Development and validation of a prognostic model for death 30 days after adult emergency laparotomy

The probability of death after emergency laparotomy varies greatly between patients. Accurate pre-operative risk prediction is fundamental to planning care and improving outcomes. We aimed to develop a model limited to a few pre-operative factors that performed well irrespective of surgical indication: obstruction; sepsis; ischaemia; bleeding; and other. We derived a model with data from the National Emergency Laparotomy Audit for patients who had emergency laparotomy between December 2016 and November 2018. We tested the model on patients who underwent emergency laparotomy between December 2018 and November 2019. There were 4077/40,816 (10%) deaths 30 days after surgery in the derivation cohort. The final model had 13 pre-operative variables: surgical indication; age; blood pressure; heart rate; respiratory history; urgency; biochemical markers; anticipated malignancy; anticipated peritoneal soiling; and ASA physical status. The predicted mortality probability deciles ranged from 0.1% to 47%. There were 1888/11,187 deaths in the test cohort. The scaled Brier score, integrated calibration index and concordance for the model were 20%, 0.006 and 0.86, respectively. Model metrics were similar for the five surgical indications. In conclusion, we think that this prognostic model is suitable to support decision-making before emergency laparotomy as well as for risk adjustment for comparing organisations

Preterm Birth in Caucasians Is Associated with Coagulation and Inflammation Pathway Gene Variants

Spontaneous preterm birth (<37 weeks gestation—PTB) occurs in ∼12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30×10−3) and genotypic association (p = 2.0×10−6) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77–4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00×10−3). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34×10−4). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15–3.19] (p = 2.00×10−3). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p<0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB

Leprosy in a patient infected with HIV

A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex

Socioeconomic deprivation and mortality after emergency laparotomy: an observational epidemiological study

Background: Socioeconomic circumstances can influence access to healthcare, the standard of care provided, and a variety of outcomes. This study aimed to determine the association between crude and risk-adjusted 30-day mortality and socioeconomic group after emergency laparotomy, measure differences in meeting relevant perioperative standards of care, and investigate whether variation in hospital structure or process could explain any difference in mortality between socioeconomic groups. / Methods: This was an observational study of 58 790 patients, with data prospectively collected for the National Emergency Laparotomy Audit in 178 National Health Service hospitals in England between December 1, 2013 and November 31, 2016, linked with national administrative databases. The socioeconomic group was determined according to the Index of Multiple Deprivation quintile of each patient's usual place of residence. / Results: Overall, the crude 30-day mortality was 10.3%, with differences between the most-deprived (11.2%) and least-deprived (9.8%) quintiles (P<0.001). The more-deprived patients were more likely to have multiple comorbidities, were more acutely unwell at the time of surgery, and required a more-urgent surgery. After risk adjustment, the patients in the most-deprived quintile were at significantly higher risk of death compared with all other quintiles (adjusted odds ratio [95% confidence interval]: Q1 [most deprived]: reference; Q2: 0.83 [0.76–0.92]; Q3: 0.84 [0.76–0.92]; Q4: 0.87 [0.79–0.96]; Q5 [least deprived]: 0.77 [0.70–0.86]). We found no evidence that differences in hospital-level structure or patient-level performance in standards of care explained this association. / Conclusions: More-deprived patients have higher crude and risk-adjusted 30-day mortality after emergency laparotomy, but this is not explained by differences in the standards of care recorded within the National Emergency Laparotomy Audit

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

Do 'good values' lead to 'good' health-behaviours? Longitudinal associations between young people's values and later substance-use

&lt;p&gt;Background: Past studies have linked certain values (traditional vs. individualistic) with adolescent substance-use. The aims of this study are to replicate cross-sectional research linking values and adolescent substance-use and to determine if such values predict future substance-use.&lt;/p&gt; &lt;p&gt;Methods: A longitudinal school-based survey of 2196 young people (age 15) followed up in early adulthood (age 18/19). Participants provided data about their beliefs and values at age 15, and their substance-use (smoking, alcohol and drug-use) at ages 15 and 18/19. In addition data were collected about their social background (gender, risk-taking, deprivation, religion, etc).&lt;/p&gt; &lt;p&gt;Results: Cross-sectionally, young people with anti-authority values were more likely to use various substances, e.g. 17-67% more likely to regularly smoke (daily), drink (most days), or use drugs (weekly) for each SD above typical levels. Adjusting for social background, associations were not substantially attenuated. However in the prospective analysis, adjusting for both background and substance-use at age 15, only two (anti-authoritarian and work ethic) values were (marginally) associated with substance-use at age 18/19.&lt;/p&gt; &lt;p&gt;Conclusions: While we replicated results found in prior cross-sectional studies, evidence from this study does not support the argument that holding certain 'pro-social' or 'good' values substantively protects against later substance-use and challenges the likely effectiveness of values-based interventions in relation to later substance-use.&lt;/p&gt

An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer

<p>Abstract</p> <p>Background</p> <p>Genomics has substantially changed our approach to cancer research. Gene expression profiling, for example, has been utilized to delineate subtypes of cancer, and facilitated derivation of predictive and prognostic signatures. The emergence of technologies for the high resolution and genome-wide description of genetic and epigenetic features has enabled the identification of a multitude of causal DNA events in tumors. This has afforded the potential for large scale integration of genome and transcriptome data generated from a variety of technology platforms to acquire a better understanding of cancer.</p> <p>Results</p> <p>Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD) analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations.</p> <p>Conclusions</p> <p>Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.</p

Short Lag Times for Invasive Tropical Plants: Evidence from Experimental Plantings in Hawai'i

Background: The lag time of an invasion is the delay between arrival of an introduced species and its successful spread in a new area. To date, most estimates of lag times for plants have been indirect or anecdotal, and these estimates suggest that plant invasions are often characterized by lag times of 50 years or more. No general estimates are available of lag times for tropical plant invasions. Historical plantings and documentation were used to directly estimate lag times for tropical plant invasions in Hawai’i. Methodology/Principal Findings: Historical planting records for the Lyon Arboretum dating back to 1920 were examined to identify plants that have since become invasive pests in the Hawaiian Islands. Annual reports describing escape from plantings were then used to determine the lag times between initial plantings and earliest recorded spread of the successful invaders. Among 23 species that eventually became invasive pests, the average lag time between introduction and first evidence of spread was 14 years for woody plants and 5 years for herbaceous plants. Conclusions/Significance: These direct estimates of lag times are as much as an order of magnitude shorter than previous, indirect estimates, which were mainly based on temperate plants. Tropical invaders may have much shorter lag times than temperate species. A lack of direct and deliberate observations may have also inflated many previous lag time estimates. Although there have been documented cases of long lag times due to delayed arrival of a mutualist or environmenta