Search

BackgroundA child’s home and family environment plays a vital role in neuro-cognitive and emotional development. Assessment of a child’s home environment and social circumstances is an crucial part of holistic Paediatric assessment.AimsOur aim is to achieve full compliance with comprehensive documentation of biopsychosocial history, for all children medically admitted to the children’s inpatient unit in University Hospital Limerick.MethodsWe performed a retrospective chart review to audit documentation within our department. This was followed by teaching interventions and a survey on knowledge, attitudes and behaviour of paediatric non-consultant hospital doctors (NCHDs) towards the social history. We performed two subsequent re-audits to assess response to our interventions, and provided educational sessions to seek improvement in quality of care.ResultsResults showed a significant improvement in quality of documentation following interventions, demonstrated by a net increase of 53% in levels of documentation of some social history on first re-audit. Though this was not maintained at an optimum level throughout the course of the year with compliance reduced from 95% to 82.5% on second re-audit, there was nonetheless a sustained improvement from our baseline. Our qualitative survey suggested further initiatives and educational tools that may be helpful in supporting the ongoing optimisation of the quality of documentation of social history in our paediatric department.ConclusionWe hope this quality improvement initiative will ultimately lead to sustained improvements in the quality of patient-centred care, and early identification and intervention for children at risk in our community.

In August 2019, 3848 children in Ireland were faced with emergency homelessness [1]. In recent years, lack of affordable housing, unemployment and shortage of rental properties have been the primary driving factors for the potentially devastating impact of familial homelessness in our society [1]. Our aim was to evaluate current knowledge on the psychological impact of homelessness in children. Using the PRISMA model, we performed a review of the currently available literature on the psychological impact of homelessness on children. This concept was explored under two different categories-'transgenerational' and 'new-onset homelessness'. Hidden homelessness was also explored. Our literature review revealed several psychological morbidities which were unique to children. This includes developmental and learning delays, behavioural difficulties and increased levels of anxiety and depression [66, 77, 40, 81, 42]. This has been demonstrated by poorer performance in school testing and increased levels of aggression. Anxiety in children within this cohort has been shown to peak at time of dispersion from their stable home environment [67]. Our study highlights violence, aggression and poor academic learning outcomes to be just some of the key findings in our review of homelessness in childhood, worldwide. Unfortunately, there has been minimum research to date on paediatric homelessness within the context of the Irish population. We anticipate this review to be the first chapter in a multipart series investigation to evaluate the psychological morbidity of paediatric homelessness within the Irish Society.

In July 1968, the papal encyclical Humanae Vitae reaffirmed the ban on artificial contraception for Catholics. Utilising Dublin as a case study, this article explores how the Irish medical and social work community, their patients and the Catholic hierarchy responded to Humanae Vitae. Drawing on a range of medical and diocesan sources, as well as diverse material from the news media, this article illuminates the change in private behaviour that took place with regard to birth control between 1960 and 1972, and contrasts this behaviour with the public rhetoric and actions of many Catholics in positions of power. Furthermore, it highlights class inequality regarding access to and education on birth control; the health and welfare of working-class women often suffered greatly as a result of multiple births. It is demonstrated that while many exhibited a more liberal shift in their views on the issue of artificial birth control, this was not a straightforward change. A strong, patriarchal network of authority, made up of the Irish Catholic hierarchy and an obeisant section of the medical profession, sought to reaffirm control over Catholic women’s bodies in the wake of Humanae Vitae.

Introduction Transition from adolescence to adult care is very challenging for most patients. Without appropriate appointments and education, adolescents can get lost to follow up within one-year of transitioning to adult care (Mistry et al. Diabet Med 32(7):881–885, 2015). Loss to follow-up can increase risks of adverse short and long term diabetes-related complications, with healthcare contacts mainly limited to crisis-based management (Iversen et al. Scand J Caring Sci 33(3):723–730, 2019). Aims The purpose of this study was to evaluate the patient’s perspective of the process of transition from paediatric to adult-based diabetes services in the Mid-West Region of Ireland. Methods We implemented a new transition clinic at University Hospital Limerick with the collaboration of paediatric and adult endocrinology teams. Eighteen patients opted to attend the clinic, but only 17 patients consented to participate in a qualitative assessment study and completed questionnaires before and after the transition clinic. Results and conclusion In terms of medical management, patients had a good understanding of hypoglycaemia and insulin dose adjustment principles, but were least comfortable with carbohydrate counting. Patients self-ranked their knowledge on driving and sexual health with a diagnosis of diabetes as poor, in comparison to understanding effects of alcohol and smoking on diabetes. Overall, a majority of the respondents felt more confident in moving to adult-care after attending the transition clinic.

BACKGROUND Laparoscopic cholecystectomy (LC) is one of the most commonly performed surgical procedures. Despite this, patterns of readmission following LC are not well defined. This meta-analysis aimed to determine rates and predictors of readmission. METHODS An ethically approved International Prospective Register of Systematic Reviews (PROSPERO)-registered meta-analysis was undertaken searching PubMed, Scopus, Web of Science and Cochrane Library databases from January 2013-June 2018 adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Published literature potentially suitable for data analysis was graded using methodological index for non-randomised studies (MINORS) criteria; papers scoring ≥ 16/24 for comparative and ≥ 10/16 for non-comparative studies were included. A meta-analysis of potential risk factors was performed by computing the odds ratio using Mantel-Haenszel method and fixed-effects model with 95% confidence intervals. RESULTS Three thousand and eight hundred thirty-two articles were reduced to 44 studies qualifying for a final analysis of 1,573,715 laparoscopic cholecystectomies from 25 countries. Overall readmission rate was 3.3% (range: 0.0-11.7%); 52,628 readmissions out of 1,573,715 LCs. Surgical complications accounted for 76% of reported reasons for readmission, predominantly bile duct complications (33%), wound infection (17%) and nausea and vomiting (9%). Pain (15%) and cardiorespiratory complications (8%) account for the remainder. Obesity, single port LC and day case LC were not associated with increased rates. CONCLUSIONS Pain, nausea and vomiting and surgical complications, particularly bile duct obstruction are the most common causes for readmission. Intra-operative cholangiography may reduce readmission rates. Causes for readmission were inconsistently reported throughout. The mean readmission rate of 3.3% may act as a quality benchmark for improving LC, and clearer reporting of reasons for readmission are required to advance care.

Background and aims Childhood homelessness is a growing concern in Ireland creating a Pediatric subpopulation at increased risk of physical illnesses, many with life-long consequences. Our aim was to identify and categorize the physical morbidities prevalent in homeless children. Methods A review of the English-language literature on physical morbidities affecting homeless children (defined as Results Respiratory issues were the most commonly cited illnesses affecting homeless children; including asthma, upper respiratory tract infections, and chronic cough. Homeless children were described as being at increased risk of contracting infectious diseases, many studies placing emphasis on STI and HIV/AIDS transmission. Dermatologic concerns comprised of scabies and head lice infestation, dermatitis, and abrasions. Malnutrition manifested as a range of physical morbidities; including childhood obesity, iron deficiency anemia, and stunted growth. Studies found a higher prevalence of poor dental and ocular health in this population as well. Many articles also commented on the risk factors predisposing homeless children to these physical health concerns, which can broadly be categorized as limited access to health care, poor living conditions, and lack of education. Conclusions This literature review summarized the physical illnesses prevalent among homeless children and the contributing factors leading to them. Gaps in the literature were also identified, and included a dearth of studies focusing on younger children compared to adolescents. We believe that the current issue of child homelessness is socially and medically unacceptable and that homelessness occurring today will be one of the scandals of the next generation. Further research into prevention and intervention programs for this vulnerable population is urgently needed. Key messages This literature review shows that homeless children are at an increased risk of several physical morbidities and identified the common themes among them. Based on this literature review, it is recommended that more research be done into developing appropriate intervention and prevention strategies to help this vulnerable population.

Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This “bounce-back” response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis., The cytosolic N-glycanase NGLY1 is required for activation of the transcription factor Nrf1 and the proteasome bounce-back pathway. Proteasome inhibitor cytotoxicity increases upon NGLY1 inhibition.

In August 2019, 3848 children in Ireland were faced with emergency homelessness [1]. In recent years, lack of affordable housing, unemployment and shortage of rental properties have been the primary driving factors for the potentially devastating impact of familial homelessness in our society [1]. Our aim was to evaluate current knowledge on the psychological impact of homelessness in children. Using the PRISMA model, we performed a review of the currently available literature on the psychological impact of homelessness on children. This concept was explored under two different categories-'transgenerational' and 'new-onset homelessness'. Hidden homelessness was also explored. Our literature review revealed several psychological morbidities which were unique to children. This includes developmental and learning delays, behavioural difficulties and increased levels of anxiety and depression [66, 77, 40, 81, 42]. This has been demonstrated by poorer performance in school testing and increased levels of aggression. Anxiety in children within this cohort has been shown to peak at time of dispersion from their stable home environment [67]. Our study highlights violence, aggression and poor academic learning outcomes to be just some of the key findings in our review of homelessness in childhood, worldwide. Unfortunately, there has been minimum research to date on paediatric homelessness within the context of the Irish population. We anticipate this review to be the first chapter in a multipart series investigation to evaluate the psychological morbidity of paediatric homelessness within the Irish Society.

During uncoating, the conical capsid of HIV disassembles by dissociation of the p24 capsid protein (CA). Uncoating is known to be required for HIV replication, but the mechanism is poorly defined. Here, we examined the timing and effect of two capsid binding drugs (PF74 and BI2) on infectivity and capsid integrity in HIV-1-infected cells. The virus remained susceptible to the action of PF74 and BI2 for hours after uncoating as defined in parallel drug addition and cyclosporine (CsA) washout assays to detect the kinetics of drug susceptibility and uncoating, respectively. Resistance mutations in CA decreased the potency of these compounds, demonstrating that CA is the target of drug action. However, neither drug altered capsid integrity in a fluorescence microscopy-based assay. These data suggest that PF74 and BI2 do not alter HIV-1 uncoating but rather affect a later step in viral replication. Because both drugs bind CA, we hypothesized that a residual amount of CA associates with the viral complex after the loss of the conical capsid to serve as a target for these drugs. Superresolution structured illumination microscopy (SIM) revealed that CA localized to viral complexes in the nuclei of infected cells. Using image quantification, we determined that viral complexes localized in the nucleus displayed a smaller amount of CA than complexes at the nuclear membrane, in the cytoplasm, or in controls. Collectively, these data suggest that a subset of CA remains associated with the viral complex after uncoating and that this residual CA is the target of PF74 and BI2. IMPORTANCE The HIV-1 capsid is a target of interest for new antiviral therapies. This conical capsid is composed of monomers of the viral CA protein. During HIV-1 replication, the capsid must disassemble by a poorly defined process called uncoating. CA has also been implicated in later steps of replication, including nuclear import and integration. In this study, we used cell-based assays to examine the effect of two CA binding drugs (PF74 and BI2) on viral replication in infected cells. HIV-1 was susceptible to both drugs for hours after uncoating, suggesting that these drugs affect later steps of viral replication. High-resolution structured illumination microscopy (SIM) revealed that a subset of CA localized to viral complexes in the nuclei of cells. Collectively, these data suggest that a subset of CA remains associated with the viral complex after uncoating, which may facilitate later steps of viral replication and serve as a drug target.

Existing serum markers for breast cancer such as CA 15-3, BR 27.29 and CEA lack sensitivity and specificity. The aim of this study was to evaluate the value of new putative breast-specific markers for differentiating breast cancer from non-breast tissues. Expression of mammaglobin A (MGA), B726P, small breast epithelial mucin (SBEM) and MUC1 was measured by RT-PCR. MGA mRNA was detected in 86/162 (60%) breast cancers but in only 1/32 (3%) non-breast tissues; B726P was detected in 44/108 (41%) breast cancers but in none of 20 non-breast tissues, while SBEM was present in 52/103 (51%) breast cancers but in only 1/26 non-breast cancer tissues. In contrast to these novel markers, the established breast cancer marker MUC1 was detected in 72/99 (73%) breast cancers and in 22/32 (59%) of non-breast tissues. Combining MGA with B726P separated breast cancer from non-breast tissue with a sensitivity of 71% and a specificity of 95% while combining MGA with SBEM differentiated breast cancer from non-breast tissues with a sensitivity of 76% and a specificity of 89%. Genes such as MGA, B726P and SBEM that are expressed relatively exclusively in breast tissue are potential new markers for breast cancer.

Background Angiogenesis is essential for solid tumors, such as breast cancer, to grow. The effect of surgical removal of breast tumors on plasma endostatin and vascular endothelial growth factor (VEGF) levels was evaluated. Tumor tissues were analyzed for expression of Intratumoral microvessel density (IMVD) and endostatin. The effect of VEGF and endostatin in inducing apoptosis on human liver microvascular endothelial cells (HLMVEC) was investigated. Materials and methods Plasma from healthy volunteers, patients with fibroadenomas and breast cancer patients were assayed for endostatin and VEGF via immunoassay, pre-operatively and four weeks post-operatively. Expression of endostatin in tumor tissue was determined by Western blotting. IMVD was assessed following immunohistochemical staining with anti-CD34 antibody. Results Plasma endostatin levels, in breast cancer patients, were significantly elevated ( P = 0.015) in the post-operative (60.59 ± 7.70 ηg/ml) compared with the pre-operative group (30.62 ± 4.54 ηg/ml) and with normal age-matched controls (34.97 ± 3.76 ηg/ml). In patients with high pre-operative plasma endostatin value, IMVD was decreased to 20.1 ± 3.2 counts compared with 41.9 ± 5.4 counts in those with low pre-operative endostatin value ( P = 0.006). Neither plasma endostatin nor VEGF levels correlated with routine clinico-pathological parameters. Endostatin induced endothelial cell apoptosis and modulated the cytoprotective effect of VEGF in HLMVEC survival. Conclusion Plasma endostatin levels are increased in patients following surgical removal of the primary tumor. The decreased IMVD seen in patients with higher endostatin levels may be due to the apoptosis-inducing effect of endostatin on microvascular endothelial cells.

The effect of selective and non-selective cyclo-oxygenase inhibition on tumour growth and metastasis in an orthotopic model of breast cancer was investigated. 4T1 mammary adenocarcinoma cells were injected into the mammary fat pad of female BALB/c mice. When tumours reached a mean tumour diameter of 8.4±0.4 mm, mice were randomised into three groups (n=6 per group) and received daily intraperitoneal injections of the selective cyclo-oxygenase-2 inhibitor, SC-236, the non selective cyclo-oxygenase inhibitor, Indomethacin, or drug vehicle. Tumour diameter was recorded on alternate days. From 8 days after initiation of treatment, tumour diameter in animals treated with either SC-236 or indomethacin was significantly reduced relative to controls. Both primary tumour weight and the number of lung metastases were significantly reduced in the SC-236 and indomethacin treated mice. Microvessel density was reduced and tumor cell apoptosis increased in the primary tumour of mice treated with either the selective or non-selective cyclo-oxygenase inhibitor. In vitro, cyclo-oxygenase inhibition decreased vascular endothelial growth factor production and increased apoptosis of tumour cells. Our results suggest that cyclo-oxygenase inhibitors will be of value in the treatment of both primary and metastatic breast cancer. British Journal of Cancer (2002) 87, 231–237. doi:10.1038/sj.bjc.6600462 www.bjcancer.com © 2002 Cancer Research UK

PUBLISHED, Tumour progression is regulated by the balance of proliferation and apoptosis in the tumour cell population. To date, the role of vascular endothelial growth factor (VEGF) in tumour growth has been attributed to the induction of angiogenesis. VEGF has been shown to be a survival factor for endothelial cells, preventing apoptosis by inducing Bcl-2 expression. In both murine (4T1) and human (MDA-MB-231) metastatic mammary carcinoma cell lines, we found that VEGF upregulated Bcl-2 expression and anti-VEGF antibodies reduced Bcl-2 expression. These alterations in Bcl-2 expression were reflected by the levels of tumour cell apoptosis. VEGF resulted in reduced tumour cell apoptosis, whereas its inhibition with anti-VEGF neutralizing antibodies induced apoptosis directly in tumour cells. Therefore, in addition to its role in angiogenesis and vessel permeability, VEGF acts as a survival factor for tumour cells, inducing Bcl-2 expression and inhibiting tumour cell apoptosis.

Introduction. Chemoradiotherapy improves survival for some cancer patients. Methods of enhancing treatment response would further enhance survival rates. The effect of the addition of an antiangiogenic agent to a chemoradiotherapy regime has not previously been examined. Materials and methods. C57B16 mice were inoculated with 1 x 10 6 Lewis lung carcinoma cells into the flank and randomized to 1 of 10 treatment groups when tumor volume approached 1000 mm 3 . Animals received combinations of standard doses of intraperitoneal cisplatin, 5-fluorouracil, and the antiangiogenic agent genistein, together with 10 or 20 Gy of external beam radiotherapy. Animals were sacrificed at day 6 when tumor volume, microvessel density, and serum VEGF were determined. Results. Mean (SEM) tumor volume in the chemoradiotherapy group was 762 (212) mm 3 versus 565 (79) mm 3 in the chemoradiotherapy plus genistein group (P = 0.04, unpaired t-test). The addition of genistein produced a significant reduction in tumor microvessel density (P = 0.01) as well as serum VEGF levels (P < 0.05) compared to those animals receiving chemoradiation alone. Conclusion. This study provides proof of principle that chemoradiation can be enhanced by the addition of an antiangiogenic agent to the regime and suggests that further examination of such regimes is warranted.

Background Vascular endothelial growth factor (VEGF) levels are raised in the serum of patients with oesophageal carcinoma. The aim of this study was to evaluate the tumour microvasculature and the role of tumour-associated macrophages in VEGF production after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer. Methods Sections from 92 consecutively resected oesophageal tumours were stained for VEGF, von Willebrand factor and CD68. Twenty-seven patients received preoperative chemoradiation and 65 underwent surgical excision alone. The cellular source of VEGF was determined by parallel-section staining. Microvessel density and macrophage count were determined for each tumour by means of image analysis software. Results There were no significant differences between the two groups in age, sex or tumour type. Local downstaging of disease was evident in most specimens of tumours that had received preoperative chemoradiation. All tumours stained positive for VEGF, including those demonstrating a complete pathological response. Staining of parallel sections confirmed macrophages as the principal source of VEGF. Mean microvessel density was 6·4 per high-power field (h.p.f.) in tumours that received preoperative chemoradiation compared with 5·3 per h.p.f. in those treated by surgery alone (P = 0·130). A significant increase in tumour-associated macrophage infiltration was noted in tumours treated with neoadjuvant chemoradiation (22·1 per h.p.f.) compared with those treated by surgery alone (14·3 per h.p.f.) (P = 0·042). Conclusion Preoperative chemoradiation had little effect on the local angiogenic profile of the tumour in patients with oesophageal cancer. Tumour-infiltrating macrophages seem to be the source of persistent VEGF production after chemoradiotherapy and might explain the raised serum levels. Addition of an antiangiogenic agent to this regimen may be worthwhile in patients with oesophageal carcinoma.

BACKGROUND Lung carcinoma usually is advanced at the time of presentation and frequently shows metastatic spread. In recent times, prognostic factors such as c-erbB-2 in patients with breast carcinoma have provided useful information and beneficial therapeutic targets. The objective of this study was to evaluate angiogenesis, immune function, and telomerase expression in patients with nonsmall cell lung carcinoma (NSCLC) to determine their prognostic significance. METHODS Immunohistochemistry was used to evaluate the expression of human telomerase reverse transcriptase (hTERT; n = 115 patients), interleukin-2r (IL-2r; n = 40 patients), microvessel density (MVD; n = 81 patients), and vascular endothelial growth factor (VEGF; n = 61 patients). Three-year survival follow-up information was available for most patients, and a comprehensive review of clinicopathologic features was carried out. RESULTS Fifty percent of tumors showed nuclear staining for hTERT, 55% of tumors showed some degree of lymphocyte IL-2r expression, 33% of tumors were recorded with an MVD that was higher than average, and VEGF staining was detected in 85% of tumors. None of the parameters measured had an impact on survival. hTERT expression was correlated with lymph node status. Lymph node status and tumor size were identified as independent prognostic factors. CONCLUSIONS This study failed to identify a marker of prognosis for patients with NSCLC other than tumor size and lymph node status in this population. Telomerase expression was associated with metastases, raising the possibility that this enzyme is involved in the metastatic process. Tumor cell VEGF expression was identified frequently: This growth factor may have potential as a target for antiangiogenic therapy. Lung carcinoma typically is the result of large numbers of mutations. Further understanding of the biologic implications of these mutations will lead to the development of effective prognostic markers and treatments for patients with NSCLC. Cancer 2001;92:2648–57. © 2001 American Cancer Society.