MLSN mRNA. These results were correlated with clinicopathologic data. RESULTS: Variable, heterogeneous expression of MLSN mRNA was identified in normal, in situ and invasive melanocytes within and between cases. For the invasive PM component, 24 (80%) had focal, regional or complete loss of MLSN mRNA. The remaining 20% had either regional or total partial downregulation of MLSN mRNA. Intact MLSN mRNA expression was present regionally in 14/30 (47%), with mean relative tumor area of 38%, range 5-85%. Increasing loss of MLSN mRNA significantly correlated with increasing tumor depth and microsatellites (r = 0.1/0.4, p = 0.04). However, thin, AJCC T stage 1a PM had higher relative mean loss than intermediate AJCC T stage 2a/2b/3a thickness PM (65% vs. 34%/48%/25%). Increasing loss of MLSN mRNA significantly impacted on disease free survival (DFS) by multivariate analysis (58 vs. 0% 2 years DFS, < or = 75 vs. > 75% mRNA loss, p = 0.02). Decreased overall survival significantly correlated with increasing age and vascular invasion on multivariate analysis. CONCLUSION: Extensive loss of MLSN in PM correlated with aggressive metastatic melanoma. Ancillary testing for MLSN mRNA expression by CISH could offer a means to more accurately identify AJCC stage I and II patients at risk for metastatic disease, who could benefit from adjuvant therapy.

Decompression illness presenting as breast pain.

We present two cases of decompression illness in women in whom the initial symptom causing distress after completion of the dives was breast pain. Both women were also subsequently found to have a patent foramen ovale. We postulate that breast pain may be an unusual under-recognized manifestation of decompression illness.

Expression of matrix metalloproteinases 3, 10 and 11 (stromelysins 1, 2 and 3) and matrix metalloproteinase 7 (matrilysin) by cancer cells in non-small cell lung neoplasms. Clinicopathologic studies.

Matrix metalloproteinases (MMP's) 3, 10 and 11 (also known as stromelysins 1, 2 and 3, respectively), and matrix metalloproteinase 7 (also known as matrilysin), produced by stromal fibroblast-like cells in the vicinity of various malignancies, are suspected to have an ability to degrade components of extracellular matrix, thus promoting spread of the tumor. MMP's also have been found in epithelial tumor cells in various cancers. Tissue sections from 95 cases of non-small cell lung cancer (NSCLC) were immunostained with antibodies against MMP 3, MMP 10 and MMP 11 and sections from 99 cases of NSCLC were immunostained with an antibody against MMP 7. Cytoplasmic immunoreactivity in the tumor cells was semiquantitatively scored for intensity and distribution and correlated with tumor type, tumor grade, stage, tumor size, lymph node positivity, metastasis and survival. Overexpression of MMP 10 and MMP 11 correlated with higher grade for NSCLC (p = 0.029 and p = 0.016, respectively), and also in a subset of adenocarcinomas (AC) (p = 0.015 and p = 0.009, respectively). Also, MMP 10 and MMP 11 correlated with lymph node involvement in NSCLC (p = 0.025 and p = 0.027 respectively). No correlation was found for MMP 3. Overexpression of MMP-7 correlated with tumor stage (p = 0.0001) and was associated with adverse clinical outcome (p = 0.0001) in NSCLC and also in separate squamous cell carcinoma (SCC) (p = 0.003) and AC (p = 0.004) tumor groups.