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Background: Video-assisted thoracoscopic surgery (VATS) is widely used in lung cancer surgery, as this technique causes less pain and faster recovery than open thoracotomy. However, significant postoperative pain persists in a number of patients, often leading to increased opioid use and opioid-related adverse events in addition to prolonged admission times. Perioperatively administered glucocorticoids have been demonstrated effective in reducing pain after other types of surgeries, but the effect in VATS remains unclear., Methods: This systematic review will assess the impact of glucocorticoids on postoperative pain in adult patients undergoing VATS. We will include randomised trials comparing higher doses of glucocorticoids to lower doses, placebo or no treatment. The review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement and Cochrane methodology. The certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation system. The primary outcome is standardised dynamic pain scores within 24 h. Secondary outcomes are opioid use, time to first mobilisation, length of hospital stay and numeric rating score >3 at any point within the first 24 h following surgery. Exploratory outcomes are opioid-related adverse effects and glucocorticoid-related adverse effects classified in major and minor events. Data will be meta-analysed with sensitivity and subgroup analyses and trial sequential analyses. Furthermore, we will assess the risk of reporting bias and heterogeneity., Conclusion: This systematic review and meta-analysis will provide an overview of the current evidence of how glucocorticoids affect postoperative pain and recovery in adult patients undergoing VATS., (© 2025 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: In 2010, Denmark was the first country to implement a targeted routine antenatal anti-D prophylaxis (tRAADP) program, offering fetal RHD genotyping to all nonimmunized D negative pregnant women. The program represented a shift from only postnatal prophylaxis to a combined antenatal and postnatal prophylaxis. This study aimed to evaluate the clinical effect of tRAADP in Denmark., Study Design and Methods: This nationwide registry-based cohort study included all D negative women who gave birth between 2004-2020, identified through the National Medical Birth Register and the Departments of Clinical Immunology in Denmark. The clinical effect of tRAADP was assessed by comparing the incidence of new D immunization between 2004-2009 (non-tRAADP-cohort) and 2011-2018 (tRAADP-cohort)., Results: A total of 282 women were D immunized during pregnancy between 2004-2009 (non-tRAADP-cohort), and 167 between 2011-2018 (tRAADP-cohort). The incidence of new D immunization decreased from 0.46% (95% CI 0.41-0.52) in the non-tRAADP-cohort to 0.22% (95% CI 0.19-0.25) in the tRAADP-cohort. The risk reduction was statistically significant p < 0.001. Notably, in the tRAADP cohort 0.1% (95% CI 0.08-0.12) of new D immunizations occurred before the time of antenatal prophylaxis., Discussion: tRAADP significantly reduced the incidence of new D immunization by more than half, thus demonstrating the expected effect. However, even with full adherence to the current program, some women with early fetomaternal hemorrhage (FMH) were still at risk. Future studies may evaluate the impact of administering an additional tRAADP dose earlier in the second trimester to prevent this., (© 2024 AABB.)

Case: Fourteen-year-old boy, history of autism presented with bilateral knee instability. Imaging revealed bilateral anterior cruciate ligament (ACL) insufficiency, 20° of posterior tibial slope (PTS) on the right and 18° on the left. A guided growth technique using anterior placed tension band plates was used to correct the PTS. At 22 months, the PTS corrected to 5.5° on the right and 6° on the left. The patient's knee stability improved, and he resumed activities at 30 months., Conclusion: Pediatric ACL insufficiency in the setting of elevated PTS can be successfully corrected with a guided growth technique., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C490)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Indistinguishability between photons is a key requirement for scalable photonic quantum technologies. We experimentally demonstrate that partly distinguishable single photons can be purified to reach near-unity indistinguishability by the process of quantum interference with ancillary photons followed by heralded detection of a subset of them. We report on the indistinguishability of the purified photons by interfering two purified photons and show improvements in the photon indistinguishability of 2.774(3)% in the low-noise regime, and as high as 10.2(5)% in the high-noise regime.

Ulnar-shortening osteotomy is a reliable solution to treat ulnar impaction syndrome, but it has a significant rate of nonunion as a known complication. Generally nonunion after the procedure is attributed to noninfectious causes. When infections happen, they follow the microbiological trends of nonunions elsewhere in the body. We present a case of ulnar-shortening osteotomy using an oblique-cut osteotomy system that resulted in septic nonunion. At the time of revision surgery, Cutibacterium acnes and Staphylococcus hominis were isolated from the osteotomy site. The patient was successfully treated using intravenous antibiotics and the two-stage Masquelet technique and eventually went on to bony union. As C acnes is rarely encountered in this context, this report highlights the need to consider all possible pathogens in the workup of a potentially septic nonunion. Surgeons should consider bacteria such as C acnes that require prolonged incubation for isolation from cultures, which may not be part of many institutions' usual protocol. [ Orthopedics . 2024;47(4):e211-e213.].

The interference of nonclassical states of light enables quantum-enhanced applications reaching from metrology to computation. Most commonly, the polarization or spatial location of single photons are used as addressable degrees of freedom for turning these applications into praxis. However, the scale-up for the processing of a large number of photons of these architectures is very resource-demanding due to the rapidly increasing number of components, such as optical elements, photon sources, and detectors. Here, we demonstrate a resource-efficient architecture for multiphoton processing based on time-bin encoding in a single spatial mode. We use an efficient quantum dot single-photon source and a fast programmable time-bin interferometer to observe the interference of up to eight photons in 16 modes, all recorded only with one detector, thus considerably reducing the physical overhead previously needed for achieving equivalent tasks. Our results can form the basis for a future universal photonics quantum processor operating in a single spatial mode.

Generating large multiphoton entangled states is of main interest due to enabling universal photonic quantum computing and all-optical quantum repeater nodes. These applications exploit measurement-based quantum computation using cluster states. Remarkably, it was shown that photonic cluster states of arbitrary size can be generated by using feasible heralded linear optics fusion gates that act on heralded three-photon Greenberger-Horne-Zeilinger (GHZ) states as the initial resource state. Thus, the capability of generating heralded GHZ states is of great importance for scaling up photonic quantum computing. Here, we experimentally demonstrate this required building block by reporting a polarisation-encoded heralded GHZ state of three photons, for which we build a high-rate six-photon source (547±2  Hz) from a solid-state quantum emitter and a stable polarization-based interferometer. The detection of three ancillary photons heralds the generation of three-photon GHZ states among the remaining particles with fidelities up to F=0.7278±0.0106. Our results initiate a path for scalable entangling operations using heralded linear-optics implementations.

Background: The purpose of this study is to compare outcomes of carpal tunnel release (CTR) in patients with and without double crush syndrome (DCS), defined as concurrent carpal tunnel syndrome (CTS) and cervical radiculopathy at C5-T1 on preoperative nerve conduction studies., Methods: Patients with preoperative nerve conduction studies who underwent unilateral, isolated CTR were retrospectively identified. All patients completed preoperative and 3-month postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) and pain interference (PI), and Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaires, and responded to the anchor question: "Since your treatment, how would you rate your overall function?" (much worse, worse, slightly worse, no change, slightly improved, improved, much improved). Preoperative, postoperative, and changes in scores for UE, PI, and QuickDASH were compared, as were the anchor question responses and rates of achieving the minimal clinically important difference (MCID)., Results: Sixty-three patients with DCS and 115 patients with CTS only were included. At 3- to 4-month follow-up, absolute and change in UE, PI, and QuickDASH scores were not statistically different between patients with DCS and CTS. Rates of anchor question response and MCID achievement were comparable for patients with CTS only and DCS on each questionnaire. The MCID achievement ranged from 48.4% to 68.8% in the unmatched cohort and 48.4% to 60% in the matched group., Conclusions: At 3 to 4 months, patients with DCS experience similar patient-reported symptomatic and functional improvement, and achieve MCID of outcome measures at comparable rates to patients with CTS only. For patients with nerve compression at the carpal tunnel and cervical spine, CTR is a reasonable first step prior to proceeding with cervical spine decompression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background. Parents with a fetus diagnosed with a complex congenital heart defect (CHD) are at high risk of negative psychological outcomes. Purpose. To explore whether parents' psychological and decision-making outcomes differed based on their treatment decision and fetus/neonate survival status. Methods. We prospectively enrolled parents with a fetus diagnosed with a complex, life-threatening CHD from September 2018 to December 2020. We tested whether parents' psychological and decision-making outcomes 3 months posttreatment differed by treatment choice and survival status. Results. Our sample included 23 parents (average Age [years] : 27 ± 4, range = 21-37). Most were women ( n  = 18), non-Hispanic White ( n  = 20), and married ( n  = 21). Most parents chose surgery ( n  = 16), with 11 children surviving to the time of the survey; remaining parents ( n  = 7) chose comfort-directed care. Parents who chose comfort-directed care reported higher distress ( x ¯  = 1.51, s  = 0.75 v. x ¯  = 0.74, s  = 0.55; Mdifference = 0.77, 95% confidence interval [CI], 0.05-1.48) and perinatal grief ( x ¯  = 91.86, s  = 22.96 v. x ¯  = 63.38, s  = 20.15; Mdifference = 27.18, 95% CI, 6.20-48.16) than parents who chose surgery, regardless of survival status. Parents who chose comfort-directed care reported higher depression ( x ¯  = 1.64, s  = 0.95 v. x ¯  = 0.65, s  = 0.49; Mdifference = 0.99, 95% CI, 0.10-1.88) than parents whose child survived following surgery. Parents choosing comfort-directed care reported higher regret ( x ¯  = 26.43, s  = 8.02 v. x ¯  = 5.00, s  = 7.07; Mdifference = 21.43, 95% CI, 11.59-31.27) and decisional conflict ( x ¯  = 20.98, s  = 10.00 v. x ¯  = 3.44, s  = 4.74; Mdifference = 17.54, 95% CI; 7.75-27.34) than parents whose child had not survived following surgery. Parents whose child survived following surgery reported lower grief (Mdifference = -19.71; 95% CI, -39.41 to -0.01) than parents whose child had not. Conclusions. The results highlight the potential for interventions and care tailored to parents' treatment decisions and outcomes to support parental coping and well-being., Highlights: Question: Do the psychological and decision-making outcomes of parents differ based on their treatment decision and survival outcome following prenatal diagnosis with complex CHD? Findings: In this exploratory study, parents who decided to pursue comfort-directed care after a prenatal diagnosis reported higher levels of psychological distress and grief as well as higher decisional conflict and regret than parents who decided to pursue surgery. Meaning: The findings from this exploratory study highlight potential differences in parents' psychological and decision-making outcomes following a diagnosis of complex CHD for their fetus, which appear to relate to the treatment approach and the treatment outcome and may require tailoring of psychological and decision support., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: American Heart Association’s Strategically Focused Research Network – Children’s grant (17SFRN33660465) to Dr. Fagerlin. Dr. Thorpe was supported by grant No. 51300302 from the American Heart Association Children’s Strategically Focused Research Network fellowship awarded to Dr. Fagerlin. Dr. Delaney’s effort was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award T32HL007576 from the National Heart, Lung, and Blood Institute. The American Heart Association had no role in the design or conduct of the study., (© The Author(s) 2023.)

Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori ., Competing Interests: DECLARATION OF INTERESTS The authors declare the following competing interests: T. Borén and L. Hammarström are founders of Helicure AB and, own the IP-rights to the anti-BabA ABbA-IgG1 (US patent US8025880B2) and own the IP-rights to the gastric cancer vaccine and diagnostics described in the two manuscripts by Bugaytsova et al., 2023 (Patent Application SE 2350423–6). (2) P. Malfertheiner was the PI of the vaccine clinical study, EUDRACT #2007-003511-31, by Novartis Vaccines.

Purpose: This exploratory study examines differences in parents' quality of life by treatment decision and the child's survival outcome in the context of life-threatening congenital heart disease (CHD)., Design and Methods: Parents of a fetus or neonate diagnosed with severe CHD enrolled in the observational control group of a clinical trial (NCT04437069) and completed quality of life (i.e., contact with clinicians, social support, partner relationship, state of mind), mental and physical health survey measures. Comparisons were made between parents who chose comfort-directed care or surgery and between those whose child did and did not survive., Results: Parents who chose surgery and their child did not survive reported the most contact with their clinicians. Parents who chose comfort-directed care reported lower social support than parents who chose surgery and their child did not survive as well as poorer state of mind compared to parents who chose surgery., Conclusions: Some aspects of parents' quality of life differed based on their treatment decision. Parents who choose comfort-directed care are vulnerable to some negative outcomes., Practice Implications: Decision support tools and bereavement resources to assist parents with making and coping with a complex treatment decision is important for clinical care., Competing Interests: Declaration of Competing Interest The authors have indicated they have no financial relationships and no potential conflicts of interest relevant to this article to disclose., (Published by Elsevier Inc.)

Helicobacter pylori is the major risk factor for gastric cancer. H. pylori harboring the type IV secretion system (T4SS) and its effector CagA encoded on the cag pathogenicity Island ( cag PAI) increases the risk. H. pylori PMSS1 has a multi- cagA genotype, modulating cagA copy number dynamically from zero to four copies. To examine the effect of the immune response on cagA copy number change, we utilized a mouse model with different immune status. PMSS1 recovered from Rag1 -/- mice, lacking functional T or B cells, retained more cagA copies. PMSS1 recovered from Il10 -/- mice, showing intense inflammation, had fewer cagA copies compared to those recovered from wild-type mice. Moreover, cagA copy number of PMSS1 recovered from wild-type and Il10 -/- mice was positively correlated with the capacity to induce IL-8 secretion at four weeks of infection. Since recombination in cagY influences T4SS function, including CagA translocation and IL-8 induction, we constructed a multiple linear regression model to predict H. pylori -induced IL-8 expression based on cagA copy number and cagY recombination status; H. pylori induces more IL-8 secretion when the strain has more cagA copies and intact cagY . This study shows that H. pylori PMSS1 in mice with less intense immune response possess higher cagA copy number than those infected in mice with more intense immune response and thus the multi- cagA genotype, along with cagY recombination, functions as an immune-sensitive regulator of H. pylori virulence.

Purpose: To investigate the interaction between exercise modality (i.e., upper- and lower-body exercise) and sex in physiological responses and power output (PO) across the entire intensity spectrum (i.e., from low to maximal intensity). Methods: Ten male and 10 female cross-country (XC) skiers performed a stepwise incremental test to exhaustion consisting of 5 min stages with increasing workload employing upper-body poling (UP) and running (RUN) on two separate days. Mixed measures ANOVA were performed to investigate the interactions between exercise modalities (i.e., UP and RUN) and sex in physiological responses and PO across the entire exercise intensity spectrum. Results: The difference between UP and RUN (Δ UP-RUN ), was not different in the female compared with the male XC skiers for peak oxygen uptake (18 ± 6 vs. 18 ± 6 mL·kg -1 ·min -1 , p = 0.843) and peak PO (84 ± 18 vs. 91 ± 22 W, p = 0.207). At most given blood lactate and rating of perceived exertion values, Δ UP-RUN was larger in the male compared with the female skiers for oxygen uptake and PO, but these differences disappeared when the responses were expressed as % of the modality-specific peak. Conclusion: Modality-differences (i.e., Δ UP-RUN ) in peak physiological responses and PO did not differ between the female and male XC skiers. This indicates that increased focus on upper-body strength and endurance training in female skiers in recent years may have closed the gap between upper- and lower-body endurance capacity compared with male XC skiers. In addition, no sex-related considerations need to be made when using relative physiological responses for intensity regulation within a specific exercise modality., 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 © 2021 Hansen, Sandbakk, Ettema and Baumgart.)

Introduction: Parents who receive the diagnosis of a life-threatening, complex heart defect in their fetus or neonate face a difficult choice between pursuing termination (for fetal diagnoses), palliative care or complex surgical interventions. Shared decision making (SDM) is recommended in clinical contexts where there is clinical equipoise. SDM can be facilitated by decision aids. The International Patient Decision Aids Standards collaboration recommends the inclusion of values clarification methods (VCMs), yet little evidence exists concerning the incremental impact of VCMs on patient or surrogate decision making. This protocol describes a randomised clinical trial to evaluate the effect of a decision aid (with and without a VCM) on parental mental health and decision making within a clinical encounter., Methods and Analysis: Parents who have a fetus or neonate diagnosed with one of six complex congenital heart defects at a single tertiary centre will be recruited. Data collection for the prospective observational control group was conducted September 2018 to December 2020 (N=35) and data collection for two intervention groups is ongoing (began October 2020). At least 100 participants will be randomised 1:1 to two intervention groups (decision aid only vs decision aid with VCM). For the intervention groups, data will be collected at four time points: (1) at diagnosis, (2) postreceipt of decision aid, (3) postdecision and (4) 3 months postdecision. Data collection for the control group was the same, except they did not receive a survey at time 2. Linear mixed effects models will assess differences between study arms in distress (primary outcome), grief and decision quality (secondary outcomes) at 3-month post-treatment decision., Ethics and Dissemination: This study was approved by the University of Utah Institutional Review Board. Study findings have and will continue to be presented at national conferences and within scientific research journals., Trial Registration Number: NCT04437069 (Pre-results)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The field of tissue engineering has been continuously evolving since its inception over three decades ago with numerous new advancements in biomaterials and cell sources and widening applications to most tissues in the body. Despite the substantial promise and great opportunities for the advancement of current medical therapies and procedures, the field has yet to capture wide clinical translation due to some remaining challenges, including oxygen availability within constructs, both in vitro and in vivo. While this insufficiency of nutrients, specifically oxygen, is a limitation within the current frameworks of this field, the literature shows promise in new technological advances to efficiently provide adequate delivery of nutrients to cells. This review attempts to capture the most recent advances in the field of oxygen transport in hydrogel-based tissue engineering, including a comparison of current research as it pertains to the modeling, sensing, and optimization of oxygen within hydrogel constructs as well as new technological innovations to overcome traditional diffusion-based limitations. The application of these findings can further the advancement and development of better hydrogel-based tissue engineered constructs for future clinical translation and adoption., (Copyright © 2021 by ASME.)

Rationale and Objectives: Recent evidence suggests an inhomogeneous distribution of intramuscular rotator cuff fat infiltration (FI) in a small sample of individuals with rotator cuff tears, yet clinically just a few slices at the scapular Y-view are used to evaluate FI in patients with rotator cuff tears. The purpose of this study was to determine if assessment of FI using the scapular Y-view is representative of the entire muscle in patients with full-thickness rotator cuff tears, and whether this varies by tear size., Materials and Methods: Patients (N = 25) diagnosed with full-thickness rotator cuff tear and confirmed with magnetic resonance imaging (MRI) were included. Fat-water sequences were used to objectively quantify mean FI (%) in the entire 3D muscle and the mean from 3 slices at the Y-view. Mixed-model 2 × 2 ANOVAs were used to assess for differences between methods, and if results vary by tear-size., Results: There were no statistically significant differences between mean amount of FI of the entire 3D muscle and mean Y-view in the supraspinatus or infraspinatus muscles (p > 0.05). Additionally, this did not differ across tear size groups (p > 0.05)., Conclusion: Results of this study suggest FI assessed in the Y-view is not different (mean difference < 1.0%) from FI of the entire 3D muscle in patients with full-thickness rotator cuff tears. Therefore, the clinical utility of evaluating rotator cuff intramuscular fat infiltration with the Y-view is further supported in patients with full-thickness rotator cuff tears across tear sizes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Initial propranolol recommendations for infantile hemangioma published in 2013 were intended as provisional best practices to be updated as evidence-based data emerged., Methods: A retrospective multicenter study was performed to evaluate utility of prolonged monitoring after first propranolol dose and escalation(s). Inclusion criteria included diagnosis of hemangioma requiring propranolol of greater than or equal to 0.3 mg/kg per dose, younger than 2 years, and heart rate monitoring for greater than or equal to 1 hour. Data collected included demographics, dose, vital signs, and adverse events., Results: A total of 783 subjects met inclusion criteria; median age at initiation was 112 days. None of the 1148 episodes of prolonged monitoring warranted immediate intervention or drug discontinuation. No symptomatic bradycardia or hypotension occurred during monitoring. Mean heart rate change from baseline to 1 hour was -8.19/min (±15.54/min) and baseline to 2 hours was -9.24/min (±15.84/min). Three preterm subjects had dose adjustments because of prescriber concerns about asymptomatic vital sign changes. No significant difference existed in pretreatment heart rate or in heart rate change between individuals with later adverse events during treatment and those without., Conclusion: Prolonged monitoring for initiation and escalation of oral propranolol rarely changed management and did not predict future adverse events. Few serious adverse events occurred during therapy; none were cardiovascular., (Copyright © 2021. Published by Elsevier Inc.)

[Figure: see text].

Alpha-synuclein is a 15 kDa protein associated with neurodegenerative diseases such as Parkinson disease and multiple-system atrophy where pathological forms of alpha-synuclein aggregate and become neurotoxic. Here we describe the nonclinical program to support a first-in-human (FIH) single ascending dose (SAD) study for Lu AF82422, a human recombinant, anti-alpha-synuclein monoclonal antibody (mAb) in development for treatment of synucleinopathies. Alpha-synuclein is primarily expressed in brain, peripheral nerves and in blood cells. A tissue cross-reactivity assessment showed that Lu AF82422 binding was generally restricted to nervous tissues. Flow cytometry analysis did not show extracellular surface binding of Lu AF82422 to human platelets, erythrocytes, granulocytes, or lymphocytes, but to a low fraction of monocytes, without any functional consequences on activation or phagocytic capacity. A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to 600 mg/kg administered intravenously every 10 days. Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested. Target engagement was shown in plasma and cerebrospinal fluid. Taken together, the nonclinical data indicated no safety signal of concern and provided adequate safety margins between observed safe doses in animals and the planned dose levels in the FIH SAD study.

Background: Although the practice of checking a urinalysis prior to elective total knee arthroplasty (TKA) is relatively common, very little has been reported on the association between a preoperative urinary tract infection (UTI) and adverse events in primary TKA. The goal of this study is to investigate the risk of postoperative complication following TKA as it relates to preoperative UTI., Methods: Patients undergoing TKA were queried in the National Surgical Quality Improvement Program. Morbid events were classified as minor (transfusion, pneumonia, wound dehiscence, UTI, and renal insufficiency) and serious (wound infection, thromboembolic event, renal failure, myocardial infarction, prolonged ventilation, unplanned intubation, sepsis, and death). Risk factors for adverse events were analyzed in both univariate and multivariate fashion., Results: A total of 203,851 patients undergoing TKA met inclusion criteria and 507 patients had a UTI present at time of surgery (UTI PATOS). A propensity matched analysis controlling for age, gender, body mass index, operative year, and American Society of Anesthesiologists score identified 507 patients without a UTI PATOS to serve as the control group. Following adjustment for baseline characteristics, operative year, and American Society of Anesthesiologists score, UTI PATOS was associated with increased risk for serious adverse events (odds ratio [OR] 2.746, 95% confidence interval [CI] 1.546-4.878, P = .0006), occurrence of any morbid event (OR 1.894, 95% CI 1.299-2.761, P = .0009), and reoperation (OR 4, 95% CI 2.592-6.169, P < .0001)., Conclusion: This study suggests that a UTI present at time of TKA increases the risk of multiple postoperative complications and reoperation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Helicobacter pylori type IV secretion system (T4SS) encoded on the cag pathogenicity island ( cag PAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of cagY , though single nucleotide polymorphisms (SNPs) in cagY or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model. Here, we sought to identify physiologically relevant conditions under which T4SS function is maintained in the murine model. We found that loss of H. pylori T4SS function in mice was blunted by systemic Salmonella coinfection and completely eliminated by dietary iron restriction. Both have epidemiologic parallels in humans, since H. pylori strains from individuals in developing countries, where iron deficiency and systemic infections are common, are also more often cag PAI + than strains from developed countries. These results have implications for our fundamental understanding of the cag PAI and also provide experimental tools that permit the study of T4SS function in the murine model. IMPORTANCE The type IV secretion system (T4SS) is the major Helicobacter pylori virulence factor, though its function is lost during murine infection. Loss of function also occurs in gerbils and in humans, suggesting that it is biologically relevant, but the conditions under which T4SS regulation occurs are unknown. Here, we found that systemic coinfection with Salmonella and iron deprivation each promote retention of T4SS function. These results improve our understanding of the cag pathogenicity island ( cag PAI) and provide experimental tools that permit the study of T4SS function in the murine model., (Copyright © 2020 Skoog et al.)

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Chronic Helicobacter pylori colonization in animal models often leads to downregulation of the type IV secretion system (T4SS), typically by recombination in cagY , which is an essential T4SS gene. However, 17 other cag pathogenicity island ( cag PAI) genes, as well as some non- cag PAI genes, are also essential for T4SS function. To get a more complete picture of how H. pylori regulates the T4SS during animal colonization, we examined cagY in 534 mouse-passaged isolates that lost T4SS function, defined as a normalized interleukin-8 (IL-8) value of <0.3 relative to the input H. pylori strain PMSS1. In order to analyze the genetic changes in the strains with unchanged cagY , we sequenced the entire pathogenicity island of 60 such isolates using single-molecule, real-time (SMRT) sequencing technology (PacBio, Menlo Park, CA), and we compared the results to the PMSS1 wild type (WT). Of the 534 strains, 271 (51%) showed evidence of recombination in cagY , but we also found indels or nonsynonymous changes in 13 other essential cag PAI genes implicated in H. pylori T4SS function, most commonly cag5 , cag10 , and cagA While cagY recombination is the most common mechanism by which H. pylori downregulates T4SS function during murine infection, loss of function is also associated with changes in other essential cag PAI genes., (Copyright © 2020 American Society for Microbiology.)

Importance: Oral propranolol is widely considered to be first-line therapy for complicated infantile hemangioma, but its use in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome has been debated owing to concerns that the cardiovascular effects of the drug may increase the risk for arterial ischemic stroke., Objective: To assess the incidence of adverse events among patients with PHACE syndrome receiving oral propranolol for infantile hemangioma., Design, Setting, and Participants: This multicenter retrospective cohort study assessed the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed., Exposures: Patients received oral propranolol, 0.3 mg/kg/dose or more., Main Outcomes and Measures: The main outcome was the rate and severity of adverse events occurring throughout the course of treatment with oral propranolol, as documented in the medical records. Adverse events were graded from 1 to 5 using a scale derived from the Common Terminology Criteria for Adverse Events and were considered to be serious if they were grade 3 or higher., Results: A total of 76 patients (59 girls and 17 boys; median age at propranolol initiation, 56 days [range, 0-396 days]) met the inclusion criteria. There were no reports of serious adverse events (ie, stroke, transient ischemic attack, or cardiovascular events) during treatment with oral propranolol. A total of 46 nonserious adverse events were reported among 29 patients (38.2%); the most commonly reported nonserious adverse events were sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. In a comparison with 726 infants who received oral propranolol for hemangioma but did not meet criteria for PHACE syndrome, there was no significant difference in the rate of serious adverse events experienced during treatment (0 of 76 patients with PHACE syndrome and 3 of 726 patients without PHACE syndrome [0.4%])., Conclusions and Relevance: This study found that oral propranolol was used to treat infantile hemangioma in 76 patients with PHACE syndrome and that no serious adverse events were experienced. These data provide support for the safety of oral propranolol in this patient population.

Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations to skeletal muscle homeostasis. Although recent research has investigated the tissue-specific responses to ischemia, the role of the muscle stem cell in the regeneration of its niche components within skeletal muscle has been limited. To elucidate the regenerative mechanism of the muscle stem cell in response to ischemic insults, we explored cellular interactions between the vasculature, neural network, and muscle fiber within the muscle stem cell niche. Using a surgical murine hindlimb ischemia model, we first discovered a significant increase in subsynaptic nuclei and remodeling of the neuromuscular junction following ischemia-induced denervation. In addition, ischemic injury causes significant alterations to the myofiber through a muscle stem cell-mediated accumulation of total myonuclei and a concomitant decrease in myonuclear domain size, possibly to enhance the transcriptional and translation output and restore muscle mass. Results also revealed an accumulation of total mitochondrial content per myonucleus in ischemic myofibers to compensate for impaired mitochondrial function and high turnover rate. Taken together, the findings from this study suggest that the muscle stem cell plays a role in motor neuron reinnervation, myonuclear accretion, and mitochondrial biogenesis for skeletal muscle regeneration following ischemic injury.

The genera Methanospirillum and Methanosaeta contain species of anaerobic archaea that grow and divide within proteinaceous tubular sheaths that protect them from environmental stressors. The sheaths of Methanosaeta thermophila PT are composed of the 60.9 kDa major sheath protein MspA. In this study we show that sheaths purified from Methanospirillum hungatei JF-1 are regularly striated tubular structures with amyloid-like properties similar to those of M. thermophila PT. Depolymerizing the sheaths from M. hungatei JF-1 allowed us to identify a 40.6 kDa protein (WP&#95;011449234.1) that shares 23% sequence similarity to MspA from M. thermophila PT (ABK14853.1), indicating that they might be distant homologs. The genome of M. hungatei JF-1 encodes six homologs of the identified MspA protein. Several homologs also exist in the related strains Methanospirillum stamsii Pt1 (7 homologs, 28-66% sequence identity), M. lacunae Ki8-1 C (15 homologs, 29-60% sequence identity) and Methanolinea tarda NOBI-1 (2 homologs, 31% sequence identity). The MspA protein discovered here could accordingly represent a more widely found sheath protein than the MspA from M. thermophila PT, which currently has no homologs in the NCBI Reference Sequence database (RefSeq).

Despite the increasing trends, reports on long-term follow-up are limited on transitioning from parenteral to oral treprostinil therapy in patients with pulmonary arterial hypertension (PAH). We investigated both the effectiveness of parenteral to oral treprostinil transition and the characteristics associated with transition failure over a duration of two years. The study included 37 Group I functional class I and II patients with PAH on combination therapy. Patients were excluded if cardiac index ≤2.2 L/min/m 2 , right atrial pressure ≥11 mmHg, or 6-min walk distance ≤250 m. Patients were categorized as successful ( S Transition) or unsuccessful ( U Transition) transition based on clinical stability, or a parenteral comparator ( C Parenteral) if they remained on parenteral therapy (no transition). All patients underwent two right heart catheterizations, one at enrollment and a second post transition. Of 24 total transition patients, 46% were classified as U Transition. U Transition occurred on average 577 days post transition. Both U Transition and S Transition had similar hemodynamics at diagnosis and treprostinil dose before and after transition. Before transition, the pulmonary vascular resistance (PVR) was significantly higher in the U Transition (6.7 ± 2 WU) vs. S Transition group (3.5 ± 1.5 WU). At follow-up catheterization, the U Transition group demonstrated further increases in PVR, greater than the C Parenteral group, without recovery despite "rescue" therapy in the U Transition group. A pre-transition PVR of 4.16 WU discriminated the U Transition from the S Transition group. While a subset of PAH patients on combination therapy may be safely transitioned from parenteral to oral treprostinil, caution should be exercised in patients with elevated baseline PVR to avoid irreversible destabilization.

In vitro studies have implicated the small heat shock protein HSPB1 in a range of physiological functions. However, its in vivo relevance is unclear as the phenotype of unstressed HSPB1 -/- mice is unremarkable. To determine the impact of HSPB1 in injury, HSPB1 -/- and wild type (WT) mice were subjected to cecal ligation and puncture, a model of polymicrobial sepsis. Ten-day mortality was significantly higher in HSPB1 -/- mice following the onset of sepsis (65% vs. 35%). Ex vivo mechanical testing revealed that common carotid arteries from HSPB1 -/- mice were more compliant than those in WT mice over pressures of 50-120 mm Hg. Septic HSPB1 -/- mice also had increased peritoneal levels of IFN-γ and decreased systemic levels of IL-6 and KC. There were no differences in frequency of either splenic CD4 + or CD8 + T cells, nor were there differences in apoptosis in either cell type. However, splenic CD4 + T cells and CD8 + T cells from HSPB1 -/- mice produced significantly less TNF and IL-2 following ex vivo stimulation. Systemic and local bacterial burden was similar in HSPB1 -/- and WT mice. Thus while HSPB1 -/- mice are uncompromised under basal conditions, HSPB1 has a critical function in vivo in sepsis, potentially mediated through alterations in arterial compliance and the immune response.

Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island ( cag PAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4 + T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human α 5 β 1 integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to α 5 β 1 integrin. Using a cell-free microfluidic assay, we found that H. pylori binding to α 5 β 1 integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed when H. pylori is in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to α 5 β 1 integrin. Bacteria with variant cagY alleles that reduced T4SS function showed comparable reduction in binding to α 5 β 1 integrin, although CagY was still expressed on the bacterial surface. We speculate that cagY- dependent modulation of H. pylori T4SS function is mediated by alterations in binding to α 5 β 1 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection. IMPORTANCE Infection with H. pylori can cause peptic ulcers and is the most important risk factor for gastric cancer, the third most common cause of cancer death worldwide. The major H. pylori virulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We previously showed that recombination in CagY, an essential T4SS component, modulates the function of the T4SS. Here we found that these recombination events produce parallel changes in specific binding to α 5 β 1 integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. We propose that CagY-dependent binding to α 5 β 1 integrin acts like a molecular rheostat that alters T4SS function and modulates the host immune response to promote persistent infection., (Copyright © 2018 Skoog et al.)

Epidemiologic studies have reported an inverse relationship between childhood Helicobacter pylori infection and development of allergic asthma. Because lung epithelium plays an important role in allergic asthma pathogenesis, we hypothesized that H. pylori may directly influence airway epithelial cell innate immune function, particularly in early childhood. To test our hypothesis, we established an in vitro H. pylori infection model using primary tracheobronchial epithelial cell cultures derived from infant, juvenile and adult rhesus monkeys. Airway epithelial cell cultures were infected with wild-type or cag pathogenicity island mutant H. pylori strains, followed by evaluation of IL-8 and IL-6 protein synthesis. We found that H. pylori primarily increased IL-8 synthesis in a MOI and age-dependent fashion, with a greater than 4-fold induction in infant versus adult cultures. H. pylori-induced IL-8 synthesis in infant and juvenile cultures was significantly reduced by cag pathogenicity island mutants, indicating a requirement for the type IV secretion system. Although peptidoglycan recognition of nucleotide binding oligomerization domain-containing protein 1 (NOD1) and NF-kappaB have been implicated as key cytokine signaling molecules for H. pylori infection in gastric epithelium, NOD1 (ML130) or NF-kappaB (JSH-23) inhibitors minimally affected IL-8 synthesis in airway epithelial cell cultures following H. pylori infection. In contrast, inhibition of the p38 MAP kinase pathway (SB203580) resulted in almost complete suppression of H. pylori-induced IL-8 synthesis. Collectively, these results indicate that H. pylori can preferentially elicit IL-8 synthesis in a model of pediatric airway epithelium using the type IV secretion system via p38 MAP kinase.

Most Helicobacter pylori strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of babA is lost, either by phase variation or by gene conversion, in which the babB paralog recombines into the babA locus. The functional significance of loss of babA expression is unknown. Here we report that in rhesus monkeys, there is independent selective pressure for loss of babA and for overexpression of BabB, which confers a fitness advantage. Surprisingly, loss of babA by phase variation or gene conversion is not dependent on the capacity of BabA protein to bind Leb, which suggests that it may have other, unrecognized functions. These findings have implications for the role of outer membrane protein diversity in persistent H. pylori infection., (Copyright © 2017 American Society for Microbiology.)

Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Le b expression or the capacity of BabA to bind Le b . Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Le b .

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Many bacterial genomes are highly variable but nonetheless are typically published as a single assembled genome. Experiments tracking bacterial genome evolution have not looked at the variation present at a given point in time. Here, we analyzed the mouse-passaged Helicobacter pylori strain SS1 and its parent PMSS1 to assess intra- and intergenomic variability. Using high sequence coverage depth and experimental validation, we detected extensive genome plasticity within these H. pylori isolates, including movement of the transposable element IS 607 , large and small inversions, multiple single nucleotide polymorphisms, and variation in cagA copy number. The cagA gene was found as 1 to 4 tandem copies located off the cag island in both SS1 and PMSS1; this copy number variation correlated with protein expression. To gain insight into the changes that occurred during mouse adaptation, we also compared SS1 and PMSS1 and observed 46 differences that were distinct from the within-genome variation. The most substantial was an insertion in cagY , which encodes a protein required for a type IV secretion system function. We detected modifications in genes coding for two proteins known to affect mouse colonization, the HpaA neuraminyllactose-binding protein and the FutB α-1,3 lipopolysaccharide (LPS) fucosyltransferase, as well as genes predicted to modulate diverse properties. In sum, our work suggests that data from consensus genome assemblies from single colonies may be misleading by failing to represent the variability present. Furthermore, we show that high-depth genomic sequencing data of a population can be analyzed to gain insight into the normal variation within bacterial strains. IMPORTANCE Although it is well known that many bacterial genomes are highly variable, it is nonetheless traditional to refer to, analyze, and publish "the genome" of a bacterial strain. Variability is usually reduced ("only sequence from a single colony"), ignored ("just publish the consensus"), or placed in the "too-hard" basket ("analysis of raw read data is more robust"). Now that whole-genome sequences are regularly used to assess virulence and track outbreaks, a better understanding of the baseline genomic variation present within single strains is needed. Here, we describe the variability seen in typical working stocks and colonies of pathogen Helicobacter pylori model strains SS1 and PMSS1 as revealed by use of high-coverage mate pair next-generation sequencing (NGS) and confirmed by traditional laboratory techniques. This work demonstrates that reliance on a consensus assembly as "the genome" of a bacterial strain may be misleading., (Copyright © 2017 Draper et al.)

Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, N ɛ -(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth., Competing Interests: Disclosure/Duality of Interest: none

Helicobacter pylori commonly infects the epithelial layer of the human stomach and in some individuals causes peptic ulcers, gastric adenocarcinoma or gastric lymphoma. Helicobacter pylori is a genetically diverse species, and the most important bacterial virulence factor that increases the risk of developing disease, versus asymptomatic colonization, is the cytotoxin associated gene pathogenicity island (cagPAI). Socially housed rhesus macaques are often naturally infected with H. pylori similar to that which colonizes humans, but little is known about the cagPAI. Here we show that H. pylori strains isolated from naturally infected rhesus macaques have a cagPAI very similar to that found in human clinical isolates, and like human isolates, it encodes a functional type IV secretion system. These results provide further support for the relevance of rhesus macaques as a valid experimental model for H. pylori infection in humans., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Peptic ulcer disease and gastric cancer are caused most often by Helicobacter pylori strains that harbor the cag pathogenicity island, which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models. We examined the role of the immune response in cagY-dependent modulation of T4SS function., Methods: H pylori T4SS function was assessed by measuring CagA translocation and the capacity to induce interleukin (IL)8 in gastric epithelial cells. cagY recombination was determined by changes in polymerase chain reaction restriction fragment-length polymorphisms. T4SS function and cagY in H pylori from C57BL/6 mice were compared with strains recovered from Rag1-/- mice, T- and B-cell-deficient mice, mice with deletion of the interferon gamma receptor (IFNGR) or IL10, and Rag1-/- mice that received adoptive transfer of control or Ifng-/- CD4+ T cells. To assess relevance to human beings, T4SS function and cagY recombination were assessed in strains obtained sequentially from a patient after 7.4 years of infection., Results: H pylori infection of T-cell-deficient and Ifngr1-/- mice, and transfer of CD4+ T cells to Rag1-/- mice, showed that cagY-mediated loss of T4SS function requires a T-helper 1-mediated immune response. Loss of T4SS function and cagY recombination were more pronounced in Il10-/- mice, and in control mice infected with H pylori that expressed a more inflammatory form of cagY. Complementation analysis of H pylori strains isolated from a patient over time showed changes in T4SS function that were dependent on recombination in cagY., Conclusions: Analysis of H pylori strains from mice and from a chronically infected patient showed that CagY functions as an immune-sensitive regulator of T4SS function. We propose that this is a bacterial adaptation to maximize persistent infection and transmission to a new host under conditions of a robust inflammatory response., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Incidental findings in the rat eye are not uncommon in acute and long-term toxicological studies. These findings can be associated with a number of causes unrelated to treatment with the test article, including congenital malformation, trauma, infection, metabolic disease, genetic predisposition, and age-related changes. The occurrence of pigment deposition in the retina of Wistar Hannover (Crl:WI (Han)) rats in a 4-week toxicity study is reported in this communication. The microscopic examination of the eyes in the 4-week toxicity study revealed focal yellow-brown pigment deposits in the retina, mainly located in the ganglion cell layer. The retinal pigment deposits were randomly distributed in the control and treated groups and were considered incidental. The deposits were clearly positive for ferric iron in the Perls' stain but not for lipofuscin by the Schmorl's and Long Ziehl-Neelsen methods. The iron-containing pigment is likely to represent hemosiderin accumulation after retinal micro-hemorrhage or could be indicative of the normal intraretinal iron transport and turnover., (© 2015 by The Author(s).)

The evolution rate and genetic changes that occur during chronic infection with Helicobacter pylori have been analysed, but little is known about the genomic changes during the initial, acute bacterial infection phase. Here we analyse the rate and pattern of genome evolution in H. pylori from the genomes of two input strains isolated from human volunteers with asymptomatic infection, and the genomes of two output strains collected 20 and 44 days after re-infection. Similarly, we analyse genome evolution in bacteria from the genome sequences of input and output strains sequentially taken after experimental infection of a rhesus macaque. The estimated mutation rate reveals a mutation burst during the acute infection phase that is over 10 times faster than the mutation rate during chronic infection, and orders of magnitude faster than mutation rates in any other bacteria. The elevated frequency of mutations in outer membrane protein genes suggests that the mutation burst facilitates rapid host adaptation of the bacteria.

Purpose: The population-based incidence of severe osteonecrosis (ON) necessitating total joint arthroplasty (TJA) in patients with hematological cancer is unknown. This study assessed the incidence of ON requiring primary TJA in children and young adults treated for leukemia or lymphoma. Methods: Patients diagnosed with leukemia or lymphoma before 31 years of age were identified from the Finnish and Danish Cancer Registries. These data were combined with those from the National Hospital Discharge and the Finnish Arthroplasty Registers. Data on the orthopedic procedures performed and the appropriate diagnosis codes given before the age of 40 were also retrieved. Results: The estimated cumulative incidence of TJA was 4.5% at 20 years for patients treated for chronic myeloid leukemia, followed by 2.1% for patients treated for acute myeloid leukemia. It was considerably lower in patients with acute lymphoblastic leukemia (ALL; 0.4%). Multivariate analysis revealed that allogeneic stem cell transplantation (allo-SCT) increased the risk of TJA (hazard ratio [HR]=9.4; 95% CI: 5.3-16.9). The risk of TJA was higher in patients diagnosed with cancer at 10-19 and 20-30 years of age than in those diagnosed before the age of 10 (HR=24; 95% CI: 3.1-176 and HR=26; 95% CI: 3.6-192 respectively). Conclusion: The incidence of ON requiring TJA was highest among patients with myeloid leukemias and lowest in patients treated for ALL. Allo-SCT and age ≥10 years at diagnosis were the most important risk factors for ON requiring TJA in hematological malignancies.

Background: Nursing documentation is essential for facilitating the flow of information to guarantee continuity, quality and safety in care. High-quality nursing documentation is frequently lacking; the implementation of computerized decision support systems is expected to improve clinical practice and nursing documentation., Aim: The present study aimed at investigate the effects of a computerized decision support system and an educational program as intervention strategies for improved nursing documentation practice on pressure ulcers and malnutrition in nursing homes., Design, Setting and Participants: An intervention study with two intervention groups and one control group was used. Fifteen nursing homes in southern Norway were included. A convenience sample of electronic healthcare records from 46 units was included. Inclusion criteria were records with presence of pressure ulcers and/or malnutrition. The residents were assessed before and after an intervention of a computerized decision support system in the electronic healthcare records. Data were collected through a review of 150 records before (2007) and 141 records after the intervention (2009)., Methods: The nurses in intervention group 1 were offered educational sessions and were trained to use the computerized decision support system, which they used for eight months in 2008 and 2009. The nurses in intervention group 2 were offered the same educational program but did not use the computerized decision support system. The nurses in the control group were not subject to any intervention. The resident records were examined for the completeness and comprehensiveness of the documentation of pressure ulcers and malnutrition with three data collection forms and the data were analyzed with non-parametric statistics., Results: The implementation of the computerized decision support system and the educational program resulted in a more complete and comprehensive documentation of pressure ulcer- and malnutrition-related nursing assessments and nursing interventions., Conclusion: This study provides evidence that the computerized decision support system and an educational program as implementation strategies had a positive influence on nursing documentation practice., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pro-inflammatory cytokine, interleukin-8 (IL-8). CagY is an essential component of the H. pylori T4SS that has an unusual sequence structure, in which an extraordinary number of direct DNA repeats is predicted to cause rearrangements that invariably yield in-frame insertions or deletions. Here we demonstrate in murine and non-human primate models that immune-driven host selection of rearrangements in CagY is sufficient to cause gain or loss of function in the H. pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and "tunes" the host inflammatory response so as to maximize persistent infection.

Although nursing personnel have used personal digital assistants (PDAs) to support home health care services for the past ten years, little is known about their experiences. This study was conducted to examine experiences of nursing personnel using a specialized home health care computer software application called Gerica. In addition, this research analyzed how well this application aligned with the workflow of the nursing personnel in their daily care of patients. The evaluation methods included user observations and learnability testing. Nursing personnel from two different municipalities were observed while performing real tasks in natural settings. This study shows that the nursing personnel were satisfied with the PDA user interface and the Gerica software; however, they identified areas for improvement. For example, the nursing personnel were concerned about trusting the reliability of the PDA in order to eliminate the need for handwritten documentation. Solutions to meet these shortcomings for nursing managers and vendors are discussed.

The Helicobacter pyloricag pathogenicity island (cag PAI) encodes a type IV secretion system that is more commonly found in strains isolated from patients with gastroduodenal disease than from those with asymptomatic gastritis. Genome-wide organization of the transcriptional units in H. pylori strain 26695 was recently established using RNA sequence analysis (Sharma et al., 2010). Here we used quantitative reverse-transcription polymerase chain reaction of open reading frames and intergenic regions to identify putative cag PAI operons in H. pylori; these operons were analyzed further by transcript profiling after deletion of selected promoter regions. Additionally, we used a promoter-trap system to identify functional cag PAI promoters. The results demonstrated that expression of genes on the H. pyloricag PAI varies by nearly five orders of magnitude and that the organization of cag PAI genes into transcriptional units is conserved among several H. pylori strains, including, 26695, J99, G27, and J166. We found evidence for 20 transcripts within the cag PAI, many of which likely overlap. Our data suggests that there are at least 11 operons: cag1-4, cag3-4, cag10-9, cag8-7, cag6-5, cag11-12, cag16-17, cag19-18, cag21-20, cag23-22, and cag25-24, as well as five monocistronic genes (cag4, cag13, cag14, cag15, and cag26). Additionally, the location of four of our functionally identified promoters suggests they are directing expression of, in one case, a truncated version of cag26 and in the other three, transcripts that are antisense to cag7, cag17, and cag23. We verified expression of two of these antisense transcripts, those antisense to cag17 and cag23, by reverse-transcription polymerase chain reaction. Taken together, our results suggest that the cag PAI transcriptional profile is generally conserved among H. pylori strains, 26695, J99, G27, and J166, and is likely complex.

Cold tolerance and metabolic responses to freezing of three slug species common in Scandinavia (Arion ater, Arion rufus and Arion lusitanicus) are reported. Autumn collected slugs were cold acclimated in the laboratory and subjected to freezing conditions simulating likely winter temperatures in their habitat. Slugs spontaneously froze at about -4 °C when cooled under dry conditions, but freezing of body fluids was readily induced at -1 °C when in contact with external ice crystals. All three species survived freezing for 2 days at -1 °C, and some A. rufus and A. lusitanicus also survived freezing at -2 °C. (1)H NMR spectroscopy revealed that freezing of body fluids resulted in accumulation of lactate, succinate and glucose. Accumulation of lactate and succinate indicates that ATP production occurred via fermentative pathways, which is likely a result of oxygen depletion in frozen tissues. Glucose increased from about 6 to 22 μg/mg dry tissue upon freezing in A. rufus, but less so in A. ater and A. lusitanicus. Glucose may thus act as a cryoprotectant in these slugs, although the concentrations are not as high as reported for other freeze tolerant invertebrates., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The best-studied Helicobacter pylori virulence factor associated with development of peptic ulcer disease or gastric cancer (GC) rather than asymptomatic nonatrophic gastritis (NAG) is the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host epithelial cells. Here we used real-time reverse transcription-PCR (RT-PCR) to measure the in vivo expression of genes on the cagPAI and of other virulence genes in patients with NAG, duodenal ulcer (DU), or GC. In vivo expression of H. pylori virulence genes was greater overall in gastric biopsy specimens of patients with GC than in those of patients with NAG or DU. However, since in vitro expression of cagA was not greater in H. pylori strains from patients with GC than in those from patients with NAG or DU, increased expression in GC in vivo is likely a result of environmental conditions in the gastric mucosa, though it may in turn cause more severe pathology. Increased expression of virulence genes in GC may represent a stress response to elevated pH or other environmental conditions in the stomach of patients with GC, which may be less hospitable to H. pylori colonization than the acidic environment in patients with NAG or DU.