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Background: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated., Objective: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET., Methods: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55)., Results: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ 2  = 6.40, P = 0.006)., Conclusions: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD., (© 2024. The Author(s).)

Introduction: Consistent delineation of the breast conserving surgery (BCS) tumour bed (TB) for breast cancer remains a challenge for radiation oncologists. Accurate delineation allows for better local control and reduces toxicity when planning partial breast or TB boost radiation therapy (RT)., Methods: In the operating theatre (OT) breast surgeons inserted stabilised hyaluronic acid (sHA) gel as small drops approximately one cm into the walls surrounding the resection cavity. Surgical feasibility was determined by the rate of successful sHA gel insertion procedure, the ease of insertion as rated by surgeons, the time required for insertion procedure, the quantity used, and any adverse events (AE) relating to sHA gel insertion., Results: Thirty-five patients were enrolled. All patients underwent sHA gel insertion successfully. The procedure added a median of 2.8 min to the OT time and was rated as 'easy' in 89 % of patients. There were no immediate AE in OT. Five (14 %) patients experienced a grade 2 or higher AE. Three of the five patients were prescribed oral antibiotics for breast infection. Two of the five patients experienced a grade 3 AE - haematoma which required evacuation in OT day 1 post-BCS, and infected seroma which required drainage and washout in OT 2 months post-BCS. All five patients recovered and underwent the planned adjuvant therapies for their BC. The AE data reflects common risks with standard BCS and are not clearly attributed to sHA gel insertion alone., Conclusion: We show that sHA gel is surgically feasible as a marker to help define the TB cavity for post-BCS adjuvant MRI-based RT planning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Michael Chao reports equipment, drugs, or supplies was provided by Palette Life Sciences. Michael Chao reports a relationship with Palette Life Sciences that includes: consulting or advisory.’., (© 2024 The Author(s).)

Purpose: To assess the degree of pathologic complete response (pCR), postoperative surgical complication rates, and oncological outcomes in women with locally advanced breast cancer or high-risk breast cancers treated with neoadjuvant radiation therapy (NART)., Methods and Materials: This retrospective, multi-institutional review involved 138 clinically staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential neoadjuvant chemotherapy and NART, followed by mastectomy with or without axillary surgery and immediate autologous breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathologic response, and factors affecting postoperative complications. Kaplan-Meier curves were performed to assess locoregional recurrence-free, distant metastasis-free, and overall survival outcomes., Results: Median age was 47 years (interquartile range, 42-52). The median follow-up was 35.2 months (interquartile range, 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier classification) or 42.1% (as defined by Miller-Payne scores) of patients. Greater pCR rates were achieved for HER2+ (73.8%-85.7%) and triple-negative phenotypes (47.6%-57.1%). There were 21 grade 3 surgical complications including 10 grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At 3-years' follow-up, the locoregional recurrence-free survival was 98.1%, distant metastasis-free survival was 83.6%, and overall survival was 95.3%%., Conclusions: NART is feasible to facilitate a single-stage mastectomy and immediate autologous breast reconstruction. This study demonstrated comparable rates of postoperative complication to standard of care, and high rates of pCR, which translates to high rates of locoregional control, distant metastasis-free survival, and overall survival., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Most diseases of the spine disproportionately impact older persons, with the modal (i.e., commonest) patient a female in their 8th decade of life. We examined the corpus of spinal RCTs to determine how many included "average" spine patients. We searched PubMed for randomized clinical trials published in the top 7 spine journals over a period of 5 years from 2016 to 2020 and extracted nominal upper age cut-offs and the distribution of ages actually recruited. We identified 186 trials of 26,238 patients. We found that only 4.8% of trials could be applied to an "average" 75-year-old patient. This age-based exclusion was not dependent on funding source. Age-based exclusion was exacerbated by explicit upper age cut-offs, however, the age-based exclusion went beyond explicit age cut-offs. Only few trials were applicable to older patients even amongst trials with no age cut-off specified. Age-based exclusion from clinical trials starts at late middle age. The mismatch between spinal patient's age seen in clinical practice and spinal patient's age in trials was so severe that over the 5 years (2016-2020) almost no RCT evidence was produced applicable to the "average" aged-patient across the body of literature available. In conclusion, age-based exclusion is ubiquitous, multifactorial, and happens on a supratrial level. Eliminating age-based exclusion involves more than an arbitrary lifting of explicitly stated upper age cut-offs. Instead, recommendations include increasing input from geriatricians and ethics committees, establishing updated or new models of cares, and creating new protocols to facilitate further research., (© 2023. Crown.)

Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6c high monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6c high monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6c high monocyte axis in heart fibrosis., (© 2022. The Author(s).)

Objective: To describe the incidence of infertility, pregnancy complications, and breastfeeding practices among Australian and New Zealand doctors and identify factors associated with increased pregnancy complication rates., Methods: A survey of ANZ doctors using an online questionnaire during November 2021., Results: One thousand ninety-nine completed responses were received. The median age of female doctors at the time of their first child was 32.4. Fertility testing was undertaken by 37%, with 27% having in vitro fertilization. More than 60% of respondents delayed family planning due to work. Pregnancy loss occurred in 36% of respondents, and 50% suffered a pregnancy complication. There were significant differences between specialists, with surgeons working longer hours before and after pregnancy, but having greater access to maternity leave than general practitioners., Conclusion: Female doctors delay starting and completing their family due to work-related demands and structural biases in career progression, which may result in higher infertility and pregnancy complication rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kevric, Suter, Hodgson and Chew.)

Background: A chloride test is an integral part of a basic metabolic panel that is essential for the assessment of a patient's acid-base and electrolyte status. While many methods are available commercially for the routine measurement of chloride, there is a need to address the accuracy and variability among the measurement results, especially with the prevalence of patients seeking treatment across different healthcare providers for alternative opinions., Method: A method based on sector field inductively coupled plasma isotope dilution mass spectrometry (SF-ICP-IDMS) was developed for the measurement of chloride in human serum. The SF-ICP-IDMS method was then used to assign the target values in the Health Sciences Authority (HSA) External Quality Assessment (EQA) Programme to evaluate the results of chloride test from participating clinical laboratories., Results: The accuracy of the measurements was evaluated by comparing the results with the certified values of Electrolytes in Frozen Human Serum Certified Reference Materials (SRM 956c and SRM 956d) from the National Institute of Standards and Technology (NIST) at different chloride concentration levels. Over a five-year period from 2014-2018, the number of clinical laboratories which participated in the EQA Programme increased from 23 to 33. Comparison of robust means from the laboratories' results with our assigned target values revealed a reduction in relative deviation over time. The relationship between the deviation of each brand of clinical analysers and the chloride levels was established, where a larger deviation was uncovered at low chloride concentration. The SF-ICP-IDMS method was further demonstrated to be comparable with methods used by other metrology institutes in an international comparison organised by HSA under the auspice of the Consultative Committee for Amount of Substance - Metrology in Chemistry and Biology (CCQM)., Conclusion: The use of metrologically traceable assigned target values enabled the study of method biasness from a small pool of dataset in each of the four brands of clinical analysers in HSA EQA Programme. This work underscores the need to improve the accuracy of chloride measurements by regular participation in an accuracy-based EQA Programme., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Introduction: The UK Government imposed a COVID19 lockdown (LD) restricting all but essential activities from 24th March 2020. Subsequently, there has been a significant reduction in casualty attendances nationwide including for ophthalmic emergencies. We aim to study the presentation of rhegmatogenous retinal detachments (RRD) and significant vitreous haemorrhage caused by posterior vitreous detachment (PVD-VH) in three tertiary centres covering most of the North West of England in the 6 weeks before and during the lockdown., Methods: A retrospective multicenter non-randomised consecutive case series study was designed to collect information on all cases of RRD and PVD-VH requiring surgery presenting to the vitreoretinal departments of Manchester Royal Eye Hospital, East Lancashire NHS Foundation Trust and the Lancashire NHS Foundation Trust from 11th February to 4th May 2020., Results: A total of 137 eyes of 137 patients were identified between the three centres of which 132 eyes were operated for RRD. Of these, 86 (64.7%) were operated pre-LD compared with 46 eyes (34.8%) during LD. Forty-five out of 86 eyes (52.3%) were macula-off pre-LD compared with 31 out of 46 eyes (67.3%) during LD ( p  = 0.06). There was lower proportion of non-PVD related RRD during LD (11 pre-LD to 1 during LD, p  = 0.05). PVR was present in four cases during LD compared to 2 before ( p  = 0.19)., Conclusion: There was a clinically significant reduction in the overall incidence of RRD in our centres with an increase in the proportion of macula-off and proliferative vitreoretinopathy during the LD period compared to a similar period before.

Introduction: Neoadjuvant radiotherapy (NART) as part of a multi-modality approach for locally advanced breast cancer (LABC) requires further investigation. Importantly, this approach may allow for a single-staged surgical procedure, with mastectomy and immediate autologous reconstruction. Multiple other potential benefits of NART include improved pathological downstaging of breast disease, reduced overall treatment time, elimination of time period with breast tissue deficit and improved patient satisfaction., Methods: This is a retrospective multi-institutional review of patients with LABC and high-risk breast disease undergoing NART. Eligible patients sequentially underwent neoadjuvant chemotherapy (NACT) with or without HER2-targeted therapy, NART, followed by mastectomy with immediate autologous breast reconstruction (BR) 4- to 6 weeks post-completion of radiotherapy. Patient and tumour characteristics were analysed using descriptive statistics. Surgical complications were assessed using the Clavien-Dindo Classification (Ann Surg 2004; 240: 205)., Results: From 3/2013 to 9/2019, 153 patients were treated with NART. The median age was 47 years (IQR 42-52), with median body mass index of 27. Eighteen patients experienced Grade 3 acute surgical complications. This included 13 Grade 3B breast-site events and 9 Grade 3B donor-site events, where further surgical intervention was required for management of wound infection, wound dehiscence, flap or mastectomy skin necrosis, haematoma and internal mammary venous anastomotic thrombosis. No autologous flap loss was observed., Conclusion: Neoadjuvant radiotherapy facilitates a single-stage surgical procedure with mastectomy and immediate autologous BR, eliminating the delay to reconstructive surgery and thus shortening a woman's breast cancer journey. The findings of this review support the use of NART, with comparable rates of surgical complications to standard sequencing., (© 2021 The Royal Australian and New Zealand College of Radiologists.)

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT 1 ) receptors in the kidney, stimulating Na + reabsorption. AT 1 receptors in tubular epithelia control expression and stimulation of Na + transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT 1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na + excretion in SMKO mice, we considered whether alterations in Na + transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na + transporters and associated proteins. Here, we show that levels of Na + -K + -2Cl - cotransporter isoform 2 (NKCC2) and Na + /H + exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser 71 ), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na + channel. However, the increases in α- and γ-epithelial Na + channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na + excretion observed after cell-specific deletion of AT 1 receptors from smooth muscle cells is associated with altered Na + transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na + transporters and contributing to the regulation of pressure natriuresis. NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4 + ) and non-containing (XO4 - ) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4 + microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4 + microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4 - microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4 + microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.

Purpose: To determine the diagnostic parameters of breast ultrasound (US) in the setting of routine radiological surveillance after a diagnosis of breast cancer and evaluate costs of the inclusion of breast US as well as any survival benefit of US detected cases of recurrence in surveillance., Methods: 622 patients underwent breast cancer surgery and follow up at Austin Health from July 2009 to December 2015. Retrospective data analysis was performed to determine; diagnostic parameters, financial costs of US and survival outcomes of US detected cases of recurrence., Results: Patients underwent 1-9 years of breast cancer surveillance, with a median of 4.24 years. 390 (62.7%) patients underwent additional breast US surveillance to mammography. 232 (38.3%) fit criteria for use of additional breast US. 199 abnormal imaging episodes occurred, leading to 16 screen detected-cases of locoregional recurrence. US alone generated 107 abnormal images and found 9 cancers. US had a sensitivity of 44.1%, specificity of 95.2% and positive predictive value of 11.7% in comparison to mammography; 20.6%, 97.4% and 9.9% respectively. US had a biopsy rate of 4.0% and lead to an incremental cancer detection rate of 0.38%. The cost of incremental cancer found was $31,463.72 AUD. Survival outcomes based on method of detection of recurrence were insignificant (p value = 0.71)., Conclusions: Breast US has a sensitivity of 44.1% and detected seven recurrences that were mammographically occult. Breast US has a similar PPV to mammography in surveillance. Breast US generated considerable biopsy rates and costs. Survival analysis was not able to detect any benefit of US detected cases of recurrence., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The majority of patients with non-metastatic breast cancer will undergo surgery. This involves complex decisions that inevitably increase time from diagnosis to surgery beyond the currently recommended 30 days. This study aims to analyse factors that increase time to surgery and establish whether it is justifiable in the context of improved individualised breast cancer management., Methods: A retrospective analysis of all patients at Austin Health surgically managed for non-metastatic invasive breast carcinoma between 2013 and 2019 was conducted. Time to surgery (TTS) was defined as time between informed diagnosis and cancer surgery. The patients were grouped into TTS groups of ≤30 days and >30 days. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of time interval between diagnosis and surgery., Results: Seven hundred and thirty-one patients were included in our TTS analysis, only half of this cohort received surgery within the recommended 30 days. Many of the factors identified to be associated with increased TTS are the key to optimal management. Median follow-up for the cohort was 30 months. Between wait groups of ≤30 and >30 days, there were no significant association found between TTS and survival outcomes for DFS (HR 1.20 95% CI 0.56-2.60) and OS (HR 1.58 95% CI 0.82-3.03)., Conclusion: Breast cancer management involves complex factors that significantly increase TTS. Surgery within 30 days of diagnosis is not associated with improved DFS and OS. Outcomes from this study support a revision of current recommendations for TTS in non-metastatic breast cancer care.

Background: Mouse allergen reduction is associated with improvements in asthma among sensitized and exposed children, but whether clinical characteristics predict responsiveness to allergen reduction is unclear., Objective: To examine the effects of clinical characteristics on relationships between mouse allergen reduction and asthma outcomes., Methods: We performed a secondary analysis of data from a randomized clinical trial of a mouse allergen intervention, examining the effects of atopy, demographic characteristics, lung function, asthma control, and asthma severity on relationships between mouse allergen reduction and asthma outcomes., Results: Participants were predominantly low-income and minority (78% black, 22% Hispanic), and had persistent asthma. Among less atopic participants (<6 positive skin prick test results), each 50% reduction in mouse allergen was associated with fewer symptoms (incidence rate ratio [95% CI]: maximal symptoms: 0.94 [0.92-0.96]). There was little effect of mouse allergen reduction on symptoms among more atopic participants (P > .05). The interactions between atopic status and mouse allergen reduction were statistically significant for all symptom outcomes; however, there was no evidence that atopic status influenced the effect of mouse allergen reduction on exacerbation-related outcomes. Older children (≥9 years) tended to experience greater improvement in some asthma outcomes with reduction in mouse allergen exposure than younger children. There was no evidence that either mouse-specific IgE or lung function influenced the effect of mouse allergen reduction on any asthma outcomes., Conclusions: Although there may be variability in the clinical response to mouse allergen reduction among low-income, minority children with asthma, there were no clinical characteristics that clearly identified a subgroup at which the intervention should be targeted., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

There is currently little information available about how individual cell types contribute to Alzheimer's disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex samples from control and Alzheimer's disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer's disease. We report that the Alzheimer's disease risk gene APOE is specifically repressed in Alzheimer's disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer's disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer's disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer's disease. For example, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer's disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer's disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at http://adsn.ddnetbio.com.

Microglia, the main immune cells of the central nervous system, are increasingly implicated in Alzheimer's disease (AD). Manifold transcriptomic studies in the brain have not only highlighted microglia's role in AD pathogenesis, but also mapped crucial pathological processes and identified new therapeutic targets. An important component of many of these transcriptomic studies is the investigation of gene expression networks in AD brain, which has provided important new insights into how coordinated gene regulatory programs in microglia (and other cell types) underlie AD pathogenesis. Given the rapid technological advancements in transcriptional profiling, spanning from microarrays to single-cell RNA sequencing (scRNA-seq), tools used for mapping gene expression networks have evolved to keep pace with the unique features of each transcriptomic platform. In this article, we review the trajectory of transcriptomic network analyses in AD from brain to microglia, highlighting the corresponding methodological developments. Lastly, we discuss examples of how transcriptional network analysis provides new insights into AD mechanisms and pathogenesis., Competing Interests: The authors declare no conflict of interest

Objective(s): Cardiovascular disease (CVD) remains a leading cause of mortality in chronic kidney disease (CKD) patients. Interventions targeting traditional risk factors have largely proven ineffective in CKD patients in part because of the increased role of nontraditional risk factors such as chronic inflammation. Omega-3 fatty acids (ω3FA) are inexpensive and safe natural agents, which target inflammation and have potential cardioprotective benefits. The aim of the study was to determine the effects of ω3FA supplementation upon serum interleukin (IL)-12, IL-18, and highly sensitive C-reactive protein (hsCRP) in patients with Stage 3-4 CKD., Methods: We performed a post-hoc analysis of a randomized placebo-controlled trial in 73 nondiabetic CKD patients to determine the effects of ω3FA supplementation (4 g daily for 8 weeks) upon serum levels of IL-12, IL-18, and hsCRP., Results: There were no preintervention differences in IL-12, IL-18, or hsCRP between treatment groups. Postintervention levels of IL-12, IL-18, and hsCRP were similar between the treatment groups. However, IL-12 and IL-18 increased in both treatment groups over the intervention period, whereas hsCRP remained unchanged. The magnitude of increase in serum IL-18 (ΔIL-18) was significantly less in participants in the ω3FA treatment group compared to placebo (P = .047)., Conclusion(s): This study has shown that 4 g daily ω3FA supplementation may lower serum IL-18 levels in patients with moderate CKD. Although there were no apparent effects on several other markers of inflammation, this study provides evidence for a specific effect of ω3FA on inflammatory pathways., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: Diastolic dysfunction (DD) is an important cause of cardiovascular disease (CVD) mortality in chronic kidney disease (CKD) patients. Non-traditional risk factors, such as arterial stiffness and inflammation, are implicated in the pathogenesis of DD in CKD patients., Aim: To determine the association between inflammatory markers (interleukin (IL)-12, IL-18, highly sensitive C-reactive protein (hsCRP)) and non-invasive markers of arterial stiffness (24-h pulse pressure (PP)) with DD in stages 3-4 CKD patients., Methods: We performed a sub-analysis of 78 non-diabetic stages 3-4 CKD subjects to determine the relationship between 24-h PP, IL-12, IL-18 and hsCRP with DD., Results: DD was present in 38 subjects (49%). Subjects with DD were significantly older (61.0 ± 1.9 vs 50.2 ± 2.0 years; P < 0.001) and had higher 24-h PP (48(95% confidence interval 45, 52) vs 43(95% confidence interval 41, 45) mmHg; P < 0.005); 24-h PP was associated with DD (P = 0.02), but this was no longer significant after adjustment for age (P = 0.31). Serum IL-12, IL-18 and hsCRP levels were not significantly different between subjects with or without DD., Conclusion: Asymptomatic subclinical DD was present in 50% of a cohort of stages 3-4 CKD patients but was not associated with IL-12, IL-18 or hsCRP. The association between 24-h PP and DD was no longer apparent following adjustment for age, but given the small sample size, our findings will need to be explored in larger-sized cohorts of individuals with moderate-stage CKD., (© 2018 Royal Australasian College of Physicians.)

Background: Epidemiological studies have consistently shown that increased mammographic density (MD) is a strong risk factor for breast cancer. We previously observed an elevated number of vimentin + /CD45 + leukocytes in high MD (HMD) epithelium. In the present study, we aimed to investigate the subtypes of immune cell infiltrates in HMD and low MD (LMD) breast tissue., Methods: Fifty-four women undergoing prophylactic mastectomy at Peter MacCallum Cancer Centre or St. Vincent's Hospital were enrolled. Upon completion of mastectomy, HMD and LMD areas were resected under radiological guidance in collaboration with BreastScreen Victoria and were subsequently fixed, processed, and sectioned. Fifteen paired HMD and LMD specimens were further selected according to their fibroglandular characteristics (reasonable amount [> 20%] of tissue per block on H&E stains) for subsequent IHC analysis of immune cell infiltration., Results: Overall, immune cell infiltrates were predominantly present in breast ducts and lobules rather than in the stroma, with CD68 + macrophages and CD20 + B lymphocytes also surrounding the vasculature. Macrophages, dendritic cells (DCs), B lymphocytes, and programmed cell death protein 1 (PD-1) expression were significantly increased in HMD epithelium compared with LMD. Moreover, significantly higher levels of DCs, CD4 + T cells, and PD-1 were also observed in HMD stroma than in LMD stroma. The increased expression of interleukin (IL)-6 and IL-4, with unaltered interferon-γ, indicate a proinflammatory microenvironment., Conclusions: Our work indicates that the immune system may be activated very early in breast cancer development and may in part underpin the breast cancer risk associated with HMD.

Importance: Professionally delivered integrated pest management (IPM) interventions can reduce home mouse allergen concentrations, but whether they reduce asthma morbidity among mouse-sensitized and exposed children and adolescents is unknown., Objective: To determine the effect of an IPM intervention on asthma morbidity among mouse-sensitized and exposed children and adolescents with asthma., Design, Setting, and Participants: Randomized clinical trial conducted in Baltimore, Maryland, and Boston, Massachusetts. Participants were mouse-sensitized and exposed children and adolescents (aged 5-17 years) with asthma randomized to receive professionally delivered IPM plus pest management education or pest management education alone. Enrollment occurred between May 2010 and August 2014; the final follow-up visit occurred on September 25, 2015., Interventions: Integrated pest management consisted of application of rodenticide, sealing of holes that could serve as entry points for mice, trap placement, targeted cleaning, allergen-proof mattress and pillow encasements, and portable air purifiers. Infestation was assessed every 3 months, and if infestation persisted or recurred, additional treatments were delivered. All participants received pest management education, which consisted of written material and demonstration of the materials needed to set traps and seal holes., Main Outcomes and Measures: The primary outcome was maximal symptom days defined as the highest number of days of symptoms in the previous 2 weeks among 3 types of symptoms (days of slowed activity due to asthma; number of nights of waking with asthma symptoms; and days of coughing, wheezing, or chest tightness) across 6, 9, and 12 months., Results: Of 361 children and adolescents who were randomized (mean [SD] age, 9.8 [3.2] years; 38% female; 181 in IPM plus pest management education group and 180 in pest management education alone group), 334 were included in the primary analysis. For the primary outcome, there was no statistically significant between-group difference for maximal symptom days across 6, 9, and 12 months with a median of 2.0 (interquartile range, 0.7-4.7) maximal symptom days in the IPM plus pest management education group and 2.7 (interquartile range, 1.3-5.0) maximal symptom days in the pest management education alone group (P = .16) and a ratio of symptom frequencies of 0.86 (95% CI, 0.69-1.06)., Conclusions and Relevance: Among mouse-sensitized and exposed children and adolescents with asthma, an intensive year-long integrated pest management intervention plus pest management education vs pest management education alone resulted in no significant difference in maximal symptom days from 6 to 12 months., Trial Registration: clinicaltrials.gov Identifier: NCT01251224.

Objective: Evaluation of regional lung function is valuable prior to lung surgery in patients with chronic lung disease. Our aim was to evaluate the reproducibility of a locally developed single photon emission tomography/computed tomography (SPET/CT) programme between and within three observers in assessing lobar pulmonary volumes, perfusion and ventilation., Subjects and Methods: Twelve lung transplantation candidates had VQ SPET and diagnostic CT to determine lobar pulmonary function and plan surgery. Their data were used retrospectively in an in-house developed programme which delineates the lung fissures on the diagnostic CT as an anatomical template used to estimate the volume of each of 5 lung lobes. These anatomical volumes were then applied to the corresponding ventilation ( 99m Tc technegas) and perfusion ( 99m Tc MAA) SPET studies. The data were anonymised, duplicated and then processed in random order blindly by 3 readers several weeks apart. Nine studies could be adequately processed. The programme failed in delineating lung volumes in 2 subjects and there was data corruption in the third. The results were evaluated for inter- and intra- observer variability using an intra-class Correlation Coefficient (ICC). An ICC score was calculated for each lobe for volume, ventilation and perfusion., Results: Inter- and intra- observer ICC scores for ventilation, and perfusion scans were all very high. Similar very strong ICC concordance scores were noted for volume except intra-observer ICC scores for left upper lobe (0.76) and right mid lobe (0.66) where scores showed strong concordance by standard statistical descriptors. The method was sensitive enough to demonstrate the expected gradient of ventilation/perfusion even in these patients with substantial pathology., Conclusion: Our method of lobar VQ SPET with CT quantitation has high inter- and intra- observer concordance and in this preliminary data set seems to be a reliable and reproducible test for semi-quantitation of differential volume, ventilation and perfusion of the lobes of the lungs.

Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17α-ethinylestradiol (EE2). Here we systematically analyzed effects of DRS in binary mixtures with progesterone (P4) and EE2. First, we determined the in vitro activity of single compounds in recombinant yeast assays that express the human progesterone, androgen, or estrogen receptor, followed by determination of mixture activities of DRS and P4, DRS and EE2, as well as medroxyprogesterone acetate (MPA) and dydrogesterone (DDG). Mixtures of DRS and P4, as well as of DRS and EE2 showed additive progestogenic and androgenic activities. However, DDG and MPA showed non-additive progestogenic and androgenic activities. We then analyzed the in vivo activity of single compounds and mixtures of DRS and P4, as well as DRS and EE2, by assessing transcriptional changes of up to 14 selected target genes in zebrafish embryos at 48h post fertilization (hpf), and in eleuthero-embryos at 96hpf and 144hpf. DRS, P4, and EE2 led to significant transcriptional alteration of genes, including those encoding hormone receptors (pgr, esr1), a steroidogenic enzyme (hsd17b3), and estrogenic markers (vtg1, cyp19b), in particular at 144 hpf. In general, DRS showed stronger transcriptional changes than P4. In mixtures of DRS and P4, they were mainly non-additive (antagonistic interaction). In mixtures of DRS and EE2, transcriptional responses of esr1, vtg1 and cyp19b were dominated by EE2, suggesting an antagonistic interaction or independent action. Equi-effective mixtures of DRS and EE2, based on progesterone receptor transcripts, showed antagonistic interactions. Our data suggest that interactions in mixtures assessed in vitro in recombinant yeast cannot be translated to the in vivo situation. The receptor-based responses did not correspond well to the transcriptional responses in embryos which are much more complex due to the interplay between hormonal pathways, receptor crosstalk, and hormonal feedback loops., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Isotope dilution mass spectrometry and standard addition techniques were developed for the analysis of four elements (Ca, As, Cd and Pb) in a mushroom powder material. Results from the validated methods were compared to those of other national metrology institutes in the CCQM-K89 intercomparisons and the results were in excellent agreement with the reference values. The same methods were then used for the assignment of reference values to a mushroom powder Certified Reference Material (CRM). The certified values obtained for Ca, As, Cd and Pb were 1.444 ± 0.099 mg/g, 5.61 ± 0.59 mg/kg, 1.191 ± 0.079 mg/kg and 5.23 ± 0.94 mg/kg, respectively. The expanded measurement uncertainties were obtained by combining the uncertainty contributions from characterization (uchar) and between-bottle homogeneity (ubb)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Decoding of directional information in the motor cortex traditionally utilizes only firing rate information. However, information from other features could be extracted and combined with firing rate in order to increase classification accuracy. This study proposes the combination of firing rate and spike-train synchrony information in the decoding of motor cortical activity. Synchrony measures used are Event Synchronization (ES), SPIKE-Distance, and ISI-Distance. All data used for analyses were obtained from implanted electrode recordings of the primary motor cortex of a monkey that was trained to manipulate a motorized vehicle with 4 degrees of freedom (left, right, front and stop) via joystick control. Firstly, synchrony features could decode time periods, which were otherwise incorrectly decoded by firing rate alone, above chance levels. Secondly, using an ensemble classifier design for offline analysis, combining firing rate and ISI-distance information increases overall decoding accuracy by 1.1%. These results show that synchrony features in spike-trains do contain information not carried in firing rate. In addition, these results also demonstrate the feasibility of combining synchrony and firing rate for improving the classification accuracy of invasive brain-machine interface (BMI) in the control of neural prosthetics.

Introduction: Mammographic density (MD), after adjustment for a women's age and body mass index, is a strong and independent risk factor for breast cancer (BC). Although the BC risk attributable to increased MD is significant in healthy women, the biological basis of high mammographic density (HMD) causation and how it raises BC risk remain elusive. We assessed the histological and immunohistochemical differences between matched HMD and low mammographic density (LMD) breast tissues from healthy women to define which cell features may mediate the increased MD and MD-associated BC risk., Methods: Tissues were obtained between 2008 and 2013 from 41 women undergoing prophylactic mastectomy because of their high BC risk profile. Tissue slices resected from the mastectomy specimens were X-rayed, then HMD and LMD regions were dissected based on radiological appearance. The histological composition, aromatase immunoreactivity, hormone receptor status and proliferation status were assessed, as were collagen amount and orientation, epithelial subsets and immune cell status., Results: HMD tissue had a significantly greater proportion of stroma, collagen and epithelium, as well as less fat, than LMD tissue did. Second harmonic generation imaging demonstrated more organised stromal collagen in HMD tissues than in LMD tissues. There was significantly more aromatase immunoreactivity in both the stromal and glandular regions of HMD tissues than in those regions of LMD tissues, although no significant differences in levels of oestrogen receptor, progesterone receptor or Ki-67 expression were detected. The number of macrophages within the epithelium or stroma did not change; however, HMD stroma exhibited less CD206(+) alternatively activated macrophages. Epithelial cell maturation was not altered in HMD samples, and no evidence of epithelial-mesenchymal transition was seen; however, there was a significant increase in vimentin(+)/CD45(+) immune cells within the epithelial layer in HMD tissues., Conclusions: We confirmed increased proportions of stroma and epithelium, increased aromatase activity and no changes in hormone receptor or Ki-67 marker status in HMD tissue. The HMD region showed increased collagen deposition and organisation as well as decreased alternatively activated macrophages in the stroma. The HMD epithelium may be a site for local inflammation, as we observed a significant increase in CD45(+)/vimentin(+) immune cells in this area.

Introduction: The adverse effects of delayed admission to the intensive care unit (ICU) have been recognized in previous studies. However, the definitions of delayed admission varies across studies. This study proposed a model to define "delayed admission", and explored the effect of ICU-waiting time on patients' outcome., Methods: This retrospective cohort study included non-traumatic adult patients on mechanical ventilation in the emergency department (ED), from July 2009 to June 2010. The primary outcomes measures were 21-ventilator-day mortality and prolonged hospital stays (over 30 days). Models of Cox regression and logistic regression were used for multivariate analysis. The non-delayed ICU-waiting was defined as a period in which the time effect on mortality was not statistically significant in a Cox regression model. To identify a suitable cut-off point between "delayed" and "non-delayed", subsets from the overall data were made based on ICU-waiting time and the hazard ratio of ICU-waiting hour in each subset was iteratively calculated. The cut-off time was then used to evaluate the impact of delayed ICU admission on mortality and prolonged length of hospital stay., Results: The final analysis included 1,242 patients. The time effect on mortality emerged after 4 hours, thus we deduced ICU-waiting time in ED > 4 hours as delayed. By logistic regression analysis, delayed ICU admission affected the outcomes of 21 ventilator-days mortality and prolonged hospital stay, with odds ratio of 1.41 (95% confidence interval, 1.05 to 1.89) and 1.56 (95% confidence interval, 1.07 to 2.27) respectively., Conclusions: For patients on mechanical ventilation at the ED, delayed ICU admission is associated with higher probability of mortality and additional resource expenditure. A benchmark waiting time of no more than 4 hours for ICU admission is recommended.

Benzotriazole UV-stabilizers (BUVs) are applied in materials for protection against UV-irradiation. They are widely used, bioaccumulate and share structural similarities to benzotriazole. Benzotriazole (1HBT) finds application as corrosion inhibitor in dishwashing detergents, antifreeze (vehicles) and aircraft de-icing agent. BUVs and 1HBT are persistent and ubiquitous in the aquatic environment, but there is little understanding of the ecotoxicological implications. Here, we comparatively analyze the hormonal activity in vitro and effects in zebrafish eleuthero-embryos in vivo. 2-(2-Hydroxy-5-methylphenyl)benzotriazole (UV-P), 2-(3-t-butyl-2-hydroxy-5-methylphenyl)-5-chlorobenzotriazole (UV-326), UV-327, UV-328, UV-329 and UV-320 showed no estrogenicity (YES assay) and androgenicity (YAS assay). However, UV-P and 1HBT showed significant antiandrogenic activity. We assessed the transcription profiles of up to 26 genes associated with different toxicological pathways in zebrafish eleuthero-embryos to elucidate potential modes of action of UV-P, UV-326 and 1HBT. Embryos were experimentally exposed for 144hpf to three measured concentrations of 15.8, 70.8, and 690μg/L UV-P, 7.5, 31.7, and 84.3μg/L UV-326 and 7.9, 97.3 and 1197.3μg/L 1HBT. Among the 26 transcripts, the induction of the aryl hydrocarbon receptor (AHR) pathway by UV-P and UV-326 was the most significant finding. UV-P led to dose-related induction of AHR1, ARNT2 and cyp1a1, as well as of phase II enzymes glutathione-S-transferase (gstp1) and ugt1a. UV-326 led to a significant induction of cyp1a1 and AHR2, but down-regulation of gstp1 at 84μg/L. Only little transcriptional alterations occurred in genes related to apoptosis, oxidative stress, hormone receptors, and steroidogenesis including aromatase. 1HBT led to only a few expressional changes at 1197μg/L. Our data lead to the conclusion that UV-P and UV-326 activate the AHR-pathway, whereas 1HBT shows only little transcriptional alterations. It should be noted, however, that effects have been observed at concentration much higher than those occurring in the environment. Forthcoming studies should show whether the observed antiandrogenic activities and transcriptional changes translate into physiological effects ., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Wide application of the UV-filter octocrylene (OC) in cosmetics leads to contamination of the aquatic environment, but effects of OC remain unclear. Here we determine bioaccumulation and molecular effects of OC. Adult male zebrafish were exposed to 22, 209 and 383 μg/L and embryos to 69, 293 and 925 μg/L OC. OC accumulated in fish up to 17 μg/g. Calculated BCF varied between 41 and 136. Microarray analysis in brain and liver following exposure to 383 μg/L OC revealed alteration of 628 and 136 transcripts, respectively. Most prominent GO processes included developmental processes, organ development, hematopoiesis, formation of blood vessels, blood circulation, fat cell differentiation and metabolism. Validation by RT-qPCR in brain and liver of adult fish and embryos included a series of genes. Blood levels of 11-ketotestosterone were not altered. The transcriptomics data suggest that OC mainly affects transcription of genes related to developmental processes in the brain and liver as well as metabolic processes in the liver., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Subtle variations in the isotopic composition of elements carry unique information about physical and chemical processes in nature and are now exploited widely in diverse areas of research. Reliable measurement of natural isotope abundance variations is among the biggest challenges in inorganic mass spectrometry as they are highly sensitive to methodological bias. For decades, double spiking of the sample with a mix of two stable isotopes has been considered the reference technique for measuring such variations both by multicollector-inductively coupled plasma mass spectrometry (MC-ICPMS) and multicollector-thermal ionization mass spectrometry (MC-TIMS). However, this technique can only be applied to elements having at least four stable isotopes. Here we present a novel approach that requires measurement of three isotope signals only and which is more robust than the conventional double spiking technique. This became possible by gravimetric mixing of the sample with an isotopic spike in different proportions and by applying principles of isotope dilution for data analysis (GS-IDA). The potential and principle use of the technique is demonstrated for Mg in human urine using MC-TIMS for isotopic analysis. Mg is an element inaccessible to double spiking methods as it consists of three stable isotopes only and shows great potential for metabolically induced isotope effects waiting to be explored.

Despite the importance of stating the measurement uncertainty in chemical analysis, concepts are still not widely applied by the broader scientific community. The Guide to the expression of uncertainty in measurement approves the use of both the partial derivative approach and the Monte Carlo approach. There are two limitations to the partial derivative approach. Firstly, it involves the computation of first-order derivatives of each component of the output quantity. This requires some mathematical skills and can be tedious if the mathematical model is complex. Secondly, it is not able to predict the probability distribution of the output quantity accurately if the input quantities are not normally distributed. Knowledge of the probability distribution is essential to determine the coverage interval. The Monte Carlo approach performs random sampling from probability distributions of the input quantities; hence, there is no need to compute first-order derivatives. In addition, it gives the probability density function of the output quantity as the end result, from which the coverage interval can be determined. Here we demonstrate how the Monte Carlo approach can be easily implemented to estimate measurement uncertainty using a standard spreadsheet software program such as Microsoft Excel. It is our aim to provide the analytical community with a tool to estimate measurement uncertainty using software that is already widely available and that is so simple to apply that it can even be used by students with basic computer skills and minimal mathematical knowledge.

α-Conotoxins are small disulfide-constrained peptides that act as potent and selective antagonists on specific subtypes of nicotinic acetylcholine receptors (nAChRs). We previously cloned two α-conotoxins, Mr1.1 from the molluscivorous Conus marmoreus and Lp1.4 from the vermivorous Conus leopardus. Both of them have the typical 4/7-type framework of the subfamily of α-conotoxins that act on neuronal nAChRs. In this work, we chemically synthesized these two toxins and characterized their functional properties. The synthetic Mr1.1 could primarily inhibit acetylcholine (ACh)-evoked currents reversibly in the oocyte-expressed rat α7 nAChR, whereas Lp1.4 was an unexpected specific blocker of the mouse fetal muscle α1β1γδ receptor. Although their inhibition affinities were relatively low, their unique receptor recognition profiles make them valuable tools for toxin-receptor interaction studies. Mr1.1 could also suppress the inflammatory response to pain in vivo, suggesting that it should be further investigated with respect to its molecular role in analgesia and its mechanism or therapeutic target for the treatment of pain.

As part of continuing studies of the identification of gene organization and cloning of novel alpha-conotoxins, the first alpha4/4-conotoxin identified in a vermivorous Conus species, designated Qc1.2, was originally obtained by cDNA and genomic DNA cloning from Conus quercinus collected in the South China Sea. The predicted mature toxin of Qc1.2 contains 14 amino acid residues with two disulfide bonds (I-III, II-IV connectivity) in a native globular configuration. The mature peptide of Qc1.2 is supposed to contain an N-terminal post-translationally processed pyroglutamate residue and a free carboxyl C-terminus. This peptide was chemically synthesized and refolded for further characterization of its functional properties. The synthetic Qc1.2 has two interconvertible conformations in aqueous solution, which may be due to the cis-trans isomerization of the two successive Pro residues in its first Cys loop. Using the Xenopus oocyte heterologous expression system, Qc1.2 was shown to selectively inhibit both rat neuronal alpha3beta2 and alpha3beta4 subtypes of nicotinic acetylcholine receptors with low potency. A block of about 63% and 37% of the ACh-evoked currents was observed, respectively, and the toxin dissociated rapidly from the receptors. Compared with other characterized alpha-conotoxin members, the unusual structural features in Qc1.2 that confer to its receptor recognition profile are addressed.

Background: Cockroaches and mice, which are common in urban homes, are sources of allergens capable of triggering asthma symptoms. Traditional pest control involves the use of scheduled applications of pesticides by professionals as well as pesticide use by residents. In contrast, integrated pest management (IPM) involves sanitation, building maintenance, and limited use of least toxic pesticides., Objectives: We implemented and evaluated IPM compared with traditional practice for its impact on pests, allergens, pesticide use, and resident satisfaction in a large urban public housing authority., Methods: We assigned IPM or control status to 13 buildings in five housing developments, and evaluated conditions at baseline, 3 months, and 6 months in 280 apartments in Brooklyn and Manhattan, in New York City (New York). We measured cockroach and mouse populations, collected cockroach and mouse urinary protein allergens in dust, and interviewed residents. All statistical models controlled for baseline levels of pests or allergens., Results: Compared with controls, apartments receiving IPM had significantly lower counts of cockroaches at 3 months and greater success in reducing or sustaining low counts of cockroaches at both 3 and 6 months. IPM was associated with lower cockroach allergen levels in kitchens at 3 months and in beds and kitchens at 6 months. Pesticide use was reduced in IPM relative to control apartments. Residents of IPM apartments also rated building services more positively., Conclusions: In contrast to previous IPM studies, which involved extensive cleaning, repeat visits, and often extensive resident education, we found that an easily replicable single IPM visit was more effective than the regular application of pesticides alone in managing pests and their consequences.

Background and Purpose: Tuberculosis (TB) is a worldwide health challenge. Emergency department (ED) is the major public access to the health care system. Delayed diagnosis of active pulmonary TB was believed to precipitate mortality and morbidity. The study was designed to investigate clinical characteristics and factors in patients with delayed diagnosis of active TB in ED., Methods: We used a retrospective chart review., Patients: A total of 103 patients were enrolled between December 2003 and March 2006., Results: Typical chest radiographic findings were noted in 79.8% of nondelayed TB group and 31.6% of delayed TB group (P < .001). Diagnosis of pneumonia was made at ED in 22.6% of nondelayed TB group and 68.4% of delayed TB group (P < .001). Length of initiation of TB treatment intervention was 0 days (0-1 days) and 9 days (6-16 days), respectively (P < .001). In-hospital mortality rate was 15.5% and 47.4%, respectively (P < .01). Age (odds ratio, 1.07; 95% confidence interval, 1.01-1.1) and intensive care unit admission (odds ratio, 5.01; 95% confidence interval, 1.18-21.3) were associated with lower in-hospital survival. Delayed ED diagnosis of TB was associated with mortality in results of univariate analysis (P = .002), but no statistical significance was noted in the final result of stepwise logistic regression analysis., Conclusion: Intensive care unit admission and age are associated with mortality. Awareness of varying features of pulmonary TB by physicians is important.

Cone snails comprise approximately 700 species of venomous molluscs which have evolved the ability to generate multiple toxins with varied and exquisite selectivity. alpha-Conotoxin is a powerful tool for defining the composition and function of nicotinic acetylcholine receptors which play a crucial role in excitatory neurotransmission and are important targets for drugs and insecticides. An alpha4/7 conotoxin, Lp1.1, originally identified by cDNA and genomic DNA cloning from Conus leopardus, was found devoid of the highly conserved Pro residue in the first intercysteine loop. To further study this toxin, alpha-Lp1.1 was chemically synthesized and refolded into its globular disulfide isomer. The synthetic Lp1.1 induced seizure and paralysis on freshwater goldfish and selectively reversibly inhibited ACh-evoked currents in Xenopus oocytes expressing rat alpha3beta2 and alpha6alpha3beta2 nAChRs. Comparing the distinct primary structure with other functionally related alpha-conotoxins could indicate structural features in Lp1.1 that may be associated with its unique receptor recognition profile.

Background: To validate the use of the Charlson Comorbidity Index (CCI) for predicting admission of patients revisiting the Emergency Department (ED) within 72 hours., Methods: Non-trauma patients aged above 17 years old who revisited an urban ED within 72 hours during January of 2004 were included in this retrospective observational study. Demographic data, diagnosis, CCI, in-hospital mortality rate and length of hospital stay were reviewed, and comparisons were made between the patients who were admitted or discharged on their return visits., Results: Of the 168 enrolled patients, 60 were admitted to a ward and 108 were discharged. Revisiting patients with high CCIs (> or = 2) had a higher admission rate (67.3% vs. 22.7%; p < 0.001) and an increased adjusted odds ratio of admission (odds ratio (OR) 2.06; 95% confidence interval (CI) 1.14-3.75) than low CCI patients. Admitted revisiting patients with high CCIs had poorer prognoses, longer hospital stays (11.79 +/- 8.92 days vs. 6.78 +/- 5.17 days; p < 0.05) and a higher in-hospital mortality rate (15.2% vs. 3.7%; p = 0.209)., Conclusion: CCI was well correlated with the admission possibility of patients revisiting the ED within 72 hours. More clinical management and discharge strategies should target those revisiting patients who have more comorbidities.

Every cone snail produces a mixture of different conotoxins and secretes them to immobilize their prey and predators. alpha3/5 Conotoxins, isolated from fish-hunting cone snails, target muscle nicotinic acetylcholine receptors. The structure and function of alpha3/5 conotoxin from the piscivorous Conus achatinus have not been studied. We synthesized two pentadecamer peptides, Ac1.1a and Ac1.1b, with appropriate disulfide bonding, based on cDNA sequences of alpha3/5 conotoxins from C. achatinus. Ac1.1a and Ac1.1b differ by only one amino acid residue. They have similar potency on blocking recombinant mouse muscle acetylcholine receptor expressed in Xenopus laevis oocytes, with IC50 values of 36 nM and 26 nM, respectively. For Ac1.1b, deletion of the first three N-terminal amino acids did not change its activity, indicating that the N-terminus is not involved in the interaction with its receptor. Furthermore, our experiments indicate that both toxins strongly prefer the alpha1-delta subunit interface instead of the alpha1-gamma binding site on the mouse muscle nicotinic acetylcholine receptor. These peptides provide additional tools for the study of the structure and function of nicotinic receptor.

Children with Down syndrome have an increased risk of cryptorchidism, but the reported incidence is unclear. In a proportion of these children, the testes are within the scrotum at birth but later appear to have ascended to an ectopic position. Records of patients diagnosed with trisomy 21 who had surgery for undescended testes in two tertiary paediatric centres over a 10-year period were examined. Information on liveborn males with Down syndrome was obtained from the Victorian Genetic Registry, and then the incidence of congenital and acquired undescended testes was determined. The incidence of undescended testes in Down syndrome was found to be 6.52% (24/368), with 4.35% (16/368) being acquired undescended or ascending testes. In conclusion, there is an increased incidence of cryptorchidism in Down syndrome; in particular, there is a significant proportion of acquired undescended testes.