Worse histopathology and prognosis in women with breast cancer diagnosed during the second trimester of pregnancy.

BACKGROUND: Evidence suggests that women with breast cancer diagnosed during pregnancy (PrBC) and within 2 years of delivery (PPBC) have similar survival compared to women diagnosed not near pregnancy if adjusted for stage and subtype. To investigate whether this is true for all subtypes and for both pregnancy and post-delivery periods, we examined clinicopathologic features and survival in women with breast cancer by trimesters and 6-month post-delivery intervals. MATERIALS AND METHODS: Women diagnosed with invasive breast cancer during 1992-2018 at ages 18-44 years were identified in the Swedish Cancer Register, with information on childbirths from the Swedish Multi-Generation Register and clinical data from Breast Cancer Quality Registers. Each woman with PrBC or PPBC was matched 1 : 2 by age and year to comparators diagnosed with breast cancer not near pregnancy. Distributions of stage, grade, and surrogate subtypes were compared. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer mortality were estimated using Cox regression. RESULTS: We identified 1430 women with PrBC and PPBC (181 during pregnancy, 499 during the first and 750 during the second year after delivery). Compared to 2860 comparators, women with PrBC and PPBC in the first year after delivery had a significantly higher proportion of luminal human epidermal growth factor receptor 2 (HER2)-positive, HER2-positive and triple-negative tumours, and more advanced stage at diagnosis. After adjustment for age, year, parity, country of birth, hospital region, subtype, and stage, women diagnosed during the second trimester had a worse prognosis than matched comparators (HR 1.8, 95% CI: 1.0-3.2). CONCLUSIONS: Women diagnosed during pregnancy or within the first year after delivery have a worse prognosis than women diagnosed not near pregnancy due to adverse tumour biology and advanced stage at diagnosis. A worse prognosis for women diagnosed during the second trimester remained after multivariable adjustment, possibly reflecting difficulties to provide optimal treatment during ongoing pregnancy.

Estimating the impact of stimulant use on initiation of buprenorphine and extended-release naltrexone in two clinical trials and real-world populations.

BACKGROUND: Co-use of stimulants and opioids is rapidly increasing. Randomized clinical trials (RCTs) have established the efficacy of medications for opioid use disorder (MOUD), but stimulant use may decrease the likelihood of initiating MOUD treatment. Furthermore, trial participants may not represent "real-world" populations who would benefit from treatment. METHODS: We conducted a two-stage analysis. First, associations between stimulant use (time-varying urine drug screens for cocaine, methamphetamine, or amphetamines) and initiation of buprenorphine or extended-release naltrexone (XR-NTX) were estimated across two RCTs (CTN-0051 X:BOT and CTN-0067 CHOICES) using adjusted Cox regression models. Second, results were generalized to three target populations who would benefit from MOUD: Housed adults identifying the need for OUD treatment, as characterized by the National Survey on Drug Use and Health (NSDUH); adults entering OUD treatment, as characterized by Treatment Episodes Dataset (TEDS); and adults living in rural regions of the U.S. with high rates of injection drug use, as characterized by the Rural Opioids Initiative (ROI). Generalizability analyses adjusted for differences in demographic characteristics, substance use, housing status, and depression between RCT and target populations using inverse probability of selection weighting. RESULTS: Analyses included 673 clinical trial participants, 139 NSDUH respondents (weighted to represent 661,650 people), 71,751 TEDS treatment episodes, and 1,933 ROI participants. The majority were aged 30-49 years, male, and non-Hispanic White. In RCTs, stimulant use reduced the likelihood of MOUD initiation by 32% (adjusted HR [aHR] = 0.68, 95% CI 0.49-0.94, p = 0.019). Stimulant use associations were slightly attenuated and non-significant among housed adults needing treatment (25% reduction, aHR = 0.75, 0.48-1.18, p = 0.215) and adults entering OUD treatment (28% reduction, aHR = 0.72, 0.51-1.01, p = 0.061). The association was more pronounced, but still non-significant among rural people injecting drugs (39% reduction, aHR = 0.61, 0.35-1.06, p = 0.081). Stimulant use had a larger negative impact on XR-NTX initiation compared to buprenorphine, especially in the rural population (76% reduction, aHR = 0.24, 0.08-0.69, p = 0.008). CONCLUSIONS: Stimulant use is a barrier to buprenorphine or XR-NTX initiation in clinical trials and real-world populations that would benefit from OUD treatment. Interventions to address stimulant use among patients with OUD are urgently needed, especially among rural people injecting drugs, who already suffer from limited access to MOUD.

Accelerated DNA methylation age in adolescent girls: associations with elevated diurnal cortisol and reduced hippocampal volume.

Numerous studies have linked exposure to stress to adverse health outcomes through the effects of cortisol, a product of the stress response system, on cellular aging processes. Accelerated DNA methylation age is a promising epigenetic marker associated with stress and disease risk that may constitute a link from stress response to changes in neural structures. Specifically, elevated glucocorticoid signaling likely contributes to accelerating DNA methylation age, which may signify a maladaptive stress-related cascade that leads to hippocampal atrophy. We examined the relations among diurnal cortisol levels, DNA methylation age and hippocampal volume in a longitudinal study of 46 adolescent girls. We computed area under the curve from two daily cortisol collection periods, and calculated DNA methylation age using previously established methods based on a set of CpG sites associated with chronological age. We computed a residual score by partialling out chronological age; higher discrepancies reflect relatively accelerated DNA methylation age. We assessed hippocampal volume via T1-weighted images and automated volumetric segmentation. We found that greater diurnal cortisol production was associated with accelerated DNA methylation age, which in turn was associated with reduced left hippocampal volume. Finally, accelerated DNA methylation age significantly mediated the association between diurnal cortisol and left hippocampal volume. Thus, accelerated DNA methylation age may be an epigenetic marker linking hypothalamic-pituitary-adrenal axis dysregulation with neural structure. If these findings are replicated, the current study provides a method for advancing our understanding of mechanisms by which glucocorticoid signaling is associated with cellular aging and brain development.

'Don't forget the children' - test before it is too late.

In 2009, 'Don't forget the children' guideline recommended that all new HIV-positive patients attending adult HIV services should have any existing children identified and tested for HIV alongside a coherent documentation process. A retrospective case note review was performed on 173 HIV-positive women registered at the Royal South Hants adult HIV service until 31 January 2014. Data were assessed as a whole (n = 173) and, in addition, two comparator groups were formulated: (a) pre-guidelines (n = 108) and (b) post-guidelines (n = 65). Out of 80 children eligible for HIV testing, only 43 (54%) had clear documentation of a test result, and in the remaining 37 (46%), it was either not considered or not followed through. Documentation of need for testing increased significantly from 67% in pre-guideline group to 100% in the post-guideline group (p < 0.001). The median time from recognition of need to test to actual testing remained 24 months in both groups. Although this audit demonstrated improvement in identification of at-risk children and their testing, there is still need for improvement.

A trans-diagnostic review of anxiety disorder comorbidity and the impact of multiple exclusion criteria on studying clinical outcomes in anxiety disorders.

Anxiety disorders are highly comorbid with each other and with other serious mental disorders. As our field progresses, we have the opportunity to pursue treatment study designs that consider these comorbidities. In this perspective review, we first characterized the prevalence of multiple anxiety disorder comorbidity by reanalyzing national survey data, then conducted an English-language PubMed search of studies analyzing the impact of exclusion criteria on treatment outcome data. In the prevalence data, 60% of people with an anxiety disorder had one or more additional anxiety or depression diagnosis. Because our commonly applied exclusion criteria focus on a single diagnosis and do not consider a multiple comorbidity profile, the impact of the criteria may be to exclude up to 92% of anxiety disorder treatment seekers. Moreover, the findings do not suggest a consistent relationship between the number of exclusion criteria and the effect size of treatment outcomes. Thus, future studies might consider a more trans-diagnostic rationale for determining exclusion criteria, one that is generalizable to real-world settings in which multiple diagnoses commonly co-occur. The findings also encourage a more systematic reporting of rationales for the choice of-and the implications of-each exclusion criterion.

Comparison of fully and semi-automated area-based methods for measuring mammographic density and predicting breast cancer risk.

BACKGROUND: Mammographic density is a strong risk factor for breast cancer but the lack of valid fully automated methods for quantifying it has precluded its use in clinical and screening settings. We compared the performance of a recently developed automated approach, based on the public domain ImageJ programme, to the well-established semi-automated Cumulus method. METHODS: We undertook a case-control study within the intervention arm of the Age Trial, in which ∼54,000 British women were offered annual mammography at ages 40-49 years. A total of 299 breast cancer cases diagnosed during follow-up and 422 matched (on screening centre, date of birth and dates of screenings) controls were included. Medio-lateral oblique (MLO) images taken closest to age 41 and at least one year before the index case's diagnosis were digitised for each participant. Cumulus readings were performed in the left MLO and ImageJ-based readings in both left and right MLOs. Conditional logistic regression was used to examine density-breast cancer associations. RESULTS: The association between density readings taken from one single MLO and breast cancer risk was weaker for the ImageJ-based method than for Cumulus (age-body mass index-adjusted odds ratio (OR) per one s.d. increase in percent density (95% CI): 1.52 (1.24-1.86) and 1.61 (1.33-1.94), respectively). The ImageJ-based density-cancer association strengthened when the mean of left-right MLO readings was used: OR=1.61 (1.31-1.98). CONCLUSIONS: The mean of left-right MLO readings yielded by the ImageJ-based method was as strong a predictor of risk as Cumulus readings from a single MLO image. The ImageJ-based method, using the mean of two measurements, is a valid automated alternative to Cumulus for measuring density in analogue films.

Reduced nucleus accumbens reactivity and adolescent depression following early-life stress.

Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention.

Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival.

We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5' end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5' end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer.

Three microsatellites from the T1DGC MHC data set show highly significant association with type 1 diabetes, independent of the HLA-DRB1, -DQA1 and -DQB1 genes.

AIM: The aim of this study was to test the microsatellites in the Type 1 Diabetes Genetics Consortium major histocompatibility complex (MHC) data set for association with type 1 diabetes (T1D) independent of the HLA-DRB1, -DQA1 and -DQB1 genes. METHODS: The data set was edited to contain only one affected child per family, and broad ethnic subgroups were defined. Genotypes for HLA-DRB1, -DQA1 and -DQB1 were replaced by a haplotype code spanning all three loci, with phase inferred based on common haplotypes. The final data set contained 8190 samples in 2301 families, 59 microsatellites and the DRB1-DQA1-DQB1 haplotype code. Statistical analyses consisted of conditional logistic regression and haplotype estimations and linkage disequilibrium calculations. RESULTS: The data set was screened using a main effects test approach adjusted for DRB1-DQA1-DQB1, and significant results tested for validity. After these procedures, four markers remained significant at the Bonferroni-corrected threshold: D6S2773 (p = 0.00014), DG6S185 (p = 0.00015), DG6S398 (p = 0.00043) and D6S2998 (p = 0.00015). These results were supported by allelic tests conditioned on DRB1-DQA1-DQB1 haplotypes, except for DG6S185, which may contain artefacts. CONCLUSIONS: We have identified three microsatellites that mark additional risk factors for T1D at highly significant levels in the MHC. Further analyses are needed to establish the relationship with other possible genetic determinants in this region.

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B.

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

Influence of bioengineered skin substitutes on diabetic foot ulcer and venous leg ulcer outcomes.

This systematic review indicates that bioengineered skin substitutes with a dermal component may improve healing outcomes in diabetic foot ulcers and venous leg ulcers. However, better designed trials with longer follow-up periods are needed.

Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men.

OBJECTIVE: Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects. SUBJECTS AND METHODS: Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m(-2)), 199 obese subjects with normal glucose tolerance (NGT, BMI> or =30 kg m(-2)) and 188 control subjects (NGT, BMI< or =26 kg m(-2)), were genotyped. RESULTS: A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMI> or =30 kg m(-2) (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI<30 kg m(-2) (P=0.051 and 0.084) and disappeared in T2D patients with BMI< or =26 kg m(-2). Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects. CONCLUSIONS: The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

Post traumatic intra-abdominal pseudo-aneurysms in children.

Pseudoaneurysms are uncommon following blunt abdominal trauma. A review of the literature has shown that such cases are usually managed aggressively. We report our experience of two cases of post traumatic intra-abdominal pseudoaneurysms which were managed conservatively.

Assessing the welfare of genetically altered mice.

In 2003, under the auspices of the main UK funders of biological and biomedical research, a working group was established with a remit to review potential welfare issues for genetically altered (GA) mice, to summarize current practice, and to recommend contemporary best practice for welfare assessments. The working group has produced a report which makes practical recommendations for GA mouse welfare assessment and dissemination of welfare information between establishments using a 'mouse passport'. The report can be found at www.nc3rs.org.uk/GAmice and www.lal.org.uk/gaa and includes templates for the recommended welfare assessment scheme and the mouse passport. An overview is provided below.

A CMOS Camera-Based Pulse Oximetry Imaging System.

In this paper a CMOS camera-based system for non-contact pulse oximetry imaging in transmission mode is described. Attention is drawn to the current uses of conventional pulse oximetry and the potential application of pulse oximetry imaging to developing objective wound assessment systems.

Gene expression profiling for prognosis using Cox regression.

Given the promise of rich biological information in microarray data we will expect an increasing demand for a robust, practical and well-tested methodology to provide patient prognosis based on gene expression data. In standard settings, with few clinical predictors, such a methodology has been provided by the Cox proportional hazard model, but no corresponding methodology is available to deal with the full set of genes in microarray data. Furthermore, we want the procedure to be able to deal with the general survival data that include censored information. Conceptually such a procedure can be constructed quite easily, but its implementation will never be straightforward due to computational problems. We have developed an approach that relies on an extension of the Cox proportional likelihood that allows random effects parameters. In this approach, we use the full set of genes in the analysis and deal with survival data in the most general way. We describe the development of the model and the steps in the implementation, including a fast computational formula based on a subsampling of the risk set and the singular value decomposition. Finally, we illustrate the methodology using a data set obtained from a cohort of breast cancer patients.

Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering.

Terahertz (THz) imaging is in its early stages of development but already the potential clinical impact of this new imaging modality is clear. From cancer research to DNA analysis THz technology is improving or even making possible imaging of hitherto inaccessible phenomena. In this paper we present a short review of THz imaging from the point of view of biomedical engineering. We discuss the current state of the art in terms of THz imaging systems; describe current applications, future potential and our own approaches to harnessing this novel technology. We draw attention to open problems in the area with respect to the limitations of the technology before concluding with descriptions of our future work in the area.

Factors affecting outcomes of traumatically extruded permanent teeth in children.

PURPOSE: The objectives of the present study were to determine the prevalence of residual extrusion, pulpal necrosis, and resorption for extruded permanent teeth and to establish the effect of presentation and treatment factors. METHODS: Seventy-two traumatically extruded permanent incisors were studied at the Departments of Paediatric Dentistry in Belfast, Newcastle upon Tyne, and Glasgow. The mean age of the patients was 10.1 years (range=6 to 18 years). Clinical and radiographic outcomes were analyzed and related to presenting and treatment factors. RESULTS: The initial degree of extrusion was moderate for 46 teeth (64%), and the median delay prior to repositioning was 3 hours (range=1 to 168 hours). Pulp necrosis occurred in 31 teeth (43%), residual extrusion was present in 16 teeth (23%), and inflammatory resorption occurred in 11 teeth (15%). Residual extrusion was significantly associated with a delay in repositioning the tooth, pulpal necrosis was significantly more common in teeth with closed apices and in severely extruded teeth, and inflammatory resorption was more common after pulpal necrosis. CONCLUSIONS: Residual extrusion could be minimized by earlier presentation and repositioning. The risk of pulpal necrosis is greatest for severely extruded teeth and for those with closed apices.