Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

Benefits of the enhanced recovery after surgery pathway for orthognathic surgery.

The enhanced recovery after surgery (ERAS) protocol was designed to improve patient outcomes and decrease complications, opioid use, and postoperative nausea and vomiting (PONV). The aim of this retrospective cohort study was to examine the effectiveness of ERAS protocols implemented in orthognathic surgeries from 2017 to 2018 at the University of Alabama at Birmingham Hospital by measuring opioid use and PONV. Two groups were identified through chart review, a non-ERAS group (traditional) of patients who had surgery without a protocol and an ERAS group of patients who had surgery with the ERAS protocol. The anesthesia and surgical teams followed a standardized protocol for perioperative management. All procedures were performed by a single surgeon and included single- and double-jaw surgeries and adjunctive procedures. The patient charts were analyzed for postoperative opioid consumption (measured in morphine milligram equivalents, MME) and PONV. IBM SPSS Statistics version 26 was used to conduct the statistical analyses. The ERAS group received less opioids during the postoperative period than the control group (31.2 MME vs 54.6 MME, P= 0.002). The ERAS group also had a lower incidence of PONV, with 1.2 episodes of PONV compared to 2.4 episodes in the non-ERAS group (P= 0.008). This study demonstrates that the ERAS protocol is effective in decreasing postoperative opioid consumption and PONV.

Do oropharyngeal throat packs prevent fluid ingestion during orthognathic surgery?

The oropharyngeal throat pack is commonly used in oral and maxillofacial surgery despite debated evidence regarding its barrier function. The study objectives were to investigate whether the oropharyngeal pack reduces blood ingestion and to evaluate its relationship with postoperative nausea and vomiting (PONV) and throat pain. This was a single-center, parallel group, single-blind randomized controlled trial. Participants undergoing orthognathic surgery, age ≥16 years, were included in the study. After intubation and prior to surgery start, the treatment group received oropharyngeal packing; the control group received no packing. Outcome variables were the quality of gastric contents aspirated by nasogastric tube (bloody or not bloody), PONV, and throat pain (visual analog scale). Thirty patients (treatment n = 15; control n = 15) were randomized and analyzed. There was no difference between the groups in quality of gastric contents (P = 1.00) or incidence of PONV at 2 hours and 24 hours (P = 1.00). Throat pain incidence and severity at 2 hours were both higher in the treatment group, but this was not statistically significant (P = 0.128, P = 0.223). The results indicate that the oropharyngeal pack is not an effective barrier against blood ingestion. Oropharyngeal packs do not improve or worsen PONV, but may increase throat pain.

Skin Toxicity in Early Breast Cancer Patients Treated with Field-In-Field Breast Intensity-Modulated Radiotherapy versus Helical Inverse Breast Intensity-Modulated Radiotherapy: Results of a Phase III Randomised Controlled Trial.

AIMS: Skin toxicity is a common adverse effect of breast radiotherapy. We investigated whether inverse-planned intensity-modulated radiotherapy (IMRT) would reduce the incidence of skin toxicity compared with forward field-in-field breast IMRT (FiF-IMRT) in early stage breast cancer. MATERIALS AND METHODS: This phase III randomised controlled trial compared whole-breast irradiation with either FiF-IMRT or helical tomotherapy IMRT (HT-IMRT), with skin toxicity as the primary end point. Patients received 50 Gy in 25 fractions and were assessed to compare skin toxicity between treatment arms. RESULTS: In total, 177 patients were available for assessment and the median follow-up was 73.1 months. Inverse IMRT achieved more homogeneous coverage than FiF-IMRT; erythema and moist desquamation were higher with FiF-IMRT compared with HT-IMRT (61% versus 34%; P < 0.001; 33% versus 11%; P < 0.001, respectively). Multivariate analysis showed large breast volume, FiF-IMRT and chemotherapy were independent factors associated with worse acute toxicity. There was no difference between treatment arms in the incidence of late toxicities. The 5-year recurrence-free survival was 96.3% for both FiF-IMRT and HT-IMRT and the 5-year overall survival was 96.3% for FiF-IMRT and 97.4% for HT-IMRT. CONCLUSIONS: Our study showed significant reduction in acute skin toxicity using HT-IMRT compared with FiF-IMRT, without significant reduction in late skin toxicities. On the basis of these findings, inverse-planned IMRT could be used in routine practice for whole-breast irradiation with careful plan optimisation to achieve the required dose constraints for organs at risk.

Delayed Photoactivation of Dual-cure Composites: Effect on Cuspal Flexure, Depth-of-cure, and Mechanical Properties.

OBJECTIVES:: This study tested whether delayed photoactivation could reduce shrinkage stresses in dual-cure composites and how it affected the depth-of-cure and mechanical properties. METHODS AND MATERIALS:: Two dual-cure composites (ACTIVA and Bulk EZ) were subjected to two polymerization protocols: photoactivation at 45 seconds (immediate) or 165 seconds (2 minutes delayed) after extrusion. Typodont premolars with standardized preparations were restored with the composites, and cuspal flexure caused by polymerization shrinkage was determined with three-dimensional scanning of the external tooth surfaces before restoration (baseline) and at 10 minutes and one hour after photoactivation. Bond integrity (intact interface) was verified with dye penetration. Depth-of-cure was determined by measuring Vickers hardness through the depth at 1-mm increments. Elastic modulus and maximum stress were determined by four-point bending tests (n=10). Results were analyzed with two- or three-way analysis of variance and pairwise comparisons (Bonferroni; α=0.05). RESULTS:: Delayed photoactivation significantly reduced cuspal flexure for both composites at 10 minutes and one hour ( p≤0.003). Interface was >99% intact in every group. Depth-of-cure, elastic modulus, and flexural strength were not significantly different between the immediate and delayed photoactivation ( p>0.05). The hardness of ACTIVA reduced significantly with depth ( p<0.001), whereas the hardness of Bulk EZ was constant throughout the depth ( p=0.942). CONCLUSIONS:: Delayed photoactivation of dual-cure restorative composites can reduce shrinkage stresses without negatively affecting the degree-of-cure or mechanical properties (elastic modulus and flexural strength).

The value of local registry data for describing cervical cancer management and outcomes over three decades in Australia.

Registry data on invasive cervical cancers (n = 1,274) from four major hospitals (1984-2012) were analysed to determine their value for informing local service delivery in Australia. The methodology comprised disease-specific survival analyses using Kaplan-Meier product-limit estimates and Cox proportional hazards models and treatment analyses using logistic regression. Five- and 10-year survivals were 72% and 68%, respectively, equating with relative survival estimates for Australia and the USA. Most common treatments were surgery and radiotherapy. Systemic therapies increased in recent years, generally with radiotherapy, but were less common for residents from less accessible areas. Surgery was more common for younger women and early-stage disease, and radiotherapy for older women and regional and more advanced disease. The proportion of glandular cancers increased in-step with national trends. Little evidence of variation in risk-adjusted survival presented over time or by Local Health District. The study illustrates the value of local registry data for describing local treatment and outcomes. They show the lower use of systemic therapies among residents of less accessible areas which warrants further investigation. Risk-adjusted treatment and outcomes did not vary by socio-economic status, suggesting equity in service delivery. These data are important for local evaluation and were not available from other sources.

Acute kidney injury during treatment for latent tuberculous infection with rifampin.

Treatment for latent tuberculous infection (LTBI) is a key strategy for the elimination of tuberculosis. Rare adverse reactions associated with LTBI treatment have been reported. We report the only case of acute kidney injury reported to Centers for Disease Control and Prevention surveillance for LTBI treatment-related adverse events. The patient experienced rapid intravascular hemolysis, resulting in heme pigment nephropathy; he was hospitalized and received three hemodialysis treatments, but recovered without sequelae. While LTBI treatment-related adverse events are rare, health care providers should maintain clinical vigilance and regularly counsel patients to facilitate prompt diagnoses and effective clinical management of affected patients.

Assessing impact of organised breast screening across small residential areas-development and internal validation of a prediction model.

Monitoring screening mammography effects in small areas is often limited by small numbers of deaths and delayed effects. We developed a risk score for breast cancer death to circumvent these limitations. Screening, if effective, would increase post-diagnostic survivals through lead-time and related effects, as well as mortality reductions. Linked cancer and BreastScreen data at four hospitals (n = 2,039) were used to investigate whether screened cases had higher recorded survivals in 13 small areas, using breast cancer deaths as the outcome (M1), and a risk of death score derived from TNM stage, grade, histology type, hormone receptor status, and related variables (M2). M1 indicated lower risk of death in screened cases in 12 of the 13 areas, achieving statistical significance (p < .05) in 5. M2 indicated lower risk scores in screened cases in all 13 areas, achieving statistical significance in 12. For cases recently screened at diagnosis (<6 months), statistically significant reductions applied in 8 areas (M1) and all 13 areas (M2). Screening effects are more detectable in small areas using these risk scores than death itself as the outcome variable. An added advantage is the application of risk scores for providing a marker of screening effect soon after diagnosis.

Colorectal cancer treatment and survival over three decades at four major public hospitals in South Australia: trends by age and in the elderly.

Data from registries at four major public hospitals in South Australia indicate increased 5-year disease-specific survivals for colorectal cancer from 48% to 63% between 1980-1986 and 2005-2010. For 80+ year olds, the increase was smaller, from 47% to 52%. Risk of case fatality halved overall, adjusting for age, gender, stage, differentiation and sub-site. Patients aged 80+ years had a lower risk reduction of about a third (hazards ratio: 0.69; 95% confidence limits, 0.52-0.92). Percentages having surgery and other specified treatments were lower for 80+ year olds than younger cases, although increases in treatment intensity occurred in this age range during 1980-2010, as seen in younger ages, in accordance with guidelines. The study illustrates the important feedback clinical registries can provide to clinicians on care patterns and outcomes in their hospital settings. Feedback can be the subject of local deliberations on how to achieve the best outcomes, including in the elderly by considering the best trade-offs between optimal cancer care and accommodations for co-morbidity and frailty. Clinical registry data can be used in comparative effectiveness research in local settings where there are sufficient case numbers.

Variability in subjective review of umbilical cord blood colony forming unit assay.

BACKGROUND: The goal of this study was to quantitatively evaluate the reproducibility of current manual counting methods of colony forming units (CFUs) from umbilical cord blood samples METHODS: Fresh and reconstituted frozen cells from 10 cord blood samples were cultured under standard conditions. The number of BFU-Es, CFU-GMs, and CFU-GEMMs were counted by three expert reviewers using the standard microscope method and manually traced CFUs on digital images of cell cultures. RESULTS: The mean colony count based on the traced digital images was 82 (22% CV) and 52 (15% CV) for the fresh and frozen samples, respectively. This was significantly greater than that observed using the microscope, 61 (13% CV) for fresh and 43 (16% CV) for frozen. The difference was mainly due to the reviewers observing more CFU-GMs in the digital images than through the microscope review. All three reviewers agreed on the presence of a colony 72% of the time based on the digital review in both fresh and frozen samples. Reviewer agreement with respect to colony type in the fresh samples was 38% (22%CV), 25% (51%CV), and 6% (115%CV) for BFU-Es, CFU-GMs, and CFU-GEMMs, respectively. Reviewer agreement increased for BFU-Es and CFU-GMs in the frozen samples where fewer colonies were present. CONCLUSIONS: Although this study showed marked variability between reviewers, the analysis of manually traced digital images has the potential to improve inter-observer variation when compared to current methods by identifying features that lead to discrepancies in colony counting and providing cases with consensus results. © 2016 International Clinical Cytometry Society.

'Venus trapped, Mars transits': Cu and Fe redox chemistry, cellular topography and in situ ligand binding in terrestrial isopod hepatopancreas.

Woodlice efficiently sequester copper (Cu) in 'cuprosomes' within hepatopancreatic 'S' cells. Binuclear 'B' cells in the hepatopancreas form iron (Fe) deposits; these cells apparently undergo an apocrine secretory diurnal cycle linked to nocturnal feeding. Synchrotron-based µ-focus X-ray spectroscopy undertaken on thin sections was used to characterize the ligands binding Cu and Fe in S and B cells of Oniscus asellus (Isopoda). Main findings were: (i) morphometry confirmed a diurnal B-cell apocrine cycle; (ii) X-ray fluorescence (XRF) mapping indicated that Cu was co-distributed with sulfur (mainly in S cells), and Fe was co-distributed with phosphate (mainly in B cells); (iii) XRF mapping revealed an intimate morphological relationship between the basal regions of adjacent S and B cells; (iv) molecular modelling and Fourier transform analyses indicated that Cu in the reduced Cu(+) state is mainly coordinated to thiol-rich ligands (Cu-S bond length 2.3 Å) in both cell types, while Fe in the oxidized Fe(3+) state is predominantly oxygen coordinated (estimated Fe-O bond length of approx. 2 Å), with an outer shell of Fe scatterers at approximately 3.05 Å; and (v) no significant differences occur in Cu or Fe speciation at key nodes in the apocrine cycle. Findings imply that S and B cells form integrated unit-pairs; a functional role for secretions from these cellular units in the digestion of recalcitrant dietary components is hypothesized.

Iron deficiency in early pregnancy using serum ferritin and soluble transferrin receptor concentrations are associated with pregnancy and birth outcomes.

BACKGROUND/OBJECTIVES: There are several biomarkers for measuring iron deficiency (ID) in pregnancy, but the prevalence of ID and its association with inflammation and adverse pregnancy outcomes is inconclusive. The aim of this work was to describe the prevalence and determinants of first trimester ID and associations with pregnancy and birth outcomes. SUBJECTS/METHODS: A record-linkage cohort study of archived serum samples of women attending first trimester screening and birth and hospital data to ascertain maternal characteristics and pregnancy outcomes. Sera were analysed for iron stores (ferritin; µg/l), lack of iron in the tissues (soluble transferrin receptor (sTfR); nmol/l) and inflammatory (C-reactive protein (CRP); mg/dl) biomarkers. Total body iron (TBI) was calculated from serum ferritin (SF) and sTfR concentrations. Multivariate logistic regression analysed risk factors and pregnancy outcomes associated with ID using the definitions: SF<12 µg/l, TfR ⩾ 21.0 nmol/l, and TBI<0 mg/kg. RESULTS: Of the 4420 women, the prevalence of ID based on ferritin, sTfR and TBI was 19.6, 15.3 and 15.7%, respectively. Risk factors of ID varied depending on which iron parameter was used and included maternal age <25 years, multiparity, socioeconomic disadvantage, high maternal body weight and inflammation. ID, defined by SF and TBI but not TfR, was associated with reduced risk of gestational diabetes mellitus (GDM). ID defined using TBI only was associated with increased risk of large-for-gestation-age (LGA) infants. CONCLUSIONS: Nearly one in five Australian women begin pregnancy with ID. Further investigation of excess maternal weight and inflammation in the relationships between ID and GDM and LGA infants is needed.

High maternal iron status, dietary iron intake and iron supplement use in pregnancy and risk of gestational diabetes mellitus: a prospective study and systematic review.

AIM: High iron measured using dietary intake and biomarkers is associated with Type 2 diabetes. It is uncertain whether a similar association exists for gestational diabetes mellitus. The aim of this systematic review was to conduct a cohort study examining first trimester body iron stores and subsequent risk of gestational diabetes, and to include these findings in a systematic review of all studies examining the association between maternal iron status, iron intake (dietary and supplemental) and the risk of gestational diabetes. METHODS: Serum samples from women with first trimester screening were linked to birth and hospital records for data on maternal characteristics and gestational diabetes diagnosis. Blood was analysed for ferritin, soluble transferrin receptor and C-reactive protein. Associations between iron biomarkers and gestational diabetes were assessed using multivariate logistic regression. A systematic review and meta-analysis, registered with PROSPERO (CRD42014013663) included studies of all designs published in English from January 1995 to July 2015 that examined the association between iron and gestational diabetes and included an appropriate comparison group. RESULTS: Of 3776 women, 3.4% subsequently developed gestational diabetes. Adjusted analyses found increased odds of gestational diabetes for ferritin (OR 1.41; 95% CI 1.11, 1.78), but not for soluble transferrin receptor (OR 1.00; 95% CI 0.97, 1.03) per unit increase of the biomarker. Two trials of iron supplementation found no association with gestational diabetes. Increased risk of gestational diabetes was associated with higher levels of ferritin and serum iron and dietary haem iron intakes. CONCLUSIONS: Increased risk of gestational diabetes among women with high serum ferritin and iron levels and dietary haem iron intakes warrants further investigation.

Tuberculosis among the homeless, United States, 1994-2010.

OBJECTIVES: 1) To describe homeless persons diagnosed with tuberculosis (TB) during the period 1994-2010, and 2) to estimate a TB incidence rate among homeless persons in the United States. METHODS: TB cases reported to the National Tuberculosis Surveillance System were analyzed by origin of birth. Incidence rates were calculated using the US Department of Housing and Urban Development homeless population estimates. Analysis of genotyping results identified clustering as a marker for transmission among homeless TB patients. RESULTS: Of 270,948 reported TB cases, 16,527 (6%) were homeless. The TB incidence rate among homeless persons ranged from 36 to 47 cases per 100,000 population in 2006-2010. Homeless TB patients had over twice the odds of not completing treatment and of belonging to a genotype cluster. US- and foreign-born homeless TB patients had respectively 8 and 12 times the odds of substance abuse. CONCLUSIONS: Compared to the general population, homeless persons had an approximately 10-fold increase in TB incidence, were less likely to complete treatment and more likely to abuse substances. Public health outreach should target homeless populations to reduce the excess burden of TB in this population.

Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog.

Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.

2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog.

Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (γ-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM.

3-dimensional imaging modalities for phenotyping genetically engineered mice.

A variety of 3-dimensional (3D) digital imaging modalities are available for whole-body assessment of genetically engineered mice: magnetic resonance microscopy (MRM), X-ray microcomputed tomography (microCT), optical projection tomography (OPT), episcopic and cryoimaging, and ultrasound biomicroscopy (UBM). Embryo and adult mouse phenotyping can be accomplished at microscopy or near microscopy spatial resolutions using these modalities. MRM and microCT are particularly well-suited for evaluating structural information at the organ level, whereas episcopic and OPT imaging provide structural and functional information from molecular fluorescence imaging at the cellular level. UBM can be used to monitor embryonic development longitudinally in utero. Specimens are not significantly altered during preparation, and structures can be viewed in their native orientations. Technologies for rapid automated data acquisition and high-throughput phenotyping have been developed and continually improve as this exciting field evolves.

Prevalence and risk factors for tuberculosis infection among personnel in two hospitals in Viet Nam.

SETTING: Two general hospitals in Viet Nam. OBJECTIVE: To assess the risk of tuberculosis (TB) infection associated with hospital employment. DESIGN: During October-December 2009, we performed a cross-sectional study of hospital personnel and, for community comparison groups, staff from nearby schools. We tested for TB infection using the tuberculin skin test; an induration ≥ 10 mm indicated TB infection. RESULTS: Of 956 hospital personnel, 380 (40%) had TB infection compared to 40 (26%) of 155 school personnel. Hospital personnel had twice the odds of TB infection compared with school personnel (OR 2.0, 95%CI 1.3-3.0) after adjustment for age and sex. Compared to hospital administrative staff, the odds of TB infection were similar among clinical staff (OR 1.0, 95%CI 0.6- 1.3), clinical support staff (OR 0.9, 95%CI 0.5-1.6) and auxiliary staff (OR 1.1, 95%CI 0.6-2.0) at the hospitals. No additional infection risk was detected in high-risk departments (OR 1.1, 95%CI 0.6-2.0). CONCLUSIONS: Hospital personnel are at increased risk of TB infection. Among hospital personnel, risk was independent of job or department, suggesting that personnel are commonly at risk and that improvements in infection control are needed throughout hospitals.

Structures of respiratory syncytial virus nucleocapsid protein from two crystal forms: details of potential packing interactions in the native helical form.

Respiratory syncytial virus (RSV) is a frequent cause of respiratory illness in infants, but there is currently no vaccine nor effective drug treatment against this virus. The RSV RNA genome is encapsidated and protected by a nucleocapsid protein; this RNA-nucleocapsid complex serves as a template for viral replication. Interest in the nucleocapsid protein has increased owing to its recent identification as the target site for novel anti-RSV compounds. The crystal structure of human respiratory syncytial virus nucleocapsid (HRSVN) was determined to 3.6 Å resolution from two crystal forms belonging to space groups P2(1)2(1)2(1) and P1, with one and four decameric rings per asymmetric unit, respectively. In contrast to a previous structure of HRSVN, the addition of phosphoprotein was not required to obtain diffraction-quality crystals. The HRSVN structures reported here, although similar to the recently published structure, present different molecular packing which may have some biological implications. The positions of the monomers are slightly shifted in the decamer, confirming the adaptability of the ring structure. The details of the inter-ring contacts in one crystal form revealed here suggest a basis for helical packing and that the stabilization of native HRSVN is via mainly ionic interactions.