Ancient DNA, lipid biomarkers and palaeoecological evidence reveals construction and life on early medieval lake settlements.

Direct evidence of ancient human occupation is typically established through archaeological excavation. Excavations are costly and destructive, and practically impossible in some lake and wetland environments. We present here an alternative approach, providing direct evidence from lake sediments using DNA metabarcoding, steroid lipid biomarkers (bile acids) and from traditional environmental analyses. Applied to an early Medieval Celtic settlement in Ireland (a crannog) this approach provides a site chronology and direct evidence of human occupation, crops, animal farming and on-site slaughtering. This is the first independently-dated, continuous molecular archive of human activity from an archeological site, demonstrating a link between animal husbandry, food resources, island use. These sites are under threat but are impossible to preserve in-situ so this approach can be used, with or without excavation, to produce a robust and full site chronology and provide direct evidence of occupation, the use of plants and animals, and activities such as butchery.

In-hospital mortality risk of intertrochanteric hip fractures: a comprehensive review of the US Medicare database from 2005 to 2010.

PURPOSE: Intertrochanteric hip fracture is a common injury in the Medicare population. Very little is known about the in-hospital mortality risk of intertrochanteric hip fractures and associated demographics for the US Medicare population. The purpose of this study is to determine the in-hospital mortality rate of closed intertrochanteric hip fractures and to evaluate demographic factors influencing an increased mortality risk. METHODS: The PearlDiver Medicare database from 2005 to 2010 was queried for closed intertrochanteric hip fractures. Stratified sampling was conducted by creating subset for individuals with a death discharge from inpatient facilities. Statistical analysis was performed where appropriate. RESULTS: Throughout 2005-2010 there were a total of 1,138,142 intertrochanteric hip fractures. There were 19,385 deaths during the initial hospital stay, yielding a mortality rate of 1.70%. There was a 1.83% mortality rate for patients 75 and older and patients over the age of 84 comprised the majority of deaths at 58%. The mortality rate was lower for females (1.39%) than for males (2.56%) (p < 0.0002). CONCLUSION: We found in the Medicare database that there is a relatively low rate of in-hospitality mortality associated with intertrochanteric hip fractures; this rate is lower than previously reported. We report a 1.70% in-hospital mortality using a complete Medicare dataset. Based on previous reporting for short term and one-year mortality risk, the present study suggests that mortality risk is greatest after patients have been released from the hospital. More attention should be paid to understanding and attenuating the mortality associated with intertrochanteric hip fractures after the acute hospital phase.

Family-focused practice within a recovery framework: practitioners' qualitative perspectives.

BACKGROUND: Family-focused practice (FFP) is an effective approach to supporting individuals with mental illness. 'Recovery' is also central to contemporary mental health care. However, there is a dearth of evidence about how the two concepts are related and subsequently implemented in practice. The aim of this study was to explore practitioners' understandings and practices of FFP within a recovery framework. METHODS: Purposive/snowball sampling was used to recruit and conduct qualitative interviews with 11 mental health practitioners in rural Australia. Concurrent sampling and data collection were informed by thematic analysis and continued until data saturation was reached. RESULTS: Participants found it difficult to articulate their understandings of FFP within a recovery framework. Nonetheless they were able to describe practices that embodied family-focused recovery. Barriers to such practices included medical models of care, where there are often a shortage of skilled staff and high demands for care. Stigma (self and from others) and confidentiality were also identified as barriers to involving family members in recovery focused care. CONCLUSIONS: Family-focused recovery care is a priority in many high-income countries. A family-focused recovery framework is needed to assist service planners, practitioners, family members and those with mental health needs and ensure such care is embedded within practice guidelines.

A Cost-Benefit Analysis of Government Compensation of Kidney Donors.

From 5000 to 10 000 kidney patients die prematurely in the United States each year, and about 100 000 more suffer the debilitating effects of dialysis, because of a shortage of transplant kidneys. To reduce this shortage, many advocate having the government compensate kidney donors. This paper presents a comprehensive cost-benefit analysis of such a change. It considers not only the substantial savings to society because kidney recipients would no longer need expensive dialysis treatments--$1.45 million per kidney recipient--but also estimates the monetary value of the longer and healthier lives that kidney recipients enjoy--about $1.3 million per recipient. These numbers dwarf the proposed $45 000-per-kidney compensation that might be needed to end the kidney shortage and eliminate the kidney transplant waiting list. From the viewpoint of society, the net benefit from saving thousands of lives each year and reducing the suffering of 100 000 more receiving dialysis would be about $46 billion per year, with the benefits exceeding the costs by a factor of 3. In addition, it would save taxpayers about $12 billion each year.

Potential economic impacts from improving breastfeeding rates in the UK.

RATIONALE: Studies suggest that increased breastfeeding rates can provide substantial financial savings, but the scale of such savings in the UK is not known. OBJECTIVE: To calculate potential cost savings attributable to increases in breastfeeding rates from the National Health Service perspective. DESIGN AND SETTINGS: Cost savings focussed on where evidence of health benefit is strongest: reductions in gastrointestinal and lower respiratory tract infections, acute otitis media in infants, necrotising enterocolitis in preterm babies and breast cancer (BC) in women. Savings were estimated using a seven-step framework in which an incidence-based disease model determined the number of cases that could have been avoided if breastfeeding rates were increased. Point estimates of cost savings were subject to a deterministic sensitivity analysis. RESULTS: Treating the four acute diseases in children costs the UK at least £89 million annually. The 2009-2010 value of lifetime costs of treating maternal BC is estimated at £959 million. Supporting mothers who are exclusively breast feeding at 1 week to continue breast feeding until 4 months can be expected to reduce the incidence of three childhood infectious diseases and save at least £11 million annually. Doubling the proportion of mothers currently breast feeding for 7-18 months in their lifetime is likely to reduce the incidence of maternal BC and save at least £31 million at 2009-2010 value. CONCLUSIONS: The economic impact of low breastfeeding rates is substantial. Investing in services that support women who want to breast feed for longer is potentially cost saving.

High mobility group box 1 promotes tumor cell migration through epigenetic silencing of semaphorin 3A.

High mobility group box 1 (HMGB1) is a 25-kDa chromatin-associated protein that aids in transcription and DNA repair by directly binding to DNA and altering its conformation. Additionally, HMGB1 can act as an extracellular ligand. When released from dying or stressed cells, HMGB1 binds to the RAGE receptor and activates the p42/44 MAP kinase (MAPK) cascade. HMGB1 is overexpressed in many types of cancer and frequently associated with tumor stage and metastasis. This has predominantly been attributed to an autocrine function that drives MAPK pathway activity. However, by using tumor cells with activating MAPK pathway mutations, we have identified a role for HMGB1 in promoting metastasis and tumor growth that is independent of this pathway. In the absence of HMGB1, these tumor cells show defective in vitro migration as well as reduced metastasis and tumor growth in vivo despite high p42/44 phosphorylation. We found that semaphorin 3A (SEMA3A), previously shown to act as a suppressor of angiogenesis and migration, was highly increased during expression in the absence of HMGB1. SEMA3A/HMGB1 double knockdown rescued the migration defect in HMGB1 single knockdown cells. HMGB1 bound at the semaphorin 3A genomic locus, promoted hetrochromatin formation, and decreased occupancy of acetylated histones. Based on human tumor gene expression databases, HMGB1 was significantly inversely correlated with SEMA3A, suggesting that this mechanism may be more widely relevant in different cancer types.

Promoting growth for preterm infants following hospital discharge.

Preterm infants, especially very preterm infants, are usually growth-restricted at the time of hospital discharge. Proposed interventions to promote catch-up growth following hospital discharge include multinutrient fortification of expressed breast milk for breastfed infants and nutrient-enriched formula milk for formula-fed infants. The current evidence to support these strategies is limited. Fortification of expressed breast milk may increase weight gain and skeletal and head growth during infancy, but more research is needed to define which nutrients confer most benefit, and which population of infants is likely to receive most benefit. Trials that have assessed feeding preterm infants with commercially available nutrient-enriched formula milk ('preterm' or 'postdischarge' formulae) compared with standard formula milk have not found consistent evidence of an effect on growth parameters or development, probably because ad libitum fed infants reduce their intake relative to the calorie-density of the milk. Future studies should focus on the effect of formulae enriched with protein and minerals rather than energy and assess the effect on lean mass and skeletal growth.

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions.

Oncolytic adenoviruses are being investigated as potential anti-cancer agents. Selective lytic replication in cancer cells is essential for an effective and safe treatment. In this study, we compared 11 oncolytic adenoviruses in relevant cell cultures to assess their use for treating oral cancer and pre-cancerous lesions. We determined the cytotoxicity of oncolytic adenovirus infection and calculated selectivity indices for cytotoxicity to cancer cells compared with normal oral keratinocytes and fibroblasts. Keratinocytes were very sensitive to wild-type adenovirus serotype 5 (Ad5); 1- to 3-log more than head and neck squamous cell carcinoma (HNSCC) cells. The potencies of oncolytic adenoviruses to kill HNSCC cells within 7 days after infection ranged from approximately 10 times less potent to approximately 10 times more potent than Ad5. The selectivity indices determined on fibroblasts and keratinocytes differed markedly. Two oncolytic adenoviruses were more selective than Ad5 for HNSCC cells compared with fibroblasts; and five viruses showed selective replication on HNSCC cells compared with keratinocytes. Overall, CRAd-S.RGD with E1A driven by the survivin promoter and an infectivity-enhancing capsid modification showed the most favourable cytotoxicity pattern; being very potent in killing HNSCC cells, only slightly less effective than Ad5 in killing pre-neoplastic keratinocytes and the least toxic to normal keratinocytes.

Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway.

Endometrial cancer is one of the tumor types in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur. It is known to possess mutations frequently in the Ras-PI3K (phosphatidylinositol 3'-kinase) pathway. We performed a comprehensive genomic survey in 31 endometrial carcinomas with paired DNA for chromosomal imbalances (25 by the 50K and 6 by the 250K single-nucleotide polymorphism (SNP) array), and screened 25 of the 31 samples for MSI status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 9 (29%), 1 to 4 changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in 5 (16%) tumors. Positive MSI was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%), and multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN. In addition to eight (26%) tumors with PTEN deletions, we detected chromosomal imbalances of NF1, K-Ras and PIK3CA in four (13%), four (13%) and six (19%) tumors, respectively. In all, 7 of the 9 CIN-extensive tumors harbor deletions in the loci of PTEN and/or NF1, whereas all the 10 MSI-positive tumors possess PTEN, PIK3CA and/or K-Ras mutations. Our results showed that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability, and suggest that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas.

Breastfeeding promotion for infants in neonatal units: a systematic review.

BACKGROUND: Breastfeeding/breastmilk feeding of infants in neonatal units is vital to the preservation of short- and long-term health, but rates are very low in many neonatal units internationally. The aim of this review was to evaluate the effectiveness of clinical, public health and health promotion interventions that may promote or inhibit breastfeeding/breastmilk feeding for infants admitted to neonatal units. METHODS: Systematic review with narrative synthesis. Studies were identified from structured searches of 19 electronic databases from inception to February 2008; hand searching of bibliographies; Advisory Group members helped identify additional sources. INCLUSION CRITERIA: controlled studies of interventions intended to increase breastfeeding/feeding with breastmilk that reported breastmilk feeding outcomes and included infants admitted to neonatal units, their mothers, families and caregivers. Data were extracted and appraised for quality using standard processes. Study selection, data extraction and quality assessment were independently checked. Study heterogeneity prevented meta-analysis. RESULTS: Forty-eight studies were identified, mainly measuring short-term outcomes of single interventions in stable infants. We report here a sub-set of 21 studies addressing interventions tested in at least one good-quality or more than one moderate-quality study. Effective interventions identified included kangaroo skin-to-skin contact, simultaneous milk expression, peer support in hospital and community, multidisciplinary staff training, and Unicef Baby Friendly accreditation of the associated maternity hospital. CONCLUSIONS: Breastfeeding/breastmilk feeding is promoted by close, continuing skin-to-skin contact between mother and infant, effective breastmilk expression, peer support in hospital and community, and staff training. Evidence gaps include health outcomes and costs of intervening with less clinically stable infants, and maternal health and well-being. Effects of public health and policy interventions and the organization of neonatal services remain unclear. Infant feeding in neonatal units should be included in public health surveillance and policy development; relevant definitions are proposed.

Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of interventions that promote or inhibit breastfeeding or feeding with breastmilk for infants admitted to neonatal units, and to identify an agenda for future research. DATA SOURCES: Electronic databases were searched (including MEDLINE and MEDLINE In-Process Citations, EMBASE, CINAHL, Maternity and Infant Care, PsycINFO, British Nursing Index and Archive, Health Management Information Consortium, Cochrane Central Register of Controlled Trials, Science Citation Index, Pascal, Latin American and Caribbean Health Sciences, MetaRegister of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessment Database, National Research Register) from inception to February 2008. Advisors identified further published or unpublished material. REVIEW METHODS: All papers fulfilled eligibility criteria covering participants, interventions, study design and outcomes. Results from primary studies were assessed and summarised in a qualitative synthesis for each type of intervention and across types of intervention. To estimate long-term cost utility, a decision tree was developed to synthesise data on enhanced staff contact, breastmilk effectiveness, incidence of necrotising enterocolitis (NEC) and sepsis, resource use, survival and utilities. RESULTS: Forty-eight studies met the selection criteria for the effectiveness review, of which 65% (31/48) were RCTs, and 17% (8/48) were conducted in the UK. Seven were rated as good quality and 28 as moderate quality. No studies met the selection criteria for the health economics review. There is strong evidence that short periods of kangaroo skin-to-skin contact increased the duration of any breastfeeding for 1 month after discharge [risk ratio (RR) 4.76, 95% confidence interval (CI) 1.19 to 19.10] and for more than 6 weeks (RR 1.95, 95% CI 1.03 to 3.70) among clinically stable infants in industrialised settings. There is strong evidence for the effectiveness of peer support at home (in Manila) for mothers of term, low birthweight infants on any breastfeeding up to 24 weeks (RR 2.18, 95% CI 1.45 to 3.29) and exclusive breastfeeding from birth to 6 months (RR 65.94, 95% CI 4.12 to 1055.70), and for the effectiveness of peer support in hospital and at home for mothers of infants in Special Care Baby Units on providing any breastmilk at 12 weeks [odds ratio (OR) 2.81, 95% CI 1.11 to 7.14; p = 0.01]. There is more limited evidence for the effectiveness of skilled professional support in a US Neonatal Intensive Care Unit on infants receiving any breastmilk at discharge (OR 2.0, 95% CI 1.2 to 3.2, p = 0.004). Multidisciplinary staff training may increase knowledge and can increase initiation rates and duration of breastfeeding, although evidence is limited. Lack of staff training is an important barrier to implementation of effective interventions. Baby Friendly accreditation of the associated maternity hospital results in improvements in several breastfeeding-related outcomes for infants in neonatal units. Limited evidence suggests that cup feeding (versus bottle feeding) may increase breastfeeding at discharge and reduce the frequency of oxygen desaturation. Breastmilk expression using simultaneous pumping with an electric pump has advantages in the first 2 weeks. Pharmaceutical galactagogues have little benefit among mothers who have recently given birth. Our economic analysis found that additional skilled professional support in hospital was more effective and less costly (due to reduced neonatal illness) than normal staff contact. Additional support ranged from 0.009 quality-adjusted life-years (QALYs) to 0.251 QALYs more beneficial per infant and ranged from 66 pounds to 586 pounds cheaper per infant across the birthweight subpopulations. Donor milk would become cost-effective given improved mechanisms for its provision. CONCLUSIONS: Despite the limitations of the evidence base, kangaroo skin-to-skin contact, peer support, simultaneous breastmilk pumping, multidisciplinary staff training and the Baby Friendly accreditation of the associated maternity hospital have been shown to be effective, and skilled support from trained staff in hospital has been shown to be potentially cost-effective. All these point to future research priorities. Many of these interventions inter-relate: it is unlikely that specific clinical interventions will be effective if used alone. There is a need for national surveillance of feeding, health and cost outcomes for infants and mothers in neonatal units; to assist this goal, we propose consensus definitions of the initiation and duration of breastfeeding/breastmilk feeding with specific reference to infants admitted to neonatal units and their mothers.

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines.

Nutlin-3 is a selective inhibitor of the p53-Mdm2 interaction, and inhibits growth in most tumor cells with wild-type p53. However, it only induces apoptosis in subsets of tumor cells. We report that the apoptotic response induced by Nutlin-3 correlates with its antitumor effects in xenograft models in athymic mice. We have investigated signals that sensitize cells to undergo apoptosis induced by Nutlin-3. We demonstrate that adenovirus E1A increases Nutlin-3-induced apoptosis through pRb inhibition in mouse embryonic fibroblast cells in a p53-dependent manner. Consistent with this, pRb depletion by siRNA transfection with Nutlin-3 synergistically increases apoptosis in HCT116 human colon cancer cells, which are insensitive to induction of apoptosis by Nutlin-3 alone. As pRb is a key negative regulator of E2F, we asked whether E2F transcriptional activity determines the apoptotic response of cancer cells to Nutlin-3. We demonstrate that transcriptional activity of E2F correlates with the apoptotic response to Nutlin-3 in various tumor cells and depletion of E2F-1 suppresses Nutlin-3-induced apoptosis in cells possessing high transcriptional activity of E2F, including retinoblastoma cells harboring mutated Rb with wild-type p53. Furthermore, we report that expression of the p53 homologue p73, a target of E2F-1, is markedly increased by Nutlin-3 in Rb-mutated tumor cells harboring wild-type p53. Depletion of p73 by siRNA transfection suppresses Nutlin-3-induced apoptosis in these cells. Taken together, our results demonstrate that E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis and p73 is important for E2F-1-mediated apoptosis induced by Nutlin-3, especially in tumor cells with mutated Rb. Furthermore, our results suggest that tumor cells, including Rb mutated cells, which harbor wild-type p53 and high E2F transcriptional activity, could be a good target for Mdm2 antagonist therapy.

Polycystic kidneys: a cautionary story.

We describe the imaging appearances of a patient with bilateral, synchronous, multiloculated renal cell carcinoma with a predominantly cystic nature. The patient had progressive chronic renal failure. He was initially erroneously diagnosed as having autosomal dominant polycystic kidney disease (ADPKD) on the basis of the imaging findings. We believe this to be the first report describing bilateral synchronous renal carcinomas replacing the renal parenchyma imitating ADPKD.

Rethinking research in breast-feeding: a critique of the evidence base identified in a systematic review of interventions to promote and support breast-feeding.

OBJECTIVE: To appraise critically the relevance and value of the evidence base to promote and support the duration of breast-feeding, with a specific focus on disadvantaged groups. DESIGN: A systematic review was conducted of intervention studies relevant to enhancing the duration of breast-feeding; topics included public health, public policy, clinical issues, and education, training and practice change. A systematic search was conducted. Eighty studies met the inclusion criteria. Data were systematically extracted and analysed. Full results and recommendations are reported elsewhere. Here a critique of the evidence base--topics, quality and gaps--is reported. RESULTS: Many studies were substantially methodologically flawed, with problems including small sample sizes, inconsistent definitions of breast-feeding and lack of appropriate outcomes. Few were based on relevant theory. Only a small number of included studies (10%) were conducted in the UK. Very few targeted disadvantaged subgroups of women. No studies of policy initiatives or of community interventions were identified. There were virtually no robust studies of interventions to prevent and treat common clinical problems, or of strategies related to women's health issues. Studies of health professional education and practice change were limited. Cost-effectiveness studies were rare. CONCLUSIONS: Policy goals both in the UK and internationally support exclusive breast-feeding until 6 months of age. The evidence base to enable women to continue to breast-feed needs to be strengthened to include robust evaluations of policies and practices related to breast-feeding; a step change is needed in the quality and quantity of research funded.

Support for breastfeeding mothers.

BACKGROUND: There is extensive evidence of the benefits of breastfeeding for infants and mothers. In 2003, the World Health Organization (WHO) recommended infants be fed exclusively on breast milk until six months of age. However, breastfeeding rates in many developed countries continue to be resistant to change. OBJECTIVES: To assess the effectiveness of support for breastfeeding mothers. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 2006), MEDLINE (1966 to November 2005), EMBASE (1974 to November 2005) and MIDIRS (1991 to September 2005). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing extra support for breastfeeding mothers with usual maternity care. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: We have included 34 trials (29,385 mother-infant pairs) from 14 countries. All forms of extra support analysed together showed an increase in duration of 'any breastfeeding' (includes partial and exclusive breastfeeding) (relative risk (RR) for stopping any breastfeeding before six months 0.91, 95% confidence interval (CI) 0.86 to 0.96). All forms of extra support together had a larger effect on duration of exclusive breastfeeding than on any breastfeeding (RR 0.81, 95% CI 0.74 to 0.89). Lay and professional support together extended duration of any breastfeeding significantly (RR before 4-6 weeks 0.65, 95% 0.51 to 0.82; RR before 2 months 0.74, 95% CI 0.66 to 0.83). Exclusive breastfeeding was significantly prolonged with use of WHO/UNICEF training (RR 0.69, 95% CI 0.52 to 0.91). Maternal satisfaction was poorly reported. AUTHORS' CONCLUSIONS: Additional professional support was effective in prolonging any breastfeeding, but its effects on exclusive breastfeeding were less clear. WHO/UNICEF training courses appeared to be effective for professional training. Additional lay support was effective in prolonging exclusive breastfeeding, while its effects on duration of any breastfeeding were uncertain. Effective support offered by professionals and lay people together was specific to breastfeeding and was offered to women who had decided to breastfeed. Further trials are required to assess the effectiveness (including cost-effectiveness) of both lay and professional support in different settings, particularly those with low rates of breastfeeding initiation, and for women who wish to breastfeed for longer than three months. Trials should consider timing and delivery of support interventions and relative effectiveness of intervention components, and should report women's views. Research into appropriate training for supporters (whether lay or professional) of breastfeeding mothers is also needed.