Search

Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders. ispartof: MOLECULAR THERAPY vol:30 issue:4 pages:1661-1674 ispartof: location:United States status: published

Medication errors are amongst the most frequently occurring healthcare-related incidents and have the potential to lead to life-threatening harm to patients. An incident reporting system is a traditional approach to the improvement of patient safety and entails the retrieval of information from incident reports. This not only provides a better understanding of causes and contributing factors but also enables the collection of data on the severity of incidents, system deficiencies and the role of human factors in safety incidents. Medication error reporting systems are often developed as a part of larger incident reporting systems that deal with other types of incidents. Although a rise in the prevalence of medication errors has led to an increased demand for medication error reporting, little is known about the characteristics and limitations of medication error reporting systems. The authors broach the subject of medication error reporting systems and propose a more robust and standardized approach.

AimTo describe the nature and causes of reported patient safety incidents relating to care in the community for children dependent on long-term ventilation with the further aim of improving safety.MethodsWe undertook an analysis of patient safety incident data relating to long-term ventilation in the community using incident reports from England and Wales’ National Reporting and Learning System occurring between January 2013 and December 2017. Manual screening by two authors identified 220 incidents which met the inclusion criteria. The free text for each report was descriptively analysed to identify the problems in the delivery of care, the contributory factors and the patient outcome.ResultsCommon problems in the delivery of care included issues with faulty equipment and the availability of equipment, and concerns around staff competency. There was a clearly stated harm to the child in 89 incidents (40%). Contributory factors included staff shortages, out of hours care, and issues with packaging and instructions for equipment.ConclusionsThis study identifies a range of problems relating to long-term ventilation in the community, some of which raise serious safety concerns. The provision of services to support children on long-term ventilation and their families needs to improve. Priorities include training of staff, maintenance and availability of equipment, support for families and coordination of care.

Background Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis. Methods To delineate the role of TGF-β signaling in lymphatic vessels, TβRIIfl/fl mice were crossed with Prox1-CreERT2 mice to generate TβRIIfl/fl; Prox1-CreERT2 mice. The TβRII gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRIIiΔLEC mice was selectively deleted using tamoxifen. The effects of TβRII gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated. Results Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRIIiΔLEC mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis. Conclusion These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.

OBJECTIVES The aims of the study were to describe medication administration incidents reported in England and Wales between 2007 and 2016, to identify which factors (reporting year, type of incident, patients' age) are most strongly related to reported severity of medication administration incidents, and to assess the extent to which relevant information was underreported or indeterminate. METHODS Medication administration incidents reported to the National Reporting & Learning System between January 1, 2007, and December 31, 2016 were obtained. Characteristics of the data were described using frequencies, and relationships between variables were explored using cross-tabulation. RESULTS A total of 517,384 incident reports were analyzed. Of these, 97.1% (n = 502,379) occurred in acute/general hospitals, mostly on wards (69.1%, n = 357,463), with medicine the most common specialty area (44.5%, n = 230,205). Medication errors were most commonly omitted doses (25.8%, n = 133,397). The majority did not cause patient harm (83.5%, n = 432,097). When only incidents causing severe harm or death (n = 1,116) were analyzed, the most common type of error was omitted doses (24.1%). Most incidents causing severe harm or death occurred in patients aged 56 years or older. For the 10-year period, the percentage of incidents with “no harm” increased (74.1% in 2007 to 86.3% in 2016). For some variables, data were often missing or indeterminate, which has implications for data analysis. CONCLUSIONS Medication administration incidents that do not cause harm are increasingly reported, whereas incidents reported as severe harm and death have declined. Data quality needs to be improved. Underreporting and indeterminate data, inaccuracies in reporting, and coding jeopardize the overall usefulness of these data.

Supplemental digital content is available in the text., Objective The aim of the study was to analyze content of incident reports during patient transitions in the context of care of older people, cardiology, orthopedics, and stroke. Methods A structured search strategy identified incident reports involving patient transitions (March 2014–August 2014, January 2015–June 2015) within 2 National Health Service Trusts (in upper and lower quartiles of incident reports/100 admissions) in care of older people, cardiology, orthopedics, and stroke. Content analysis identified the following: incident classifications; active failures; latent conditions; patient/relative involvement; and evidence of individual or organizational learning. Reported harm was interpreted with reference to National Reporting and Learning System criteria. Results A total 278 incident reports were analyzed. Fourteen incident classifications were identified, with pressure ulcers the modal category (n = 101,36%), followed by falls (n = 32, 12%), medication (n = 31, 11%), and documentation (n = 29, 10%). Half (n = 139, 50%) of incident reports related to interunit/department/team transfers. Latent conditions were explicit in 33 (12%) reports; most frequently, these related to inadequate resources/staff and concomitant time pressures (n = 13). Patient/family involvement was explicit in 61 (22%) reports. Patient well-being was explicit in 24 (9%) reports. Individual and organizational learning was evident in 3% and 7% of reports, respectively. Reported harm was significantly lower than coder-interpreted harm (P < 0.0001). Conclusions Incident report quality was suboptimal for individual and organizational learning. Underreporting level of harm suggests reporter bias, which requires reducing as much as practicable. System-level interventions are warranted to encourage use of staff reflective skills, emphasizing joint ownership of incidents. Co-producing incident reports with other clinicians involved in the transition and patients/relatives could optimize organizational learning.

To explore aged care nurses' awareness and experience of unwanted sexual behaviour (USB) in residential aged care services (RACS).An anonymous online questionnaire was administered to an opportunistic sample of RACS nurses enrolled to complete an e-learning course in Australia. From the 167 participants who expressed interest to enrol, 129 were eligible and 53 returned completed consent forms.46/53 responded of which most were females (41/45, 91.1%). Few respondents reported resident-resident USB (35%) or staff-resident USB (22%) happened once a year. Most respondents had not been informed by a resident of USB (75%) or had personally reported USB within their internal reporting system (77%). Respondents were also unaware if their facility had lodged an incident report to the regulator or law enforcement authorities within the past 12 months (34/46, 73.9%). Finally, most considered there to be no barriers to reporting USB (35/46, 77.8%).Respondents' awareness and estimates of USB directed at residents were much lower than known national prevalence rates. This lack of awareness could be a substantive barrier to recognition and optimal management of this form of abuse.

Purpose This study aims to evaluate the relationships between leadership style and reported incidents, reporting practices and patient safety initiatives in Kuwaiti hospitals. Design/methodology/approach This cross-sectional and retrospective quantitative multi-centre study was conducted in a secondary care setting. The multifactor leadership questionnaire and the patient safety questionnaire were distributed in six general hospitals to a sample of physicians, nurses and pharmacists. Incident reports were reviewed in each hospital to assess reporting practices. Findings The hospital with the most safety incident reports scored the highest on good reporting practices, whereas the hospital with the lowest score of poor reporting practices had reported fewer incidents. Reporting was better if an error reached the patient but caused no harm. Overall, reporting practices and implementation of patient safety initiatives in the hospitals were suboptimal. Nevertheless, a transformational leadership style had a positive effect on patient safety and reporting practices. Practical implications This study represents a baseline for researchers to assess the relationship between leadership style and patient safety. Moreover, it highlights significant considerations to be addressed when planning patient safety improvement programmes. More investment is needed to understand how to raise transformational leaders who are more effective on patient safety. Further studies that include primary and tertiary health-care settings and the private sector are required. Originality/value To the best of the authors’ knowledge, this study is the first in Kuwait to report on the relationship between transformational leadership and safety practices.

Background: Minocycline is a tetracycline antibiotic that is widely used to treat infections and is a first-line oral antibiotic in the treatment of moderate to severe inflammatory acne. Although it has high efficacy, several adverse reactions, including life-threatening ones, have been reported in association with its use. Objective: To identify all the potential adverse reactions due to minocycline and analyze them in terms of the number of cases reported so far, salient features, severity and clinical outcome. Methods: Comprehensive PubMed search of English and non-English literature for case reports of adverse reactions to minocycline was conducted. Results: A total of 550 cases were identified from over 200 publications. The major reported adverse events caused by minocycline are drug reaction with eosinophilia and systemic symptoms syndrome, autoimmune syndromes like hepatitis, lupus and vasculitis, acute eosinophilic pneumonia, pseudotumor cerebri, hyperpigmentation, serum sickness-like reaction, Sweet’s syndrome and drug fever. Several other reactions involving multiple organ systems have also been reported. These show an overlap of clinical features and may be associated with multiple events causing considerable morbidity. Eight of these cases resulted in the death of the patients. Conclusion: In view of the evident potential of minocycline to cause long-lasting and severe adverse effects, significant morbidity and even mortality, it should be prescribed with caution in the first-line treatment for moderate to severe acne.

Background Unsafe conditions (UCs) are circumstances that increase the probability of a patient safety event occurring. Each UC identified presents an opportunity to prevent a near miss or adverse patient event through proactive mitigation. The aim of this study was to describe the frequency, characteristics, contributing factors, and potential for harm of reported UCs. Methods This is a retrospective descriptive analysis of UC incident reports voluntarily entered into an electronic medical event reporting system at a single tertiary care women and children's hospital. Reports were reviewed and categorized using a previously published classification scheme and a modified Healthcare Failure Mode and Effects Analysis (HFMEA). Reporter role, hospital location, and time to incident resolution were also described. Results Between July 1, 2016, and June 30, 2019, 348 UCs were entered, representing 3.4% of all reports. Predominant categories of UCs were equipment (43.7%), medication (20.7%), and environmental safety (14.4%). A contributing factor was identified for >99.4% of all UCs, with 77.6% having more than one. Nurses (70.1%) submitted the highest numbers of UCs. The majority of UCs were of mild severity (79.9%) but had the potential to recur frequently (73.3%). Conclusion UCs represented a small proportion of all reported events across the hospital. Equipment and medication issues were important causes of UCs, and most UCs had one or more contributing factors. Though most UCs were of mild severity, they had a predicted potential to recur frequently, representing significant opportunities for improvement.

Adverse event reporting systems are important tools for identifying areas of risk and opportunities for education and improvement. Our goal was to examine the nature of perioperative incident reports related to care coordination that were filed by staff at an academic tertiary care center. In this retrospective data review, perioperative safety reports between 2015 and 2020 were analyzed. Information examined included the type of staff who initiated the report, location of the incident, type of incident and the severity level of event, including patient harm. Out of the 7827 reports evaluated, 61.2% of reports were filed by nurses, and 5.6% by physicians. We investigated one particular category called "coordination of care" and found the specific event most commonly reported was insufficient handoff (15.0%-26.9%), with severity level reported primarily being no to minor harm reaching the patient. However, communication failures were judged to be one of leading causes of inadvertent harm. It is imperative for hospital incident reporting systems to collect data on issues related to communication failures and to design interventions with the help of frontline staff to provide high quality, safe care to patients and to remain compliant with regulatory requirements and hospital policies.

Aims: To investigate medication dose calculation errors and other numeracy mishaps in hospitals and examine mechanisms and enablers which lead to such errors. Design: A retrospective study using descriptive statistics and thematic analysis of the nature and enablers of reported incidents. Methods: Medication dose calculation errors and other numeracy mishaps were identified from medication-related incidents reported to the Norwegian Incident Reporting System in 2016 and 2017. The main outcome measures were medications and medication classes involved, severity of harm, outcome, and error enablers. Results: In total, we identified 100 numeracy errors, of which most involved intravenous administration route (n = 70). Analgesics were the most commonly reported drug class and morphine was the most common individual medication. Overall, 78 incidents described patient harm. Frequent mechanisms were 10- or 100-fold errors, mixing up units, and incorrect strength/rate entered into infusion pumps. The most frequent error enablers were: double check omitted or deviated (n = 40), lack of safety barriers to intercept prescribing errors (n = 25), and emergency/stress (n = 21). Conclusion: Numeracy errors due to lack of or improper safeguards occurred during all medication management stages. Dose miscalculation after dilution of intravenous solutions, infusion pump programming, and double-checking were identified as unsafe practices. We discuss measures to prevent future calculation and numeracy errors. Impact: Our analysis of medication dose calculation errors and other numeracy mishaps demonstrates the need for improving safety steps and increase standardization for medication management procedures. We discuss organizational, technological, and educational measures to prevent harm from numeracy errors. This research was supported by the doctoral research funding for the first author of this paper by the University of Oslo.

The rationale of this study was to examine the effectiveness of 6-month high-impact step aerobics (SA) or moderate-intensity resistance training exercise (RT) on bone mineral density (BMD) and bone bending strength in sedentary women. Results show that SA enhanced BMD in the heel, lower leg, and lumbar spine 2. To determine the effectiveness of 6 months of high-impact step aerobics (SA) or moderate-intensity resistance training (RT) on areal bone mineral density (aBMD) and tibial bending strength in sedentary premenopausal women. Sixty-nine women (20–35 years old) who were randomly assigned to RT (n = 22), SA (n = 26), or non-treatment control (CON, n = 21) groups completed the study. SA had a minimum of 50 high-impact landings each training session. RT had a periodized lower body resistance training program incorporating eight exercises (65–85% of 1 repetition maximum: 1-RM). Both RT and SA met 3 times weekly. aBMD was assessed using dual X-ray absorptiometry (DXA). Tibial bending strength was assessed using mechanical response tissue analysis (MRTA). Measurements at 6 months were compared to baseline using ANCOVA, adjusted for baseline measures and covariates with α = 0.05. Calcaneus aBMD (0.0176 vs -0.0019 or -0.0009 g/cm2 relative to RT, p

This paper explores the characteristics of the expansion of the Wari empire. It reviews the evidence across the Andean region where the data for the relationship of the imperial elite with local ruling hierarchies is demonstrably varied. Assorted strategies pragmatically deployed by Wari served to exert its control and reflect a client state approach to its growth. The political basis for its relationship with the local elites is considered based on polygamous marriage structures and marriage alliances arranged between the imperial ruling circle and the regional chiefs, thereby creating kin structures with inequal duties and obligations of the regional polities with the imperial centre. This model is derived from Late Horizon ethnohistorical sources and tested in the available archaeological data.

Background e-Cigarette or vaping-induced lung injury (EVALI) causes a spectrum of CT lung injury patterns. Relative frequencies and associations with vaping behavior are unknown. Research Question What are the frequencies of imaging findings and CT patterns in EVALI and what is the relationship to vaping behavior? Study Design and Methods CT scans of 160 subjects with EVALI from 15 institutions were retrospectively reviewed. CT findings and patterns were defined and agreed on via consensus. The parenchymal organizing pneumonia (OP) pattern was defined as regional or diffuse ground-glass opacity (GGO) ± consolidation without centrilobular nodules (CNs). An airway-centered OP pattern was defined as diffuse CNs with little or no GGO, whereas a mixed OP pattern was a combination of the two. Other patterns included diffuse alveolar damage (DAD), acute eosinophilic-like pneumonia, and pulmonary hemorrhage. Cases were classified as atypical if they did not fit into a pattern. Imaging findings, pattern frequencies, and injury severity were correlated with substance vaped (marijuana derives [tetrahydrocannabinol] [THC] only, nicotine derivates only, and both), vaping frequency, regional geography, and state recreational THC legality. One-way analysis of variance, χ2 test, and multivariable analyses were used for statistical analysis. Results A total of 160 patients (79.4% men) with a mean age of 28.2 years (range, 15-68 years) with EVALI underwent CT scan. Seventy-seven (48.1%), 15 (9.4%), and 68 (42.5%) patients admitted to vaping THC, nicotine, or both, respectively. Common findings included diffuse or lower lobe GGO with subpleural (78.1%), lobular (59.4%), or peribronchovascular (PBV) sparing (40%). Septal thickening (50.6%), lymphadenopathy (63.1%), and CNs (36.3%) were common. PBV sparing was associated with younger age (P = .02). Of 160 subjects, 156 (97.5%) had one of six defined patterns. Parenchymal, airway-centered, and mixed OP patterns were seen in 89 (55.6%), 14 (8.8%), and 32 (20%) patients, respectively. Acute eosinophilic-like pneumonia (six of 160, 3.8%), DAD (nine of 160, 5.6%), pulmonary hemorrhage (six of 160, 3.8%), and atypical (four of 160, 2.5%) patterns were less common. Increased vaping frequency was associated with more severe injury (P = .008). Multivariable analysis showed a negative association between vaping for > 6 months and DAD pattern (P = .03). Two subjects (1.25%) with DAD pattern died. There was no relation between pattern and injury severity, geographic location, and state legality of recreational use of THC. Interpretation EVALI typically causes an OP pattern but exists on a spectrum of acute lung injury. Vaping habits do not correlate with CT patterns except for negative correlation between vaping > 6 months and DAD pattern. PBV sparing, not previously described in acute lung injury, is a common finding.

The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells from peripheral tissues to lymph nodes (LNs) and the systemic circulation. Their recently uncovered functions extend beyond drainage and include direct modulation of adaptive immunity and paracrine regulation of organ growth. The developmental mechanisms controlling lymphatic vessel growth have been described with increasing precision. It is less clear how the essential functional features of lymphatic vessels are established and maintained. We discuss the mechanisms that maintain lymphatic vessel integrity in adult tissues and control vessel repair and regeneration. This knowledge is crucial for understanding the pathological vessel changes that contribute to disease, and provides an opportunity for therapy development.

Low-dose metronomic chemotherapy (LDMC) inhibits tumor angiogenesis and growth by targeting tumor-associated endothelial cells, but the molecular mechanism has not been fully elucidated. Here, we examined the functional role of regulated in development and DNA damage responses 1 (REDD1), an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in LDMC-mediated endothelial cell dysfunction. Low-dose doxorubicin (DOX) treatment induced REDD1 expression in cultured vascular and lymphatic endothelial cells and subsequently repressed the mRNA expression of mTORC1-dependent translation of vascular endothelial growth factor receptor (Vegfr)-2/3, resulting in the inhibition of VEGF-mediated angiogenesis and lymphangiogenesis. These regulatory effects of DOX-induced REDD1 expression were additionally confirmed by loss- and gain-of-function studies. Furthermore, LDMC with DOX significantly suppressed tumor angiogenesis, lymphangiogenesis, vascular permeability, growth, and metastasis in B16 melanoma-bearing wild-type but not Redd1-deficient mice. Altogether, our findings indicate that REDD1 is a crucial determinant of LDMC-mediated functional dysregulation of tumor vascular and lymphatic endothelial cells by translational repression of Vegfr-2/3 transcripts, supporting the potential therapeutic properties of REDD1 in highly progressive or metastatic tumors., Cancer: Stress protein implicated in effects of low-dose metronomic chemotherapy Sustained low-dose metronomic chemotherapy impairs the function of tumor-associated blood vessels and lymphatic tissues due to the action of a stress response protein called REDD1. A research team from South Korea led by Young-Myeong Kim of Kangwon National University School of Medicine in Chuncheon showed that low doses of doxorubicin, a widely used anti-cancer drug, induces the expression of REDD1. This in turn inhibits the activity of vascular endothelial growth factor receptors-2/-3 that are needed for the formation of blood and lymphatic vessels, both of which can promote tumor growth. Cancer-bearing mice that lacked a working version of REDD1 did not respond to continuous low-dose treatment with doxorubicin, demonstrating the critical nature of this protein in mediating the drug regimen’s effects. The authors propose that pharmacologically enhancing REDD1 activity could help combat highly aggressive or metastatic tumors.

Brain lymphatic endothelial cells (BLECs) constitute a group of loosely connected endothelial cells that reside within the meningeal layer of the zebrafish brain without forming a vascular tubular system. BLECs have been shown to readily endocytose extracellular cargo molecules from the brain parenchyma, however, their functional relevance in relation to microglia remains enigmatic. We here compare their functional uptake efficiency for several macromolecules and bacterial components with microglia in a qualitative and quantitative manner in 5-day-old zebrafish embryos. We find BLECs to be significantly more effective in the uptake of proteins, polysaccharides and virus particles as compared to microglia, while larger particles like bacteria are only ingested by microglia but not by BLECs, implying a clear distribution of tasks between the two cell types in the brain area. In addition, we compare BLECs to the recently discovered scavenger endothelial cells (SECs) of the cardinal vein and find them to accept an identical set of substrate molecules. Our data identifies BLECs as the first brain-associated SEC population in vertebrates, and demonstrates that BLECs cooperate with microglia to remove particle waste from the brain.

The lymphatic vasculature has been widely described and explored for its key functions in fluid homeostasis and in the organization and modulation of the immune response. Besides transporting immune cells, lymphatic vessels play relevant roles in tumor growth and tumor cell dissemination. Cancer cells that have invaded into afferent lymphatics are propagated to tumor-draining lymph nodes (LNs), which represent an important hub for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites. In recent years many studies have reported new mechanisms by which the lymphatic vasculature affects cancer progression, ranging from induction of lymphangiogenesis to metastatic niche preconditioning or immune modulation. In this review, we provide an up-to-date description of lymphatic organization and function in peripheral tissues and in LNs and the changes induced to this system by tumor growth and progression. We will specifically focus on the reported interactions that occur between tumor cells and lymphatic endothelial cells (LECs), as well as on interactions between immune cells and LECs, both in the tumor microenvironment and in tumor-draining LNs. Moreover, the most recent prognostic and therapeutic implications of lymphatics in cancer will be reported and discussed in light of the new immune-modulatory roles that have been ascribed to LECs., Medicinal Research Reviews, 42 (1), ISSN:0198-6325, ISSN:1098-1128

The spindle cell variant of ameloblastic carcinoma is an extremely rare, malignant, odontogenic tumor. In the updated 2017 World Health Organization classification of odontogenic and maxillofacial bone tumors, ameloblastic carcinoma is classified as an odontogenic carcinoma, with the spindle cell variant following an aggressive course. We report a rare autopsy case of spindle cell variant of ameloblastic carcinoma, for which the patient underwent repeated surgical operations because of its persistent recurrence. The patient died 13 months after the final operation. Autopsy examination showed that the wobbliness (staggering) that the patient reported was caused by a metastatic lesion on the skull base. There was autopsy evidence of metastases in the lungs and pleura as well.

Abstract. Voluntary incident reports by commercial pilots provide essential data for airline efforts in learning from incidents (LFI). Because LFI is frequently limited by pilots not reporting incidents voluntarily, we interviewed seven commercial aviation safety experts in a focus group to derive factors influencing the voluntary reporting behavior of pilots’ self-inflicted incidents. As a result, we derived 36 factors and integrated them into a motivational framework by van den Broeck et al. (2019) . Pilots pursue various goals when voluntarily reporting incidents, such as enabling safety-related change or organizational learning. This behavior is influenced by personal antecedents, such as shame, and contextual antecedents, such as feedback. Our work expands the understanding of motivational aspects of voluntary incident reporting and discusses practical interrelations.

Lipoprotein(a) forms a subfraction of the lipid profile and is characterized by the addition of apolipprotein(a) (apo(a)) to apoB100 derived particles. Its levels are mostly genetically determined inversely related to the number of protein domain (kringle) repeats in apo(a). In epidemiological studies, it shows consistent association with cardiovascular disease (CVD) and most recently with extent of aortic stenosis. Issues with standardizing the measurement of Lp(a) are being resolved and consensus statements favor its measurement in patients at high risk of, or with family histories of CVD events. Major lipid-lowering therapies such as statin, fibrates, and ezetimibe have little effect on Lp(a) levels. Therapies such as niacin or cholesterol ester transfer protein (CETP) inhibitors lower Lp(a) as well as reducing other lipid-related risk factors but have failed to clearly reduce CVD events. Proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors reduce cholesterol and Lp(a) as well as reducing CVD events. New antisense therapies specifically targeting apo(a) and hence Lp(a) have greater and more specific effects and will help clarify the extent to which intervention in Lp(a) levels will reduce CVD events.

The diagnosis of ameloblastic carcinoma is based on a combination of cytological features of malignancy and histological pattern of an ameloblastoma. We report a very rare case of ameloblastic carcinoma arising from a pre-existing ameloblastoma of the maxilla with challenging diagnostic aspects due to atypical histology. A 74-year-old female with a swelling in the right maxillary region was referred to our hospital in March 2015. Intraoral examination revealed a 45 × 30 mm sized swelling extending from the right upper first premolar to the maxillary tuberosity. Radiographic examination revealed a tumor mass with heterogeneous enhancement from the right maxillary alveolar area to the maxillary sinus, invading the pterygopalatine fossa under the cranial base, with bone destruction of the alveolar bone, floor of the maxillary sinus, and pterygoid plate. Incisional biopsy results revealed round or short spindle cells with clear cytoplasm, with low mitotic activity, cellular atypism, and Ki-67 labeling index. A low grade malignant epithelial tumor was suspected. Tumor resection with hemimaxillectomy and partial mandibulectomy was performed in April 2015. The surgical specimen was composed of diffusely distributed spindle cells and clusters of round cells with clear cytoplasm, similar to the biopsy findings. Although cellular atypism was scant, Ki-67 labeling index was high in most sections. Ameloblastoma was detected in part of the tumor and a definitive diagnosis of ameloblastic carcinoma was made. The patient died of metastatic colon cancer 3 years and 10 months post-operatively; there was no evidence of recurrence and metastasis of ameloblastic carcinoma in that duration.

Background: Risk management is a preventive effort for a company, especially those engaged in the service sector, which is very prone to errors and complaints. For this reason, it is necessary to map the risks that occur in accordance with the work unit in it which is expected to minimize the number of accidents or errors in both patients, visitors and employees in the hospital. In the 2019 patient safety incident report data at the Surabaya A. Yani Islamic Hospital, it was found that there were incidents which included near miss 93%, not injured 4%, unexpected events 3% and Sentinel 0%. The purpose of this study was to identify and identify the application of occupational safety and health risk management at the A. Yani Islamic Hospital in Surabaya. Methods: This thesis is a qualitative research with a case study method with the aim of fully describing the implementation of K3 risk management at Surabaya A. Yani Hospital based on observation, survey and documentation data on 37 units and hospital workplaces by identifying risks. , analyze and find risk control measures. Results: The results showed that the implementation of K3 risk management in the Islamic Hospital of Surabaya A. Yani based on the results of risk identification obtained as many as 25 risks in the graha building and the old building which were further analyzed by finding 15 moderate risks and 10 high risks. can be done is by repairing damaged infrastructure and improving the existing security system at the A. Yani Islamic Hospital in Surabaya. Conclusion: The conclusion in this study is the implementation of K3 risk management at the Islamic Hospital of Surabaya A. Yani based on the process of risk identification and risk analysis, there are 25 potential risks, of which there are 15 moderate risks and 10 high risks that can potentially cause accidents to employees, visitors and patients. In this case, control efforts are made to minimize the number of incidents and accidents.

Climate change and sea-level rise are increasingly leading to higher and prolonged high tides, which, in combination with the growing intensity of rainfall and storm surges, and insufficient drainage infrastructure, result in frequent recurrent flooding in coastal cities. There is a pressing need to understand the occurrence of roadway flooding incidents in order to enact appropriate mitigation measures. Agency data for roadway flooding events are scarce and resource-intensive to collect. Crowdsourced data can provide a low-cost alternative for mapping roadway flood incidents in real time; however, the reliability is questionable. This research demonstrates a framework for asserting trustworthiness on crowdsourced flood incident data in a case study of Norfolk, Virginia. Publicly available (but spatially limited) flood incident data from the city in combination with different environmental and topographical factors are used to create a logistic regression model to predict the probability of roadway flooding at any location on the roadway network. The prediction accuracy of the model was found to be 90.5%. When applying this model to crowdsourced Waze flood incident data, 71.7% of the reports were predicted to be trustworthy. This study demonstrates the potential for using Waze incident report data for roadway flooding detection, providing a framework for cities to identify trustworthy reports in real time to enable rapid situation assessment and mitigation to reduce incident impact.

BACKGROUND Ameloblastoma is a rare, benign odontogenic neoplasm which is locally aggressive and mostly present with a painless swelling. The enigma about the diagnosis of proliferative ameloblastoma and ameloblastic carcinoma is still a debate because the diagnostic criteria is not standardized or quantified which has a direct correlation on its biological behaviour and prognosis. Despite numerous studies, correlation between the histological patterns of ameloblastoma and tumour behaviour has not been consistently established. The present study was done to compare the expression levels of Ki-67 between conventional ameloblastoma, proliferative ameloblastoma and ameloblastic carcinoma and to assess the usefulness of these markers for diagnostic differentiation. METHODS A retrospective study of total of 18 cases of ameloblastoma were retrieved from the archives of Department of Oral and Maxillofacial Pathology, Saveetha Dental College from 2012 till 2019, which included conventional ameloblastoma, proliferative ameloblastoma and ameloblastic carcinoma. Immunohistochemical (IHC) analysis was done using the marker Ki-67 and labelling index were determined for the same. RESULTS The results of the current study showed that the cellular proliferative activity assessed using Ki-67 in follicular ameloblastoma was (55 %), 4 cases of plexiform ameloblastoma (22 %), 17 % of proliferative ameloblastoma and 6 % of ameloblastic carcinoma showed negative expression. CONCLUSIONS Immunophenotyping using the marker Ki-67 may be a useful tool for histological typing of ameloblastoma. KEY WORDS Ameloblastoma, Ki-67, IHC, Immunophenotyping

We herein report the identification, structural optimization, and structure-activity relationship of thieno[2,3-d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.

Background Adverse events (AE) are responsible for annual deaths that exceed deaths due to motor vehicle accidents, breast cancer, and AIDS. Many AE are considered preventable. Thus, AE needs to be detected and analyzed. Incident reporting systems (IRS) are crucial in identifying AE. Nevertheless, the incident report (IR) process is flawed with underreporting, especially from the physicians' side. This limits its efficiency in detecting AE. Therefore, we aimed to assess the practice and identify the barriers associated with incident reporting among internal medicine physicians in a large tertiary hospital through a survey. Methods A cross-sectional descriptive study. We distributed an online survey to physicians working in the Internal Medicine Department of Qatar's largest tertiary academic institute. The questionnaire was validated and piloted ahead of the start of the trial. The response rate was 53%. Results A total of 115 physicians completed the survey; 59% acknowledged the availability of an institutional IRS. However, only 29% knew how to submit an online IR, and 20% have ever submitted an IR. The survey revealed that participants were less likely to submit an IR when they or a colleague is involved in the incident; 46% and 63%, respectively. The main barriers of reporting incidents were unawareness about the IRS (36%) and the perception that IR will not bring a system change (13%); moreover, there exists the fear of retaliation (13%). When asked about solutions, 57% recommended training and awareness, and 22% recommended sharing learnings and actions from previous IR. Conclusions IRS is underutilized by internal medicine physicians. The main barrier at the time of the survey is the lack of training and awareness. Promoting awareness and sharing previous learning and actions may improve the utilization of the IRS.

Introduction Patient safety is important in all healthcare settings. Few studies have examined the state of patient safety in rehabilitation and none have examined patient safety in the setting of acquired brain injury (ABI) rehabilitation. Objectives To determine the incidence, most common types, and severities of adverse events among inpatients undergoing ABI rehabilitation. Design Retrospective case series descriptive study. Setting The inpatient ABI rehabilitation program at an academic, tertiary rehabilitation hospital in Canada. Participants 108 consecutive inpatients with acquired brain injuries. Interventions Not applicable. Main outcome measure(s) Patient charts and incident reports from the hospital's voluntary reporting system were reviewed by three board-certified physiatrists to determine the incidence, type, severity and preventability of adverse events. Adverse events were identified and classified for severity and type using the WHO International Classification for Patient Safety. Preventability was rated on a 6-point Likert scale. Results During the study period, the incidence of adverse events was 17.42 ± 3.86 per 1000 patient days. Adverse events affected 52.8% of patients. Most adverse events identified were mild in severity (98.51%) and the rest were of moderate severity. The two most common types of adverse events were 1) patient incidents (56.72%) such as falls, pressure ulcers and skin tears, and 2) patient behaviors such as missing patient, assault, or sexual behaviors (16.42%). Of the 80 adverse events identified in the study, 44.78% were preventable. The hospital's voluntary reporting system did not capture 57.9% of the adverse events identified. Conclusions Future efforts to improve patient safety in ABI rehab should focus on reducing falls, skin injuries and behaviors, and removing barriers to voluntary incident reporting. Detecting adverse events through chart reviews provide a more complete understanding of patient safety risks in ABI rehab than relying on incident reporting alone. This article is protected by copyright. All rights reserved.

Lipaza lizosomalna katalizuje reakcję hydrolizy estrów cholesterolu i triglicerydów, której produktem są wolne kwasy tłuszczowe i wolny cholesterol, będące kluczowymi mediatorami wewnątrzkomórkowej homeostazy lipidowej. Deficyt LAL jest chorobą monogenową, spowodowaną obecnością patogennych wariantów molekularnych w genie LIPA, o dziedziczeniu autosomalnym recesywnym. W deficycie LAL dochodzi do kumulacji estrów cholesterolu i trójglicerydów w lizosomach, co wtórnie powoduje zwiększoną syntezę endogennego cholesterolu, apolipoproteiny B oraz lipoprotein o niskiej gęstości (VLDL). Diagnostyka deficytu kwaśnej lipazy jest łatwa, dzięki dostępnej obecnie metodzie badania aktywności enzymu w suchej kropli krwi. Analiza molekularna jest niezbędna celem weryfikacji diagnozy klinicznej i biochemicznej oraz analizy korelacji genotyp-fenotyp. Sebelipaza alfa jest rekombinowaną ludzką lizosomalną lipazą przeznaczoną do stosowania w enzymatycznej terapii zastępczej u pacjentów z niedoborem LAL.

Lymphatic vasculature is an integral part of the cardiovascular system where it maintains interstitial fluid balance. Additionally, lymphatic vasculature regulates lipid assimilation and inflammatory response. Lymphatic vasculature is composed of lymphatic capillaries, collecting lymphatic vessels and valves that function in synergy to absorb and transport fluid against gravitational and pressure gradients. Defects in lymphatic vessels or valves leads to fluid accumulation in tissues (lymphedema), chylous ascites, chylothorax, metabolic disorders and inflammation. The past three decades of research has identified numerous molecules that are necessary for the stepwise development of lymphatic vasculature. However, approaches to treat lymphatic disorders are still limited to massages and compression bandages. Hence, better understanding of the mechanisms that regulate lymphatic vascular development and function is urgently needed to develop efficient therapies. Recent research has linked mechanical signals such as shear stress and matrix stiffness with biochemical pathways that regulate lymphatic vessel growth, patterning and maturation and valve formation. The goal of this review article is to highlight these innovative developments and speculate on unanswered questions.

Background Prokineticin family correlates with important roles in several biological processes, including homeostasis. We discovered novel functions of prokineticin1 (PROK1) in lymphangiogenesis and lymphnode metastasis in colorectal cancer. Materials and methods We examined changes in the number of lymphatic endothelial cells after PROK1 stimulation. PROK1 protein was stimulated with subcutaneously implanted in mice. Also a high-PROK1-expressing colorectal cancer cell line and anti-PROK1 antibody(Ab) were subcutaneously implanted in mice, and then examine lymphangiogenesis. PROK1 expression and the number of lymph vessels were examined in the primary lesion of 391 patients whose colorectal tumors had been resected. Results When PROK1 was used as a stimulus, the number of lymphatic cells increased compared to unstimulated cells. And the number of lymph vessels in the skin of mice increased compared to mice implanted without PROK1. The number of lymph vessels in the primary tumor tissue increased when PROK1 was highly expressed compared to cases with non-detectable PROK1 expression. When PROK1 was expressed in human colorectal tumors, the rate of lymphnode metastasis was significantly higher than that in cases with non-detectable PROK1 expression. Conclusions PROK1 is a lymphangiogenic factor involved in the formation of new lymph vessels and lymphnode metastasis in human colorectal cancer.

Knowing the frequency, extent or severity of injuries that occur to students and staff within veterinary teaching hospitals (VTHs) is necessary for proactive management of their safety. This study surveyed contemporaneously-captured incident reports likely to cause or causing injury to students and staff of veterinary teaching hospitals in Europe, the United States of America (USA), Canada, Australia, and New Zealand, recorded in 2017. Four different severities of incident were evaluated within four different cohorts of people, precipitated by five categories for cause. Within each cause-category, further subdivision was based on the nature of the incident. All colleges of veterinary medicine accredited by the American Veterinary Medical Association (AVMA) Council on Education (COE) or the Australasian Veterinary Boards Council were surveyed. Responses were received from (7/7, 100%) schools in Australia and New Zealand, 12/30 (40%) the United States of America, 1/4 (25%) Canada, 1/1 (100%) Mexico, and 1/3 (33%) United Kingdom, and no responses were received from the AVMA–COE accredited schools in the European Union. The mean incidence of incidents caused by horses was (0.4/1,000 cases), followed by food animals (0.1/1,000 cases), other animals (0.1/1,000 cases), and small animals (0.074/1,000 cases). Within veterinary teaching hospitals at many institutions, veterinary students and veterinarians are particularly at risk of injuries caused by hand-held instruments, such as scalpels and needles. Non-veterinary staff are more at risk than students or veterinarians from injuries caused by small animals. Recording and reporting of incidents is not uniform and may be lacking in detail. Some institutions’ systems for record management preclude easy evaluation, and therefore may be insufficient for proactive management of health and safety as required by accreditation bodies.

The lymphatic system is essential in maintaining tissue fluid homeostasis as well as antigen and immune cell transport to lymph nodes. Moreover, lymphatic vasculature plays an important role in various pathological processes, such as cancer. Fundamental to this research field are representative in vitro models. Here we present a microfluidic lymphatic vessel model to study lymphangiogenesis and its interaction with colon cancer organoids using a newly developed lymphatic endothelial cell (LEC) line. We generated immortalized human LECs by lentiviral transduction of human telomerase (hTERT) and BMI-1 expression cassettes into primary LECs. Immortalized LECs showed an increased growth potential, reduced senescence, and elongated lifespan with maintenance of typical LEC morphology and marker expression for over 12 months while remaining nontransformed. Immortalized LECs were introduced in a microfluidic chip, comprising a free-standing extracellular matrix, where they formed a perfusable vessel-like structure against the extracellular matrix. A gradient of lymphangiogenic factors over the extracellular matrix gel induced the formation of luminated sprouts. Adding mouse colon cancer organoids adjacent to the lymphatic vessel resulted in a stable long-lived coculture model in which cancer cell-induced lymphangiogenesis and cancer cell motility can be investigated. Thus, the development of a stable immortalized lymphatic endothelial cell line in a membrane-free, perfused microfluidic chip yields a highly standardized lymphangiogenesis and lymphatic vessel-tumor cell coculture assay.

Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell–autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.

Long-range electrostatic interactions beyond biomolecular interaction interfaces have not been extensively studied due to the limitation in engineering electric double layers in physiological fluids. Here we find that long-range electrostatic interactions play an essential role in kinetic modulation of DNA hybridizations. Protein and gold nanoparticles with different charges are encapsulated in tetrahedral frameworks to exert diverse electrostatic effects on site-specifically tethered single DNA strands. Using this strategy, we have successfully modulated the hybridization kinetics in both bulk solution and single molecule level. Experimental and theoretical studies reveal that long-range Coulomb interactions are the key factor for hybridization rates. This work validates the important role of long-range electrostatic forces in nucleic acid-biomacromolecule complexes, which may encourage new strategies of gene regulation, antisense therapy, and nucleic acid detection.

Aviation is a complicated transportation system, and safety is of paramount importance because aircraft failure often involves casualties. Prevention is clearly the best strategy for aviation transportation safety. Learning from past incident data to prevent potential accidents from happening has proved to be a successful approach. To prevent potential safety hazards and make effective prevention plans, aviation safety experts identify primary and contributing factors from incident reports. However, safety experts’ review processes have become prohibitively expensive nowadays. The number of incident reports is increasing rapidly due to the acceleration of advances in information technologies and the growth of the commercial and private aviation transportation industries. Consequently, advanced text mining algorithms should be applied to help aviation safety experts facilitate the process of incident data extraction. This paper focuses on constructing deep-learning-based models to identify causal factors from incident reports. First, we prepare the data sets used for training, validation, and testing with approximately 200,000 qualified incident reports from the Aviation Safety Reporting System (ASRS). Then, we take an open-source natural language model, which is well trained with a large corpus of Wikipedia texts, as the baseline and fine-tune it with the texts in incident reports to make it more suited to our specific research task. Finally, we build and train an attention-based long short-term memory (LSTM) model to identify primary and contributing factors in each incident report. The solution we propose has multilabel capability and is automated and customizable, and it is more accurate and adaptable than traditional machine learning methods in extant research. This novel application of deep learning algorithms to the incident reporting system can efficiently improve aviation safety.

Lymph node (LN)–resident lymphatic endothelial cells (LEC) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T-cell inhibitory molecules, including PD-L1 (CD274). Tumor-associated LECs also upregulate PD-L1, but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. In this study, we generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in consistent expansion of tumor-specific CD8+ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased efficacy of adoptive T-cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 acted primarily by inducing apoptosis in tumor-specific CD8+ central memory T cells. Overall, these findings demonstrate that LECs restrain tumor-specific immunity via PD-L1, which may explain why some patients with cancer without PD-L1 expression in the tumor microenvironment still respond to PD-L1/PD-1–targeted immunotherapy. Significance: A new lymphatic-specific PD-L1 knockout mouse model reveals that lymphatic endothelial PD-L1 expression reduces tumor immunity, inducing apoptosis in tumor-specific CD8+ central memory cells in tumor-draining lymph nodes.

All asylum seekers who arrive in Australia by boat are subject to mandatory immigration detention. Since 2001, Australia has housed asylum seekers in offshore immigration detention facilities in Na...

We used incident reports to improve treatment planning in radiation oncology to advance patient safety. First, a cluster of related reports enabled discovery of communication issues for setup instructions stemming from a text box with a limited character size. A redesigned process used structured data and image formats to reduce the proportion of inaccurate setup instructions. An upward trend in inaccurate setup instructions identified that some rotating staff were unaware of which equipment to use. Implementing default disease site setups ensured that when a patient was to commence treatment for a specific disease site, it was known which immobilizing equipment should be utilized as the basis before customization. Second, inappropriate plans were identified for proactive improvement. The process resilience was enhanced with targeted validations of generated treatment plans. The automated checks incorporated data automatically pulled from the electronic health record. Useful methods included clustering reports into categories to proactively see patterns in reported issues, collaborating with clinical experts from different perspectives, surveillance monitoring to identify new risks as conditions change, improving communications across disciplines through health information technology, and increasing system resilience with targeted validation of known gaps and variation in plans. The implementation of ILS frameworks, careful review of events and categorization, which culminate with interventions targeting the most frequent or highest severity incidents reported, increased patient safety within our department.

In order to detect single nucleotide mutations and suppress gene expression, we synthesized an artificial nucleic acid, an inchworm-type PNA-PEG conjugate (i-PPc), that possessed a chemical structure in which 8 residues of peptide nucleic acid (PNA) were linked to both ends of a polyethylene glycol molecule. I-PPc_T7FM, which forms a complementary strand with the T7 promoter region of luciferase-expressing mRNA, failed to suppress the amount of luciferase produced via gene expression. However, 10 μM of i-PPc_ATGFM, targeting the start codon of luciferase (Luc+), suppressed approximately 85% of Luc+ production compared to that of the control in the cell-free protein synthesis system. Moreover, i-PPc_ATGMM (i-PPc_ATGFM with a single base mutation) only suppressed the amount of luciferase produced by approximately 15%, and such suppression of luciferase expression has not been achieved with block-type PPc or PNA oligos. The thermodynamic parameters suggested that the difference in stability of each PNA segment of the i-PPc contributed to single nucleotide recognition. These results indicate that the i-PPc could be used in antisense therapy to target single nucleotide polymorphisms (SNP).

Background: Lymphatic endothelium plays significant roles in lymph transport and maintaining a barrier between the lymph and interstitial compartments. Lymphatic endothelial dysfunction is suspected to be a key factor in the pathogenesis of lymphatic diseases such as lymphedema. Sigma receptor-1 (σ1) was recently identified to promote endothelial-dependent production of nitric oxide and relaxation of collecting lymphatic vessels. In this study, we investigated the potential role of σ1 in lymphatic endothelial barrier function. Methods and Results: Cultured adult human dermal lymphatic endothelial cells (HDLEC) were grown into confluent monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function. Glycolytic rate of HDLEC was determined with the Agilent Seahorse system. The σ1-selective agonist PRE-084 was used to test the impact of σ1 on HDLEC monolayer barrier function and endothelial bioenergetics, whereas the contribution of basal σ1 activity was assessed with small interfering RNA (siRNA)-mediated knockdown of σ1 expression. The ability of σ1 activation to counteract interleukin (IL)-1β-induced barrier dysfunction was also tested. The results show that PRE-084 increases HDLEC TER in a concentration-dependent manner, whereas reducing σ1 expression with siRNA decreases HDLEC TER. PRE-084 also enhances glycolytic rate parameters in HDLEC. Moreover, PRE-084 treatment partially counteracts IL-1β-induced HDLEC monolayer barrier dysfunction. Conclusions: Collectively, the results suggest that σ1 contributes to basal lymphatic endothelial barrier function, potentially through its ability to enhance glycolytic energy production. Our work also highlights the therapeutic potential of σ1 agonists for preventing lymphatic barrier dysfunction caused by inflammatory mediators.

ObjectivesAdvance care planning (ACP) is essential for patient-centred care in the last phase of life. There is little evidence available on the safety of ACP. This study characterises and explores patient safety incidents arising from ACP processes in the last phase of life.MethodsThe National Reporting and Learning System collates patient safety incident reports across England and Wales. We performed a keyword search and manual review to identify relevant reports, April 2005–December 2015. Mixed-methods, combining structured data coding, exploratory and thematic analyses were undertaken to describe incidents, underlying causes and outcomes, and identify areas for improvement.ResultsWe identified 70 reports in which ACP caused a patient safety incident across three error categories: (1) ACP not completed despite being appropriate (23%, n=16). (2) ACP completed but not accessible or miscommunicated between professionals (40%, n=28). (3) ACP completed and accessible but not followed (37%, n=26). Themes included staff lacking the knowledge, confidence, competence or belief in trustworthiness of prior documentation to create or enact ACP. Adverse outcomes included cardiopulmonary resuscitation attempts contrary to ACP, other inappropriate treatment and/or transfer or admission.ConclusionThis national analysis identifies priority concerns and questions whether it is possible to develop strong system interventions to ensure safety and quality in ACP without significant improvement in human-dependent issues in social programmes such as ACP. Human-dependent issues (ie, varying patient, carer and professional understanding, and confidence in enacting prior ACP when required) should be explored in local contexts alongside systems development for ACP documentation.

H3K56 acetylation (H3K56Ac) was first identified in yeast and has recently been reported to play important roles in maintaining genomic stability, chromatin assembly, DNA replication, cell cycle progression and DNA repair. Although H3.1K56Ac has been relatively well studied, the function of H3.3K56Ac remains mostly unknown in mammals. In this study, we used H3.3K56Q and H3.3K56R mutants to study the possible function of H3.3K56 acetylation. The K-to-Q substitution mimics a constitutively acetylated lysine, while the K-to-R replacement mimics a constitutively unmodified lysine. We report that cell lines harbouring mutation of H3.3K56R exhibit increased cell death and dramatic morphology changes. Using a Tet-Off inducible system, we found an increased population of polyploid/aneuploid cells and decreased cell viability in H3.3K56R mutant cells. Consistent with these results, the H3.3K56R mutant had compromised H3.3 incorporation into several pericentric and centric heterochromatin regions we tested. Moreover, mass spectrometry analysis coupled with label-free quantification revealed that biological processes regulated by the H3.3-associating proteins, whose interaction with H3.3 was markedly increased by H3.3K56Q mutation but decreased by H3.3K56R mutation, include sister chromatid cohesion, mitotic nuclear division, and mitotic nuclear envelope disassembly. These results suggest that H3.3K56 acetylation is crucial for chromosome segregation and cell division in mammals.

Even though clinical features in autoimmune haemolytic anaemia vary according to the type of AIHA, anaemic syndrome stays common for most of the cases. A positive Coombs test or direct anti-globulin test developed in 1945 by Coombs, Mourant and Race, is the most deciding factor in AIHA diagnosis. Since the immunologic mechanisms causing erythrocyte destruction vary between AIHAs, treatment is also different. Empirical approach with glucocorticoids is the main treatment of AIHA overall, but less effective in CAD. However, the current medical literature is still with gaps concerning the management, presentation and diagnosis of the different types of AIHA altogether.

Objective This study aims to improve the classification of the fall incident severity level by considering data imbalance issues and structured features through machine learning. Materials and Methods We present an incident report classification (IRC) framework to classify the in-hospital fall incident severity level by addressing the imbalanced class problem and incorporating structured attributes. After text preprocessing, bag-of-words features, structured text features, and structured clinical features were extracted from the reports. Next, resampling techniques were incorporated into the training process. Machine learning algorithms were used to build classification models. IRC systems were trained, validated, and tested using a repeated and randomly stratified shuffle-split cross-validation method. Finally, we evaluated the system performance using the F1-measure, precision, and recall over 15 stratified test sets. Results The experimental results demonstrated that the classification system setting considering both data imbalance issues and structured features outperformed the other system settings (with a mean macro-averaged F1-measure of 0.733). Considering the structured features and resampling techniques, this classification system setting significantly improved the mean F1-measure for the rare class by 30.88% (P value Conclusions Structured features provide essential information for categorizing the fall incident severity level. Resampling methods help rebalance the class distribution of the original incident report data, which improves the performance of machine learning models. The IRC framework presented in this study effectively automates the identification of fall incident reports by the severity level.

BACKGROUND: Incident reports are the primary data source for monitoring patient safety in the hospital. Monitoring of these reports determines the success of managing safety-related incidents as an effort to improve patient care. Hospital staff plays an essential role in the management of incident reports. Each staff member has a role in managing incident reports. AIM: This article aimed to explore the role of hospital staff in the incident reporting process. METHODS: This qualitative research used an exploratory approach. The research informants were three doctors, 21 nurses, one pharmacist, and two computer administrators. Data were collected using interviews and observations of incident reporting implementation. The research data were analyzed with the qualitative analysis software Atlas.ti. RESULTS: Report management is not done solely for the formality of achieving the target. Implementation of regulations for report management is also done by all hospital staff to prioritize discipline, honesty, and responsibility according to their roles. Staff is expected to report adverse or dangerous events (incidents) that could affect patient safety. The reporting coordinator is responsible for the report’s completeness. Heads of participation room are expected to validate reports. The patient safety team is in charge of analyzing and providing feedback. Supportive attitudes from the board of directors are needed to create a reporting culture. There are several barriers to reporting management, including management support factors, facilities, and an effective feedback system. CONCLUSION: Leaders need to develop staff who focus on discipline, honesty, and responsibility in providing services to patients by prioritizing patient safety. All staff is involved in managing incident reports by playing an active role in following their duties.