Early-Life Adversity Due to Bereavement and Inflammatory Diseases in the Next Generation: A Population Study in Transgenerational Stress Exposure

Emerging evidence suggests that trauma experienced in childhood has negative transgenerational implications for offspring mental and physical health. We aimed to investigate whether early-life adversity experienced as bereavement is associated with chronic inflammatory health in offspring. The study population included 3 generations of Swedish families with a base population of 453,516 children (generation 3) born in 2001-2012. Exposure was defined as the middle generation's (generation 2) experiencing bereavement in childhood due to the death of a parent (generation 1). Outcomes in generation 3 included 2 diagnoses of inflammatory diseases, including asthma, allergic diseases, eczema, and autoimmune diseases. Survival analysis was used to identify causal pathways, including investigation of mediation by generation 2 mood disorders and socioeconomic status (SES). We found that early-life bereavement experienced by women was associated with early-onset offspring asthma (hazard ratio = 1.15, 95% confidence interval: 1.08, 1.23); mediation analysis revealed that 28%-33% of the association may be mediated by SES and 9%-20% by mood disorders. Early-life bereavement experienced by men was associated with autoimmune diseases in offspring (hazard ratio = 1.31, 95% confidence interval: 1.06, 1.62), with no evidence of mediation. In conclusion, adversity experienced early in life may contribute to an increased risk of inflammatory diseases which is partly mediated by mood disorders and SES

NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials

BACKGROUND HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. METHODS Data from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. RESULTS Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. CONCLUSIONS A single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated. TRIAL REGISTRATION C107 = NCT00064623; C119 = NCT00321672

Is increased hepatitis C virus case-finding combined with current or 8-week to 12-week direct-acting antiviral therapy cost-effective in UK prisons? A prevention benefit analysis

UNLABELLED: Prisoners have a high prevalence of hepatitis C virus (HCV), but case-finding may not have been cost-effective because treatment often exceeded average prison stay combined with a lack of continuity of care. We assessed the cost-effectiveness of increased HCV case-finding and treatment in UK prisons using short-course therapies. A dynamic HCV transmission model assesses the cost-effectiveness of doubling HCV case-finding (achieved through introducing opt-out HCV testing in UK pilot prisons) and increasing treatment in UK prisons compared to status quo voluntary risk-based testing (6% prison entrants/year), using currently recommended therapies (8-24 weeks) or interferon (IFN)-free direct-acting antivirals (DAAs; 8-12 weeks, 95% sustained virological response, £3300/week). Costs (British pounds, £) and health utilities (quality-adjusted life years) were used to calculate mean incremental cost-effectiveness ratios (ICERs). We assumed 56% referral and 2.5%/25% of referred people who inject drugs (PWID)/ex-PWID treated within 2 months of diagnosis in prison. PWID and ex-PWID or non-PWID are in prison an average 4 and 8 months, respectively. Doubling prison testing rates with existing treatments produces a mean ICER of £19,850/quality-adjusted life years gained compared to current testing/treatment and is 45% likely to be cost-effective under a £20,000 willingness-to-pay threshold. Switching to 8-week to 12-week IFN-free DAAs in prisons could increase cost-effectiveness (ICER £15,090/quality-adjusted life years gained). Excluding prevention benefit decreases cost-effectiveness. If >10% referred PWID are treated in prison (2.5% base case), either treatment could be highly cost-effective (ICER<£13,000). HCV case-finding and IFN-free DAAs could be highly cost-effective if DAA cost is 10% lower or with 8 weeks' duration. CONCLUSIONS: Increased HCV testing in UK prisons (such as through opt-out testing) is borderline cost-effective compared to status quo voluntary risk-based testing under a £20,000 willingness to pay with current treatments but likely to be cost-effective if short-course IFN-free DAAs are used and could be highly cost-effective if PWID treatment rates were increased. (Hepatology 2016;63:1796-1808)

Three steps to data quality

The quality of data in general practice clinical information systems varies enormously. This variability jeopardizes the proposed national strategy for an integrated care records service and the capacity of primary care organisations to respond coherently to the demands of clinical governance and the proposed quality-based general practice contract. This is apparent in the difficulty in automating the audit process and in comparing aggregated data from different practices. In an attempt to provide data of adequate quality to support such operational needs, increasing emphasis is being placed on the standardisation of data recording

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10^{-8}; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits

Research productivity and academics’ conceptions of research

This paper asks the question: do people with different levels of research productivity and identification as a researcher think of research differently? It discusses a study that differentiated levels of research productivity among English and Australian academics working in research-intensive environments in three broad discipline areas: science, engineering and technology; social science and humanities; and medicine and health sciences. The paper explores the different conceptions of research held by these academics in terms of their levels of research productivity, their levels of research training, whether they considered themselves an active researcher and a member of a research team, and their disciplinary differences

The Public Perception of Corporate Social Responsibility and Its Effects on Customer Behaviour in China

Abstract With the rapid economic development of China, many enterprises have developed rapidly with the growing scale and strength, and their products and services have had a profound impact on the society. However, the study finds that many enterprises are merely spectators toward corporate social responsibility (CSR); these enterprises do not play an active role in CSR. At present, the domestic and foreign scholars&apos; researches on CSR are focused on motivation, influence factors and its influence on enterprise performance, but less attention has been given to the public perception of CSR and its different effects on customer behavior from the demographic range. This paper is based on a questionnaire of public perception in CSR, advancing with the times to consider the current status of the public&apos;s perception of CSR in China, at the same time, it investigates the public&apos;s attention to the dimensions of CSR at present, and particularly analyzes the perception of CSR and its different effects on customer behaviour in the demographic indicators

An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial)

BACKGROUND: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. OBJECTIVE: To compare TARGIT within a risk-adapted approach with whole breast external beam radiotherapy over several weeks (EBRT). DESIGN AND SETTING: The TARGIT-A trial was a pragmatic, prospective, international, multicenter, non-inferiority, non-blinded, randomised (1:1 ratio), clinical trial from 33 centres in 11 countries. Originally, randomisation occurred before initial lumpectomy (prepathology) and if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added, in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but needed a reoperation to reopen the wound to give TARGIT as delayed procedure. Risk-adapted approach meant that in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, then EBRT was recommended. Pragmatically, this reflected how TARGIT would be practiced in the real world. PARTICIPANTS: Women who were >=45 years of age with unifocal invasive ductal carcinoma preferably <= 3.5cm in size; 3451 patients were recruited between March 2000 and June 2012. OUTCOMES: Primary: absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary: included toxicity, breast cancer specific and non-breast-cancer mortality. RESULTS: Values below are 5-year Kaplan-Meier rates for TARGIT vs. EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall (3·3%(2·1–5·1) vs. 1·3%(0·7–2·5),p=0.04,Pnoninferiority =0.00000012) and in the prepathology stratum(n=2298) when TARGIT was given concurrently with lumpectomy(2·1%(1·1–4·2) vs. 1·1%(0·5–2·5),p=0.31,Pnoninferiority =0.0000000013). With delayed TARGIT postpathology,(n=1153) the between-group difference was larger than 2·5% and non-inferiority was not established for this stratum((5·4%(3·0–9·7) vs. 1·7%(0·6–4·9),p=0.069,Pnoninferiority= 0.06640). The local-recurrence-free survival when TARGIT was given with lumpectomy was 93.9%(95%CI 90.9 – 95.9) vs. EBRT: 92.5%(95%CI 89.7 – 94.6),p=0.35. In a planned subgroup analysis, progesterone (PgR) receptor status was found to be the only predictor of outcome - hormone responsive patients (PgRpositive) had similar 5-year local recurrence with TARGIT during lumpectomy 1.4%(0.5-3.9) vs. EBRT 1.2%(0.5-2.9),p=0.77. Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (2·6%[1·5–4·3] vs. 1·9%[1·1–3·2];p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5%[2·3–5·2];p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm 37 deaths, 3·9%(2·7–5·8) vs. 51 deaths, 5·3%(3·9–7·3),p=0.099). Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar QALYs, had a positive incremental Net Monetary Benefit that was borderline statistically significant from zero, and had a probability of over 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health care providers by £8 million to £9.1 million each year. This does not include environmental, patient and societal costs. LIMITATIONS: The number of local recurrences is small however, the number of events for local-recurrence-free survival is not small (59 vs. 61); Occurrence of only a few events implies that the treatments are effective and any difference is unlikely to be large. The follow up not all 3451 patients is 5 years, although the number required to answer the main trial question (n=585) have more than 5 years follow up. FUTURE WORK: We shall repeat the analyses with longer follow up. Although this may not change the primary result, the larger number of events may confirm the effect on mortality and allow more detailed subgroup analyses. The TARGIT-B trial is testing whether TARGIT-Boost is superior to EBRT boost. CONCLUSION: For patients with breast cancer (women who are 45 years of age and older with hormone sensitive invasive ductal carcinoma that is up to 3.5cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective, safer and less expensive alternative to postoperative EBRT. TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov NCT00983684

Cross-sectional study of a UK cohort of neonatal vein of Galen malformation

Objective: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation (VGM) identified before 28 days of life. // Methods: Neonates with angiographically confirmed vein of Galen malformation presenting to one of the two UK treatment centres (2006‐2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomised into “good” and “poor” categories. Cross‐sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. // Results: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty‐four participated in neurocognitive assessment. Outcomes were approximately evenly split between “good” and “poor” categories across all domains, namely neurological status, general cognition, neuromotor skills, adaptive behaviour, and emotional and behavioural development. Important predictors of poor cognitive outcome were initial Bicetre score </=12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariable analysis only Bicetre score </=12 remained significant. // Interpretation: Despite modern supportive and endovascular treatment, over a third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous, as well as arterial, circulation are important in pathophysiology of brain injury

The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients

AIM: We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung metastases are or are not resected. METHODS: Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible patients were invited to consent for randomization in the PulMiCC randomized controlled trial (Stage 2). Sites were provided with case report forms for non-randomized patients to record adverse events and death at any time. They were all reviewed at 1 year. Baseline and survival data were analysed for the full cohort. RESULTS: Twenty-five clinical sites recruited 512 patients from October 2010 to January 2017. Data collection closed in October 2020. Before analysis, 28 patients with non-CRC lung lesions were excluded and three had withdrawn consent leaving 481. The date of death was known for 292 patients, 136 were alive in 2020 and 53 at earlier time points. Baseline factors and 5-year survival were analysed in three strata: 128 non-randomized patients did not have metastasectomy; 263 had elective metastasectomy; 90 were from the randomized trial. The proportions of solitary metastases for electively operated and non-operated patients were 69% and 35%. Their respective 5-year survivals were 47% and 22%. CONCLUSION: Survival without metastasectomy was greater than widely presumed. Difference in survival appeared to be largely related to selection. No inference can be drawn about the effect of metastasectomy on survival in this observational study